Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@H:28](Cl)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24]>CN(C=O)C>[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@@H:28]([S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 2 °C
Reaction time: 2.5 h
Yield: 87.2 %

Procedure:
A solution of 76 g (0.68 mol) potassium-tert.-butylate in 1.5 l DMF was cooled (−3° C.) and treated slowly (1.5 h) with 202 g (0.73 mol) triphenylmethanethiol in 0.8 l DMF (at max 1° C.). After 2.5 h at 0° C., a solution of 161 g (0.61 mol) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 0.35 l DMF was added. The reaction was stirred over night at 2° C., evaporated, dissolved in 1.5 l EtOAc, poured into 2.7 l aqueous saturated NH4Cl solution and extracted with EtOAc (2×). The organic phase was washed with aqueous saturated NaHCO3, dried over Na2SO4 and evaporated. Colum chromatographyon silica gel with hexane/EtOAc (95:5 to 7:3) gave 268 g (87%) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 504 (MH30 ).
Reaction SMILES: [OH2:1].[OH-].[Na+].[OH:4][C:5]1[CH2:9][CH2:8][C:7](=O)[C:6]=1[CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(O)(=O)C>[OH:1][CH:8]1[CH2:9][C:5](=[O:4])[C:6]([CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7]1
Reactant: O
Reactant: COC(=O)CCC#CCCC1=C(O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CCC#CCCC1=CC(O)CC1=O
Temperature: 100 °C
Reaction time: 25 h
Yield: 76 %

Procedure:
To the compound [VIII-1] (28.3 g, 0.12 mole) are added water (1200 g) and acetic acid (1.5 g), and the pH value thereof is adjusted to pH 4.4 with 5% aqueous sodium hydroxide solution. The mixture is heated with stirring at 100° C. for 25 hours. After completion of the reaction, the reaction mixture is cooled, extracted twice with methyl isobutyl ketone (300 ml) and separated. Methyl isobutyl ketone is distilled off from the organic layer to give a mixture (21.5 g, yield; 76%) of 4-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone (racemic 4-hydroxycyclopentenone) and 3-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone [IX-1] (ratio thereof=6:4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]2.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]3)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]c(C(=O)OC(C)(C)C)cc3c2)cc1
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
A solution of tert-butyl 5-amino-1H-indole-2-carboxylate (220 mg, 0.94 mmol), 4-acetylbenzoic acid (155 mg, 0.94 mmol) and TBTU (303 mg, 0.94 mmol) in DMF (6 mL) at 4° C. was treated with diisopropylethylamine (329 uL, 1.89 mmol) and stirred 40 min at 0˜5° C. The solvent was removed under vacuo. The crude product was chromatographed on silica gel eluted with 1% MeOH in CH2Cl2 to give 2 (350 mg, 98%). 1HNMR DMSO-d6) δ11.66 (bs, 1H), 10.34 (s, 1H), 8.09 (d, 1H, J=8.8 Hz), 8.07 (s, 4H), 7.55 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 7.03 (s, 1H), 2.63 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.[Li]CCCC>CCOCC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:14]1[CH2:13][CH:12]2[CH:11]=[CH:10]1
Reactant: C1=CCC=C1
Reactant: Fc1cccc(F)c1I
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1cccc2c1C1C=CC2C1

Procedure:
A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated Chromatography on Silica gel provided product as an oil (1.5 g, 45%) (TLC hexanes Rf 0.55). 1H NMR (400 MHz, CDCl3) δ 7 08 (ddd, J=7 0, 1.0, 0.8 Hz, 1H), 6.96 (ddd, J=8.5, 8.3, 7 0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5, 8.3, 0.8 Hz, 1H), 4.25 (br s, 1 H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2, 1.7, 1.7 Hz, 1H), 2.30 (ddd, J=7 2, 1.7, 1.5 Hz, 1H). GCMS m/e 160 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2Cl)=[O:4].[NH3:26]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2[NH2:26])=[O:4]
Reactant: COC(=O)c1cc2c(Cl)cnnc2c(F)c1Nc1ccc(Br)cc1F
Reactant: N
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
A solution of 7-(4-bromo-2-fluorophenylamino)-4-chloro-8-fluoro-cinnoline-6-carboxylic acid methyl ester (1.00 equiv.) in saturated NH3 in MeOH is refluxed for 16 hours. Additional saturated NH3 in MeOH is added as the reaction progresses if necessary. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21]
Reactant: CCOC(=O)C1=C(O)c2ccc(OC)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 86 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of ethyl 4-hydroxy-7-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.52 g, 1.6 mmol), tert-butyl 2-aminoacetate hydrochloride (0.39 g, 2.3 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.61 g, 4.7 mmol). The mixture was warmed to 86° C. and stirred for 4 hours, M+1=418. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.35 g of the title compound as a pale yellow solid. MS (m/z)=418 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:13]([O-:15])=[O:14])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(NCCCBr)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
A mixture of 14.4 parts of N-(3-bromopropyl)-2-nitrobenzamide, 12.2 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 16 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 3 hours using a water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 18 parts (87%) of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]-propyl]-2-nitrobenzamide as an oily residue.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:12])C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[N:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH:11]([NH2:10])[CH3:12]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cnccn2c1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CC(N)c1nc2cnccn2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of [1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethyl]-carbamic acid benzyl ester (450 mg, 1.2 mmol) and dimethylsulfide (1.0 mL) in TFA (4.0 mL) was stirred at rt overnight. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethylamine: LC-MS (ESI) m/z 240.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[N:6]=[CH:5]2.[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:20][C@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ncc3cc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)ccc32)cc1
Temperature: 80 °C
Yield: 83.3 %

