Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[S-:13][C:14]#[N:15].[K+].BrBr>C(O)(=O)C>[NH2:15][C:14]1[S:13][C:12]2[CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
A solution of ethyl 4-aminobenzoate (8.26 g, 0.05 mol) in acetic acid (100 mL) was treated with potassium thiocyanate (14.58 g, 0.15 mol) and stirred 10 minutes at room temperature to dissolve the salt. The resulting solution was cooled in an ice bath and stirred while bromine (2.6 mL, 0.05 mol) was added dropwise over 15 minutes. The cooling bath was removed and the mixture was stirred at room temperature for 2.25 hours. The mixture was stored at 5° C. for 5 hours, then filtered to remove the yellow precipitate. The filter cake was washed with diethyl ether (2×50 mL) and water (2×100 mL) and dried under vacuum to give 2-amino-6-ethoxycarbonylbenzothiazole (2.54 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][C:10](=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22][CH2:23][CH2:24][NH:25][NH2:26]>CO>[C:1]1([CH:7]2[CH:8]3[C:9]([C:10](=[CH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11][CH2:12][CH2:13]3)=[N:26][N:25]2[CH2:24][CH2:23][OH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Reactant: NNCCO
Solvent: CO
Product: OCCN1N=C2C(=Cc3ccccc3)CCCC2C1c1ccccc1

Procedure:
A suspension of the 2,6-bis(phenylmethylene)cyclohexanone from example 1a in methanol is treated with (2-hydroxyethyl)hydrazine. The mixture is heated and the resulting solution is refluxed for four hours, cooled, and the bulk of the methanol is evaporated. The resulting alcohol is triturated with ether, cooled overnight, filtered, and dried in vacuo.
Reaction SMILES: C([NH:20][C@@H:21]1[C:48](=[O:49])[N:23]2[C:24]([C:32]([O:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[S:33])=[C:25]([CH2:28][C:29](=[O:31])[NH2:30])[CH2:26][S:27][C@H:22]12)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[C:51]1([CH3:61])[CH:56]=[CH:55][C:54]([S:57]([OH:60])(=[O:59])=[O:58])=[CH:53][CH:52]=1>C(OCC)(=O)C>[C:51]1([CH3:61])[CH:52]=[CH:53][C:54]([S:57]([OH:60])(=[O:58])=[O:59])=[CH:55][CH:56]=1.[CH:35]([O:34][C:32]([C:24]1[N:23]2[C:48](=[O:49])[C@@H:21]([NH2:20])[C@H:22]2[S:27][CH2:26][C:25]=1[CH2:28][C:29](=[O:31])[NH2:30])=[S:33])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NC(=O)CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of 0.56 g (0.8 mM) of benzhydryl 7β-tritylamino-3-carbamoylmethylthio-3-cephem-4-carboxylate obtained in Example 2(a) in 10 ml of ethyl acetate, 0.18 g (0.96 mM) of p-toluenesulfonic acid monohydrate was added under ice-cooling, and the mixture was stirred for 4 hours. After the reaction, the white crystals which formed were collected by filtration to give 0.392 g of 7β-amino-3-carbamoylmethylthio-3-cephem-4-carboxylic acid benzhydryl ester p-toluenesulfonate.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:21])[N:13]2[CH3:20])[C:3]([O:5]CC)=O.[NH2:22][C:23](N)=[S:24].C([O-])(=[O:28])C.[Na+]>COC(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:8]([CH:2]2[S:24][C:23](=[O:28])[NH:22][C:3]2=[O:5])=[C:9]2[C:14]=1[N:13]([CH3:20])[C:12](=[O:21])[CH:11]=[CH:10]2
Reactant: CC(=O)[O-]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)c1ccc(OC)c2c1ccc(=O)n2C
Agent: COC(C)O
Agent: [Na+]
Product: COc1ccc(C2SC(=O)NC2=O)c2ccc(=O)n(C)c12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 56.6 %

