Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:47])([CH3:46])[C:15](=[O:45])[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([CH2:27][CH3:28])[S:26][C:20]=2[N:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[C:18]1=[O:44]>O.C(OCC)(=O)C>[CH3:47][C:14]([CH3:46])([CH3:13])[C:15](=[O:45])[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([CH2:27][CH3:28])[S:26][C:20]=2[N:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[NH:3][C:4](=[O:7])[O:5][N:43]=3)=[CH:32][CH:31]=2)[C:18]1=[O:44]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.87 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (8 mL) was stirred at 50° C. for 30 min, 4′-{[3-(3,3-dimethyl-2-oxobutyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.77 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (8 mL). N,N′-Carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.64 g, 74%).
Reaction SMILES: CN([CH:4]=[C:5]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH:6]=O)C.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].[O-]CC.[Na+].C(OC(=O)C)(=O)C>O.C(O)C>[C:23]([C:25]1[C:26](=[O:27])[NH:28][CH:4]=[C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:6]=1)#[N:24]
Reactant: CN(C)C=C(C=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#Cc1cc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]c1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of 3-(N,N-dimethylamino)-2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylaldehyde (cis and trans mixture) (4.00 g), 2-cyanoacetamide (2.31 g), sodium ethoxide (4.67 g) and ethanol (40 ml) was refluxed for 2 hours. After cooling the reaction mixture was added acetic anhydride (24 ml) and water (120 ml) and stirred at room temperature. The resultant precipitates were collected and recrystallized from a mixture of N,N-dimethylformamide and water to give 3-(3-cyano-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.08 g).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=2)=[O:27])[CH2:22][CH2:21]1.C=O>C(#N)C>[N:19]1([CH:20]2[CH2:21][CH2:22][N:23]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=3)=[O:27])[CH2:24][CH2:25]2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:1]1
Reactant: CCCCc1ccc(C(=O)N2CCC(Nc3ccccc3N)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: CC#N
Product: CCCCc1ccc(C(=O)N2CCC(n3cnc4ccccc43)CC2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
p-Toluenesulfonic acid (catalytic amount) was added to a solution of [4-(2-amino-phenylamino)-piperidin-1-yl]-(4-butyl-phenyl)-methanone (50 mg, 0.142 mmol) and paraformaldehyde (500 mg) in acetonitrile (10 mL). The reaction was heated at 80° C. for 4 h. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel using chloroform/methanol/ammonia (96:3.6:0.4) as the eluent. The product fractions were combined and evaporated to give (4-benzoimidazol-1-yl-piperidin-1-yl)-(4-butyl-phenyl)-methanone (39 mg, 76%) as an amber oil.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)O.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O[C@@H](CBr)c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)[C@@H](CBr)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1.54 g (7.61 mmol) of (R)-2-bromo-1-pyridin-3-yl-ethanol l-1 in 20 ml of dry N,N-dimethylformamide at room temperature was added 1.55 g (22.83 mmol) of imidazole followed by 1.72 g (11.4 mmol) of tert-butyldimethylsilyl chloride. The mixture was stirred at room temperature for about 18 hours and then an additional 1.55 g (22.83 mmol) of imidazole and 1.72 g (11.4 mmol) of tert-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for about an additional 24 hours. The mixture was poured into 200 ml of water and extracted with ethyl acetate (2×200 ml). The organic extracts were combined, washed successively with water (1×40 ml), brine (1×40 ml), then dried over magnesium sulfate and concentrated in vacuo to furnish an oil. Chromatography on silica gel eluting with ethyl acetate:hexanes (2:3, v/v) provided 1.41 g (58% yield) of the desired title compound as a clear oil, αD=−51.5° (c=0.60, chloroform). Chiral HPLC analysis of the product on 4.6×250 mm Chiralcel® OD column (Chiral Technologies; Exton, Pa.) eluting with hexanes:isopropyl alcohol (7:3, v/v) at 1.0 ml/minute revealed an enantiomeric excess of 91.3%.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[F:6][C:7]([F:17])([F:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.C([O-])(=O)C.[NH4+].C(OC(=O)C)C>CCCCCC>[N+:1]([C:4]([CH3:5])=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([C:7]([F:17])([F:16])[F:6])=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=Cc1ccc(C(F)(F)F)cc1)[N+](=O)[O-]
Temperature: 115 °C
Yield: 42.9 %

Procedure:
Nitro ethane (30.94 mL, 430.73 mmol) was added to 4-trifluoromethyl-benzaldehyde (5 g, 28.71 mmol) and ammonium acetate (6.64 g, 86.15 mmol) and the resulting mixture was refluxed at 115° C. overnight. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mass was cooled and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (2% ethylacetate in hexane) afforded 2.85 g of the product (42.93% yield).