Procedure:
To a solution of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (870 mg, 2.75 mmol) in toluene (10 mL) was added in succession (S)-tert-butyl 3-aminopiperidine-1-carboxylate (660 mg, 3.3 mmol), sodium tert-butoxide (475 mg, 5 mmol), and rac-(±)-BINAP (180 mg, 0.29 mmol). The flask was evacuated and refilled with nitrogen three times, after which Pd2 dba3 (83 mg, 1.5 mol %) was added. The flask was again purged with nitrogen three times, and was then heated to 80° C. overnight. The solution was cooled to room temperature and then filtered through a pad of celite, washing with additional toluene. The toluene solution was then loaded directly onto a silica gel column that had been packed with heptane. The column was flushed with 2 column volumes of heptane, and then eluted with 40/60—EtOAc/heptane to afford the title compound (1.00 g 82%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.011 g, 0.27 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, from Example 2, Step 5) in DMF (6 mL). After stirring for 10 minutes, 1-(chloromethyl)-3-nitro-benzene, (0.058 g, 0.34 mmol, Aldrich) was added. After stirring for 45 minutes, the reaction was quenched by the addition of water and the mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS to afford product as a yellow solid (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (0.065 g, 75%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:12]1[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1ccccc1-c1nc2ncc(C(F)(F)F)cc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccccc1-c1nc(Cl)c2cc(C(F)(F)F)cnc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 970 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 0.39 ml of phosphorus oxychloride, 428 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 100° C. for 5 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 996 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-6-trifluoromethylpyrido[2,3-d]pyrimidine (Compound of Present Invention 22).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([NH:25]C(OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([NH2:25])[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Reaction time: 2.5 h

Procedure:
To a solution of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(t-butoxycarbonylamino) succinamic acid benzyl ester (389 mg, 0.851 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). After 2.5 h at ambient temperature, the solvent was removed in vacuo to give 3(R)-amino-N-(1(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt as a yellow foam that was placed with 3-(biphenyl-4-yl-)2,5-dimethoxytetrahydrofuran (182 mg, 0.641 mmol) in HOAc (1 mL) and heated to 50° C. After 2 hours, the mixture was allowed to cool, carefully stirred with saturated aqueous NaHCO3 (25 mL), and extracted into CHCl3 (3×15 mL). The combined organic layers were dried over Na2SO4 and evaporated to give a brown oil, 685 mg. Flash column chromatography with 10% MeOH/CH2Cl2 as eluant provided 276 mg (64%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(3-(biphenyl-4-yl)-1H-pyrrol-1-yl)succinamic acid benzyl ester as a yellow solid. 1H NMR (CDCl3): δ 7.70-7.48 (m, 10H), 7.44 (dd, 2H, J=7.2, 7.8 Hz), 7.38-7.12 (m, 5H), 7.08-6.98 (m, 2H), 6.89 (bm, 1H), 6.63 (dd, 1H, J=2.5, 2.5 Hz), 6.54 (dd, 1H, J=1.2, 1.2 Hz), 5.76 (d, 1H, J=7.5 Hz), 5.10 (dd, 2H, J=12.1, 15.9 Hz), 4.95 (dd, 1H, J=5.0, 8.7 Hz), 4.34-4.00 (bm, 1H), 3.66 (dd, 1H, J=3.7, 11.2 Hz), 3.49 (dd, 1H, J=5.3, 11.2 Hz), 3.37 (dd, 1H, J=5.0, 16.8 Hz), 3.18 (dd, 1H, J=8.7, 16.8 Hz), 2.74 (ddd, 2H, J=6.5, 13.7, 15.9Hz). IR(KBr): 3314, 3029, 2925, 1731, 1658, 1548, 1495, 1355, 1196, 1165, 761, 698 cm−1; Anal. calculated for C36H34N2O4.0.5 H2O: C, 76.17; H, 6.22; N, 4.94. Found: C, 76.24; H, 6.18; N, 4.97.
Reaction SMILES: [O:1]=[C:2]1[O:6][C:5]([C@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)=[N:4][N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[C:13]1([N:3]2[N:4]=[C:5]([C@@H:7]3[CH2:9][C@@H:8]3[C:10]([N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:12])[O:6][C:2]2=[O:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1nn(-c2ccccc2)c(=O)o1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C([C@H]1C[C@H]1c1nn(-c2ccccc2)c(=O)o1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (0.2 mmol) of cis-2-(5-oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-cyclopropanecarboxylic acid, 233 mg (2.0 mmol) of NEM and 67 mg (0.2 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 17.3 mg (0.2 mmol) of piperidine were added to the reaction solution. After stirring at room temperature for 16 h, the reaction mixture was filtered and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization the product was obtained as a white solid. Yield: 44 mg.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C([N:17]1[C:21](=[O:22])[C:20]([CH:24]([CH3:26])[CH3:25])([CH3:23])[N:19]=[C:18]1[C:27]1[N:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])(=O)C1C=CC=CC=1.[Cl-].[NH4+]>CO>[CH:24]([C:20]1([CH3:23])[C:21](=[O:22])[NH:17][C:18]([C:27]2[N:36]=[CH:35][C:34]([CH2:37][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:33][C:28]=2[C:29]([O:31][CH3:32])=[O:30])=[N:19]1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(CBr)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Reactant: Sc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(CSc2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
A solution of thiophenol, sodium salt and methanol is added to a solution of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(bromomethyl)nicotinic acid, methyl ester (14.08 g, 0.0298 mol) and methanol. The reaction mixture is stirred for 15 hours at room temperature, acidified with ammonium chloride (5 g, 0.0869 mol) and concentrated in vacuo to yield an oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (3:1) to (1:1) as eluant to give the title compound as a yellow solid (8.32 g, 55%), mp 135°-138° C., identified by IR and NMR spectral analyses.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>CC#N.O>[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[C:31]([C:2]2[N:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1
Yield: 57.8 %

