Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Cl[CH:26]1[CH2:31][O:30][C:29](=[O:32])[O:28][CH2:27]1>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:26]3[CH2:31][O:30][C:29](=[O:32])[O:28][CH2:27]3)[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: O=C1OCC(Cl)CO1
Product: CC(C)(C)c1cc(-c2nn(C3COC(=O)OC3)c3ncccc23)cc(C(C)(C)C)c1O

Procedure:
By using 3.2 g of the compound of Example 1 and 1.6 g of 5-chloro-2-oxo-1,3-dioxane, the reaction is carried out in a similar manner as Example 78 (i) to give 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-oxo-1,3-dioxan-5-yl)-1H-pyrazolo-[3,4-b]pyridine.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F-].[K+].[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([Si](C)(C)C)[O:20][C:13]=12>C(#N)C>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([I:1])[O:20][C:13]=12
Reactant: C[Si](C)(C)c1cc2nccc(Cl)c2o1
Reactant: O=C1CCC(=O)N1I
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccnc2cc(I)oc12
Temperature: 50 °C
Yield: 77.3 %

Procedure:
N-Iodo succinimide (110 g, 0.486 mol) and potassium fluoride (3.2 g, 0.053 mol) are added to a stirred solution of 7-Chloro-2-(trimethylsilyl)furo[3,2-b]pyridine (11 g, 0.0486 mol) in dry acetonitrile (65 ml) at RT. The reaction mixture is heated at 50° C. for 2 h under nitrogen, cooled to RT and evaporate under reduced pressure. The residue is dissolved in ethyl acetate (500 ml), washed with saturated sodium thiosulfate (100 ml×2), water (100 ml×2) and saturated brine (100 ml), dried over sodium sulphate and concentrated under reduced pressure to afford the title compound (10.5 g, 77.3%) as an off white solid. TLC: hexane/ethyl acetate: (8/2): Rf=0.60; LCMS (method D): 3.49 min (purity 97.7%), M+H+ 279.8; 1H NMR (DMSO-d6, 400 MHz) δ [ppm] 8.41-8.405 (1H, d, J=5.3 Hz), 7.545 (1H, s), 7.448-7.435 (1H, d, J=5.2 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:1][CH2:2][CH3:3])[C:8]([OH:10])=[O:9])([O-:15])=[O:14]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
9.44 g (57.5 mmol, 1.0 equiv) of 4-propyl-benzoic acid were partially dissolved in 50 mL conc. H2SO4 and chilled in an ice bath. A solution of 4.7 mL (74.7 mmol, 1.3 equiv) conc. HNO3 in mL conc. H2SO4 was added dropwise over 1-2 minutes. After stirring 1 hour at 0° C., the reaction mixture was poured into a 1 L beaker half full with ice. After stirring 10 minutes, the white solid which formed was filtered, washed 1×H2O, and dried to give 12.01 g (100%) of the title compound: mp 106-109° C.; IR (KBr) 3200-3400, 2966, 2875, 2667, 2554, 1706, 1618, 1537, 1299, 921 cm−1; 1H NMR (300 MHz, DMSO-d6) δ0.90 (t, 3H, J=7.4 Hz), 1.59 (m, 2H), 2.82 (m, 2H), 7.63 (d, 1H, J=8.0 Hz), 8.12 (dd, 1H, J=1.7, 8.0 Hz), 8.33 (d, 1H, J=1.7 Hz); 13 C NMR (75.5 MHz, DMSO-d6) δ14.2, 23.7, 34.2, 125.4, 130.5, 132.9, 133.6, 141.4, 149.5, 165.9; Anal. calcd for C10H11NO4.{fraction (1/4+L )}H2O: C, 56.20; H, 5.42; N, 6.55. Found: C, 56.12; H, 5.31; N, 6.81.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH3:20])=[N:14][C:15]=2[NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC([O-])=O.[Na+]>CC(O)=O>[CH2:3]([N:10]1[C:18]([Br:1])=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH3:20])=[N:14][C:15]=2[NH2:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 70 °C
Yield: 16 %