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3]O.ClS(O)(=O)=O>C(#N)C>[CH2:5]([C:2]1([CH2:9][CH3:10])[CH2:3][NH:1]1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(N)(CC)CO
Agent: O=S(=O)(O)Cl
Solvent: CC#N
Product: CCCCC1(CC)CN1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 73.1 %

Procedure:
Acetonitrile (150 ml) and the product from (e) (20.0 g) were mixed under nitrogen, cooled to 2°-30° C. and chlorosulphonic acid (16.04 g, Aldrich) was added dropwise keeping the temperature below 10° C. The coolant was removed and the slurry left to stir for 80 minutes at room temperature. The reaction was concentrated in vacuo and co-distilled with water (50 ml). 50% Aqueous sodium hydroxide (55.2 g) and water (50 ml) were added and the mixture was distilled at atmospheric pressure. The organic layer was collected from the distillate and dried with solid potassium hydroxide to give the desired product (12.8 g). 1H NMR consistent with proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O.O>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Yield: 60.8 %

Procedure:
To a stirred mixture of Na0H (204 mg., 5.1 mmol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for 20 hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added benzyl bromide (0.606 mL., 5.1 mmol., 1 eq.) via syringe. After 7 h. the mixture was diluted with water and extracted 4× with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product was purified by crystallization (ether/hexanes) affording 888 mg of 1-benzyl-5-bromoindole.
Reaction SMILES: C([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)(O)=O.Cl.[N+:47]([C:50]1[CH:62]=[CH:61][C:53]([CH2:54][O:55][C:56](=[O:60])[CH2:57][NH:58][CH3:59])=[CH:52][CH:51]=1)([O-:49])=[O:48].C(P(C#N)(CC)=O)C.C(N(CC)CC)C.CN(C)[CH:80]=[O:81]>>[CH3:59][N:58]([CH2:57][C:56]([O:55][CH2:54][C:53]1[CH:52]=[CH:51][C:50]([N+:47]([O-:49])=[O:48])=[CH:62][CH:61]=1)=[O:60])[C:80]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:41])([CH3:43])[CH3:42])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)=[O:81]
Reactant: CNCC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Reactant: CN(C)C=O
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N(C)CC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a suspension of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.00 g, 1.51 mmol) (obtained as described in Reference Example 41(7)) and sarcosine p-nitrobenzyl ester hydrochloride (590 mg, 2.26 mmol) (obtained as described in Reference Example 43(2)) in dimethylformamide (30 ml) were added diethylphosphoryl cyanide (0.37 ml, 2.26 mmol) and triethylamine (0.95 ml, 6.80 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[N-methyl-N-(p-nitrobenzyloxycarbonyl)methyl-carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (997 mg, yield 76%).
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-:7])(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:29])[C@H:16]1[CH2:20][CH2:19]C(=O)[N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[NH4+].[Cl-].[O:32]1CCCC1>CCCCCC>[CH3:13][O:14][C:15](=[O:29])[CH:16]([NH:17][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][C:19](=[O:32])[CH:5]=[N+:6]=[N-:7]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: COC(=O)C(CC(=O)C=[N+]=[N-])NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsilyidiazomethane (1.24 mL of a 2M solution in hexane, 2.5 mmol) in 12 mL of tetrahydrofuran at −100° C. was added n-butyllithium (1.01 mL of a 2.5 M solution in hexane, 2.5 mmol). After stirring for 30 min, the solution was transferred via an insulated cannula to a −100° C. solution of N-BOC (D)-pyroglutamic acid methyl ester (0.50 g, 2.1 mmol) in 21 mL of tetrahydrofuran. After stirring for 20 min, the mixture was poured into saturated aqueous NH4Cl, extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated, affording 0.62 g of 2-tert-butoxycarbonylamino-5-diazo-4-oxo-pentanoic acid methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.5 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 4-(4-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (54 mg, 45%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16](Br)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:32](=[O:34])=[O:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16]([C:32]([OH:34])=[O:33])[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)cn1COCC[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