Procedure:
3.02 g of ethyl chloro-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)acetate, 1.4 g of thiourea, and 2 g of sodium acetate were added to 50 ml of methoxyethanol, followed by stirring at 110° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue to precipitate a solid, and the precipitated solid was collected by filtration. The collected solid was added to a mixed solvent of 30 ml of 10% hydrochloric acid and 30 ml of ethanol, followed by heating and refluxing overnight. The resultant was concentrated to half its original volume under reduced pressure. Water was added thereto, and the mixture was cooled with ice to precipitate a solid. The precipitated solid was collected by filtration. The solid was recrystallized from a DMF-ethanol mixed solvent, giving 1.68 g (57% yield) of 5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)thiazolidine-2,4-dione as a gray powder.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2C(OC(C)(C)C)=O)[NH:5][CH:6]=1.Cl>CO.O1CCOCC1>[I:1][C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][NH:8]2)[NH:5][CH:6]=1
Reactant: C[C@H]1C[C@@H](c2nc(I)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CN[C@H](c2nc(I)c[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.5 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (1.6 g, 4.242 mmol) in MeOH (16 mL) is added a 4M HCl in dioxane solution (16 ml) at 0° C. The reaction mixture is stirred at RT overnight and evaporated to dryness to afford 4-iodo-2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-imidazole (1.37 g, 92.5%) as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.[CH2:9]=[C:10]=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:10]([CH3:9])=[O:11]
Reactant: C=C=O
Reactant: CCCCCON=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CCCCCOC(C)=O
Reaction time: 6 h
Yield: 25 %

Procedure:
The procedures of Example 14 were followed, except that 80 ml (536.9 mmoles) of n-amyl nitrite was used and that ketene was introduced at the rate of 11.3 ml/min (0.50 mmole/min). During the reaction, however, 15 ml, of a solution of triphenylphosphine (0.092 g, 0.375 mmole) and stannous chloride (0.072 g, 0.375 mmole) in N-methylpyrrolidone was added to the reaction system in 2.5 ml portions every 1 hour, and the reaction was effected at 90° C. for 6 hours. The gas chromatographic analysis revealed that di-n-amyl malonate (136.0 mmoles, 74.8%) and n-amyl acetate (45.4 mmoles, 25.0%) were obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C@H:29]([CH2:34][CH3:35])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@H:29]([OH:28])[CH2:34][CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC[C@@H](O)CC(=O)O
Agent: Cl
Product: CC[C@@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (56 mg, 52%), MS (ISP) m/z=431.5 [(M+H)+], mp 146° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (R)-3-hydroxy-pentanoic acid.
Reaction SMILES: [CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].[CH3:19][O-:20].[Na+]>C(OCC)C>[CH3:19][O:20][C:13](=[O:17])[C:14]([C:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1)=[O:15]
Reactant: c1cc2c3c(c1)ccn3CCC2
Reactant: C[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 83.8 %

Procedure:
To a solution of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline (1.67 g, 10.6 mmol) in 150 mL of anhydrous diethyl ether at 0° C. was added dropwise oxalyl chloride (1.05 mL, 12.08 mmol) and the resulting solution was stirred at 0° C. for 40 minutes. The mixture was then cooled to −78° C. and sodium methoxide (42 mL, 21 mmol, 0.5 M in methanol) was added slowly. Upon completion of the addition, the dry ice bath was removed and the reaction was warmed to 20-24° C. over 2 hours. The mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL) and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), filtered through a 2 inch plug of coarse silica gel and concentrated in vacuo to give 2.16 g (84%) of the desired compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C.[Cl-].[Na+].O>[CH2:12]([O:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#CC1(CO)CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(COCc2ccccc2)CCCC1
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol). The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])[CH3:4].Cl[CH2:23][C:24]#[N:25].O>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:23][C:24]#[N:25])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1CC#N
Temperature: 75 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of sodium hydride (0.58 g in DMF (12 mL) at 0° C. was slowly added a solution of 5-trifluoromethoxy-1H-indole-2-carboxylic acid ethyl ester (2.64 g) in DMF (12 mL) keeping the temperature below 7.5° C. After gas evolution ceased, chloroacetonitrile was added, and the reaction mixture was stirred for 2 hours at 75° C. After allowing cooling down, water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with brine then dried with magnesium sulfate, concentrated in vacuo and purified by column chromatography to yield the title compound (2.3 g, 76%). MS (EI): 312.1 (M+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>Cl>[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:17][CH2:16]1
Reactant: CC1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)O)CC1

Procedure:
A mixture of 10.0 g 2-chloro-5-nitro benzoic acid (50 mmol) and 13 mL 4-methyl-piperidine was refluxed for 2 h, 100 mL 1 N aq. HCl solution was added and it was extracted with 100 mL DCM. The organic phase was dried with Na2SO4, concentrated and purified via chromatography (silica gel, eluent: DCM:MeOH 100:1) to furnish the subtitle compound. MS [m+H]+=265.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[O:12][C:11](=[O:21])[C@@H:10]([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:24]1C=C([C@H]2[C@@H](C3C=CC(Cl)=CC=3)OC(=O)[C@H](C)C2)C=C[CH:29]=1.[CH2:45](Br)C=C.C(#N)C.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[CH2:22]([C@@:10]1([CH3:45])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[O:12][C:11]1=[O:21])[CH:24]=[CH2:29]
Reactant: C[C@@H]1C[C@@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)OC1=O
Reactant: C=CCBr
Reactant: C[C@H]1C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Temperature: -5 °C