Procedure:
A solution of tert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (Intermediate J[a2]) (100 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol) and 3-trifluoromethylbenzeneboronic acid (72 mg, 0.38 mmol) in CH3CN:H2O (4:1) (10 mL) was degassed for 30 mins, added tetrakis triphenylphosphine palladium (37 mg, 0.032 mmol), degassed for 10 mins and heated the reaction mixture at reflux temperature for 2 h. After completion, the reaction mixture was poured in ice water (100 mL), extracted with ethyl acetate (5×40 mL). The combined extract were washed with water (70 mL), brine (70 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2), by using EtOAc:Petroleum ether (1:9) to get tert-butyl (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (70 mg, 58.3%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[O:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[CH2:28][O:29][NH2:30]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[O:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[CH2:28][O:29]/[N:30]=[C:11]1\[NH:10][C@@H:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Br:20])[CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\1=2
Reactant: NOC[C@H]1COCCO1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OC[C@H]1COCCO1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 319.3 %

Procedure:
Thiolactam (31I (Example 31), 0.087 g, 0.0272 mmol), (R)—O-((1,4-dioxan-2-yl)methyl)hydroxylamine (2M (Example 2-E), 0.145 g, 1.09 mmol), and mercury (II) acetate (0.173 g, 0.045 mmol) were dissolved in 3.5 mL of dry toluene and heated in 100° C. oil bath for 1 h. The reaction was done as judged by LC/MS. The crude mixture was filtered through Celite, rinsed with methanol and then concentrated and purified on preparatory LC/MS (25-55% CH3CN in H2O) to afford (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O—((R)-1,4-dioxan-2-yl)methyl oxime (39A, 0.0405 g, 36.7% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.90 (s, 3H) 3.04 (dd, J=17.05, 8.97 Hz, 2H) 3.28 (dd, J=17.56, 4.17 Hz, 1H) 3.43 (dd, J=11.62, 9.85 Hz, 1H) 3.58-3.68 (m, 1H) 3.70-3.76 (m, 2H) 3.77-3.88 (m, 2H) 3.93-4.00 (m, 1H) 4.01-4.08 (m, 1H) 4.09-4.18 (m, 1H) 5.01 (d, J=5.05 Hz, 1H) 5.78 (s, 1H) 7.11 (td, J=8.21, 2.53 Hz, 1H) 7.37 (dd, J=7.96, 2.65 Hz, 1H) 7.41 (dd, J=8.84, 5.81 Hz, 1H). ESI-MS: m/z 468.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]O[CH2:24][CH2:23]1>ClCCl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:13][CH2:14][CH3:15])[CH:16]3[CH2:17][CH2:18][N:19]([C:28]([N:22]4[CH2:27][CH2:26][CH2:24][CH2:23]4)=[O:29])[CH2:20][CH2:21]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(Br)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(C1CCN(C(=O)N2CCCC2)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.25 M in dichloromethane, 50 μmol) was added 220 μL of 0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and 30 μL of DIEA. The reaction was stirred at 25° C. for 24 h. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford {4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone 34 (4.6 mg), [M+H]+=562.