2-[4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.2 mmol) in THF (10 mL) was cooled to −78° C. and treated with t-BuLi (1.7 M in pentane, 2.7 mL, 4.6 mmol). The reaction mixture was stirred for 1 hour and treated with solid CO2 (500 mg). The mixture was warmed to ambient temperature and mixture was concentrated. The solution was dried over MgSO4 and subjected to a 120 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0-20% MeOH-EtOAc gradient) to afford 2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid (200 mg, 22%): MS (ESI) m/z 412 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH2:13]([O:15][C:16]1[C:21](=[O:22])[NH:20][CH:19]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[C:25]([F:33])[CH:24]=2)[CH:17]=1)[CH3:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[CH:17]=[C:16]([O:15][CH2:13][CH3:14])[C:21](=[O:22])[NH:20][CH:19]=3)=[CH:24][C:25]=2[F:33])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)c[nH]c1=O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A suspension of 4-chloro-3-(trifluoromethyl)aniline (20.14 mg, 0.103 mmol) in DMF (8 mL) was added to a solution of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (30 mg, 0.103 mmol) in DMF (8 mL). HOBt (23.66 mg, 0.154 mmol), EDC (29.6 mg, 0.154 mmol) and Et3N (0.043 mL, 0.309 mmol) were added and the mixture was stirred at 50° C. for 8 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a white solid of N-(4-chloro-3-(trifluoro methyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (11.39 mg, 0.024 mmol, 23.6% yield). TLC (DCM/MeOH=10:1, Rf=0.6): 1H NMR (400 MHz, CD3OD) δ: 8.10 (s, 1H), 7.79 (d, J=8.82 Hz, 1H), 7.53 (d, J=8.82 Hz, 1H), 7.37-7.44 (m, 1H), 7.26-7.37 (m, 3H), 7.23 (d, J=1.98 Hz, 1H), 4.12 (q, J=7.06 Hz, 2H), 3.80 (s, 2H), 1.46 (t, J=6.95 Hz, 3H); ES-LCMS m/z 469.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)[C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[O:13].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:72]([NH2:76])([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:72]([NH:76][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH:23]([CH3:25])[CH3:24])[C:12](=[O:13])[C:11]1[CH:26]=[C:27]([O:29][CH2:30][CH2:31][NH:32][C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH:28]=[C:9]([Cl:8])[CH:10]=1)=[O:21])([CH3:75])([CH3:74])[CH3:73]
Reactant: CC(C)N(CCCCCC(=O)O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reactant: CC(C)(C)N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCCCCC(=O)NC(C)(C)C)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6-({3-chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-isopropyl-amino)-hexanoic acid trifluoroacetate (0.02 g) and PyBroP® (0.021 g) in DMF (1 ml) was added DIPEA (0.016 ml) followed by tert-butylamine (0.005 ml), after 1 min. The reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.0094 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][Si](C(C)(C)C)(C)C)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38]2[N:43]=[CH:42][C:41](Br)=[CH:40][N:39]=2)[CH2:33][CH2:32]1)(=O)=O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:31]2[CH2:36][CH2:35][C@H:34]([NH:37][C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)[CH2:33][CH2:32]2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc2nccnc12
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Brc1cc(O[C@H]2CC[C@@H](Nc3ncccn3)CC2)c2nccnc2c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
As shown in step 8-i of Scheme 8, to a mixture of 7-bromoquinoxalin-5-ol (compound 1018, 200 mg, 0.89 mmol) and cesium carbonate (579 mg, 1.78 mmol) in NMP (4.0 mL) was added (trans)-4-(pyrimidin-2-ylamino)cyclohexyl methanesulfonate (compound 1014, 241.1 mg, 0.8887 mmol). The mixture was stirred for 18 hours at 90° C., at which time an additional 0.5 eq of compound 1014 (241 mg, 0.89 mmol) was added. After stirring at 90° C. for an additional 6 hours, the reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated, and purified by medium pressure silica gel chromatography (0-5% MeOH/DCM) to provide N-((cis)-4-((7-bromoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 1025): 1H-NMR (300 MHz, CDCl3) δ 9.01-8.77 (m, 2H), 8.29 (d, J=4.8 Hz, 2H), 7.89 (d, J=1.9 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 6.53 (t, J=4.8 Hz, 1H), 5.43-5.22 (m, 1H), 4.79 (td, J=5.2, 2.5 Hz, 1H), 4.18-3.95 (m, 1H), 3.51 (s, 1H), 2.22 (td, J=10.2, 9.6, 5.4 Hz, 2H), 2.09-1.86 (m, 6H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]([O:15]CC)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2cccnc12
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred mixture of ethyl 2-(quinolin-8-yloxy)acetate (250 mg, 1.08 mmol) in EtOH (2 mL) was added (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (222 mg, 1.08 mmol). The mixture was stirred at 120° C. for 0.5 hour under microwave heating. After evaporation of the solvent, the residue was purified first by prep-TLC and then prep-SFC to afford (140 mg, Yield 36%). 1H NMR (400 MHz, MeOD) 6=8.91 (d, J=4.3 Hz, 1H), 8.42 (d, J=8.3 Hz, 1H), 7.69-7.54 (m, 3H), 7.30 (d, J=7.3 Hz, 1H), 7.12-6.96 (m, 4H), 4.78 (s, 2H), 4.18-4.07 (m, 1H), 3.71 (s, 2H), 3.60-3.49 (m, 1H), 3.48-3.40 (m, 1H), 2.89 (d, J=5.8 Hz, 2H), 2.84 (d, J=4.8 Hz, 2H), 2.69-2.55 (m, 2H). LCMS (m/z): 392.1 (M+1).