Procedure:
A solution of (3S,5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one and (3R,5S,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (4.5 g, 13.4 mmol) and allyl bromide (3.48 mL, 40.3 mmol) in tetrahydrofuran (22 mL) at −35° C. (acetonitrile/dry ice bath) was treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 17.45 mL, 17.45 mmol). The reaction was allowed to warm to −5° C. over 1 hour and then was quenched with 50% saturated ammonium chloride. The reaction was diluted with 100 mL of ethyl acetate and the layers were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under a vacuum to afford the title compound as a white solid upon standing under a vacuum. Chiral SFC (92% CO2, 8% methanol (20 mM ammonia), 5 mL/min, Phenomenex Lux-2 column (Phenomenex, Torrance, Calif.), 100 bar (10,000 kPa), 40° C., 5 minute method) was used to determine that the compound had an enantiomeric ratio of 96:4. (Major enantiomer: title compound, retention time=2.45 minutes, 96%; minor enantiomer (structure not shown, retention time=2.12 min, 4%). The title compound was recrystallized by adding to heptane (4.7 g slurried in 40 mL) at reflux and 1.5 mL of toluene was added dropwise to solubilize. The solution was cooled to 0° C. The white solid was filtered and rinsed with 20 mL of cold heptanes to afford a white powder. Chiral SFC (92% CO2, 8% methanol, Phenomenex Lux-2 column, same method as above) indicated an enantiomeric ratio of 99.2:0.8. (major enantiomer, 2.45 min, 99.2%; minor enantiomer: 2.12 min, 0.8%)
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1>[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: CN1CCCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: CN1CCCN(C2CCNCC2)CC1

Procedure:
Prepared analogously to Example A3f) from hexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepine by hydrogenolysis, but using Pearlman's catalyst instead of palladium/charcoal, in a quantitative yield. Colourless viscous oil.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:25])[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=1)([CH2:13][O:14][CH2:15][O:16][CH3:17])[CH2:8][O:9][CH2:10][O:11][CH3:12])C>C(O)C.O>[Br:24][C:20]1[N:19]=[C:18]([C:7]([CH2:8][O:9][CH2:10][O:11][CH3:12])([CH2:13][O:14][CH2:15][O:16][CH3:17])[C:6]([OH:25])=[O:5])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(COCOC)(COCOC)c1cccc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCOCC(COCOC)(C(=O)O)c1cccc(Br)n1
Reaction time: 8 h

Procedure:
Lithium hydroxide (10.69 g, 254.95 mmol) was added to a solution of 2-(6-bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionic acid ethyl ester (20.0 g, 50.99 mmol) in ethanol (100 ml) and water (100 ml) at rt and the reaction mixture was allowed to stir overnight. The reaction mass was concentrated under reduced pressure and acidified with dilute HCl and at 0° C. The product was extracted with ethyl acetate, washed with minimum amount of brine. Organic layer was concentrated under reduced pressure to obtain title compound as a brown liquid. Yield=18.0 g. TLC (50% ethyl acetate in hexane) Rf=0.05; LCMS: RtH9=1.383, [M+1]=364.0 and 366.0; HPLC: RtH9=3.844 min (49%) and 3.885 min. (22%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[C:20](C)[CH:19]=[CH:18][C:17]=3[CH3:23])=[N:14][N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24]N1C(=O)CCC1=O.[C:32]([Cl:36])(Cl)(Cl)Cl>>[Cl:24][CH2:23][C:17]1[CH:18]=[CH:19][C:20]([CH2:32][Cl:36])=[CH:21][C:16]=1[C:13]1[O:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:15][N:14]=1
Reactant: Cc1ccc(C)c(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)c1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Product: CC(C)(C)c1ccc(-c2nnc(-c3cc(CCl)ccc3CCl)o2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
Compound 3 (3.0 g, 9.79 mmol) and N-chloro-succinimide (3.27 g, 24.48 mmol) were dissolved in carbon tetrachloride (20 ml). The mixture was degassed and heated/irradiated by an IR lamp to reflux under argon. After 4 hours, the mixture was cooled to 0° C. The soluble part of the mixture was separated by filtration. Evaporation of the solvent afforded a solid mixture product, which was separated and purified by silica flash column chromatography using hexane to hexane/EtOAC (1:4, v/v) subsequently. The product was obtained as an off-white powder with a yield of 42%. The compound was characterized by 1H NMR and FT-IR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[C:7]2[CH3:26].[CH3:28][O:29][C:30](=[O:33])[CH2:31]Br>>[CH3:28][O:29][C:30](=[O:33])[CH2:31][O:27][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:26])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2
Reactant: COC(=O)CBr
Reactant: Cc1c(Cc2ccc(C(=O)C(C)(C)C)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Product: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 8-chloro-3-[4-(2,2-dimethylpropionyl)benzyl]-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[C:18]=2[CH2:19][C:20]([OH:22])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][CH2:31][CH3:32])[CH:24]=1>>[ClH:1].[CH2:31]([N:30]([CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[C:20](=[O:22])[CH2:19][C:18]1[N:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]2=[N:10][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:32]
Reactant: CCNCc1cccnc1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: CCN(Cc1cccnc1)C(=O)Cc1c(-c2ccc(Cl)c(Cl)c2)nc2cc(C)ccn12
Product: Cl
Yield: 70.8 %

Procedure:
According to the method of Example 14, 2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(3-pyridinylmethyl)ethylamine were used as raw materials for synthesis, to obtain white solid powder, yield 70.8%. m.p. 245-248° C., ESI-MS m/z: 454[M+H]+, 1H NMR(DMSO-d6, 400 MHz)δ: 1.06(t, 0.7H, J=7.00 Hz), 1.25(t, 2.3H, J=7.00 Hz), 2.58(s, 3H), 3.34(q, 0.5H, J=7.00 Hz), 3.58(q, 1.5H, J=7.00 Hz), 4.45(s, 0.5H), 4.57(s, 1.5H), 4.70(s, 1.5H), 4.92(s, 0.5H), 7.44-7.47(d, 1H, J=7.00 Hz), 7.56(dd, 0.2H, J=8.40 Hz, 1.96 Hz), 7.63(dd, 0.8H, J=8.40 Hz, 2.24 Hz), 7.80(s, 1H), 7.86(d, 0.2H, J=2.24 Hz), 7.87(d, 0.8H, J=1.96 Hz), 7.90(m, 1H), 7.94(d, 1H, J=8.40 Hz), 8.30-8.31(m, 1H), 8.74-8.77(m, 1H), 8.79(d, 1H, J=7.00 Hz), 8.82(m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[NH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)=[CH:40][N:41]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>COCCOC.O>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[NH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:21]3[CH:22]=[CH:23][C:18]([C:15]4[NH:14][C:13]([CH:10]5[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]5)=[N:17][CH:16]=4)=[CH:19][CH:20]=3)=[CH:44][CH:43]=2)=[CH:40][N:41]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Temperature: 80 °C
Yield: 63.7 %

Procedure:
Pd(Pb3)4 (54 mg, 0.046 mmol) was added to a mixture 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (378 mg, 0.97 mmol), 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (408 mg, 0.93 mmol), NaHCO3 (273 mg, 3.26 mmol) in 1,2-dimethoxyethane (8 mL) and water (2 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 6 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (370 mg, 64%). m/z 625.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:10]=2[N:9]=1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O>[CH:22]1([N:11]2[C:10]3[N:9]=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[NH:1][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:17]=[CH:16][C:15]=3[N:14]([CH3:18])[C:13](=[O:19])[C@H:12]2[CH2:20][CH3:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1ccccc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(=O)c3ccccc3)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91, 1 eq), benzoic acid (3 eq), HATU (3 eq), and DIPEA (4 eq) in dry THF under Ar was stirred at 90° C. for 18 h. The mixture was cooled to rt and water was added and extracted with EtOAc. The organic layer was dried with Na2SO4, concentrated and the residue was purified by silica gel column to give the title compound. LCMS (0.05% TFA): 457.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 13.75 (s, 1H), 10.00 (bs, 1H), 8.55 (bs, 1H), 8.39 (d, 1H, J=5.0 Hz), 8.31 (s, 1H), 8.07 (m, 2H), 7.69 (m, 3H), 4.46 (m, 1H), 4.39 (m, 1H), 3.38 (s, 3H), 2.02-1.63 (m, 10H), 0.77 (t, 3H, J=7.5 Hz).