Procedure:
Bromine (0.2 ml) was added to a solution of 9-benzyl-2-methyladenine 60 mg (0.25 mmol) and NaOAc (0.22 g) in AcOH (5 ml), and the mixture was heated at 70° C. for 40 min. The solvent was evaporated under vacuum, and the residue was extracted by EtOAc. The resulting organic layer was evaporated under vacuum, and the residue was purified by column chromatography (CH2Cl2 :MeOH=50:1) to obtain 9-benzyl-8-bromo-2-methyladenine as an orange solid (60 mg). A mixture of the resulting 9-benzyl-8-bromo-2-methyladenine (60 mg) and conc.HCl (5 ml) was refluxed for 3 h. After cooling, aqueous NH3 was added to crystallize the product, and the desired compound was collected by filtration (10 mg, Yield: 16%).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[O:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=[O:28])[O:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:20][CH2:19][CH2:18][O:17][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21](=[O:28])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1OCCOc2ccccc21
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1ccccc1OCCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of tert-butyl acetate (7.96 g, 68.5 mmol) in anhydrous THF (100 mL) was added freshly prepared lithium diisopropyl amine (37 mL, 1.85 M in THF) dropwise over 15 min at −78° C., and the mixture was stirred at −78° C. for 30 min. 2H-benzo[e][1,4]dioxepin-5(3H)-one (10.2 g, 62.3 mmol) was added dropwise as a solution in THF (50 mL) at −78 C, and stirring was continued for 30 min. Saturated NaHCO3 solution was added and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), and concentrated under reduced pressure to give the title compound (6.0 g, 77.9%) as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C@@H:16]([CH3:27])[CH2:15][NH:14]2.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>ClCCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[C@@H:16]([CH3:27])[CH2:15][N:14]2[C:31]([CH:28]1[CH2:30][CH2:29]1)=[O:32]
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and cyclopropanecarbonyl chloride (0.126 mL, 1.39 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.355 g, 98%) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[C:19]1([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 27.5 mg (0.066 mmol) 6-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]hexanoic acid methyl ester in 0.1 ml methanol, 0.05 ml THF and one drop of water and add 0.09 ml 2.5 M sodium hydroxide solution. Stir the mixture for 1 h at RT and then lightly acidify with 1 N hydrochloric acid. Extract the aqueous phase three times with dichloromethane. Combine the organic phases and dry over magnesium sulphate, concentrate by vacuum evaporation and dry the residue at high vacuum. 25 mg (96.1% of theor.) of the target compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13].S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:10]([CH3:9])=[CH:11][C:12]([CH3:13])=[N:1]2)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cccc(N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c2ccc(N)nc2n1
Reaction time: 24 h

Procedure:
2,6-Diaminopyridine (43.6 g., 0.4 mole), 40.0 g (0.4 mole) of 2,4-pentanedione, 200 ml. of glacial acetic acid and 5 ml. of 96% sulfuric acid were mixed, then refluxed with stirring for 24 hours. The cold solution was added slowly with good stirring and ice bath cooling to 160 g of sodium hydroxide in enough water to make 600 ml. The brown solid, which crystallized, was filtered after the solution had been cooled overnight at 5°, washed twice with cold water and dried, 25.3 g., m.p. 125°-200°. This crude material was dissolved in 130 ml. of boiling 95% ethanol and the solution chilled overnight at -15°, 19.5 g. (28%), m.p. 215°-220°. This material was suitable for the following experiment.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C[O-].[Na+].[CH2:14]([OH:16])[CH3:15].C1(C)C=CC=CC=1>CO.C(OCC)(=O)C>[C:14]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)(=[O:16])[CH3:15]
Reactant: c1cc2c(s1)CCNC2
Reactant: CCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35.1 g (200 mmole) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 38.57 g (200 mmole) of 28% w/v sodium methoxide in methanol were added to 200 ml of ethanol, and the resulting mixture was stirred at room temperature for 1 hour. The inorganic salt thus precipitated was filtered off, and the filtrate was concentrated to dryness by evaporation under reduced pressure. 50 ml of acetic anhydride were added all at once, whilst stirring, to the residue, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness by evaporation under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography, using a 6:4 by volume mixture of toluene and ethyl acetate as the eluent, to give 29.32 g of the title compound as a yellow oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[F:5][C:6]1[CH:11]=[C:10]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: COc1ccccc1F
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: -10 °C

Procedure:
To a stirring suspension consisting of aluminum trichloride (15.9 g) in dichloromethane (200 mL) cooled to an internal temperature of −10° C. under a nitrogen atmosphere is added 2-fluoroanisole (10 g) over one minute. Phenylacetyl chloride (11.6 mL) is subsequently added to the mixture at a rate that maintained the internal temperature below 0° C. The reaction mixture is allowed to warm to room temperature overnight. Water (100 mL) is cautiously added to the stirring mixture. The layers are subsequently separated and the dichloromethane layer is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate and washed with water, 1 M sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate 1-(3-fluoro-4-methoxy-phenyl)-2-phenyl-ethanone (14.1 g.)
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[NH:32][N:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:35]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[NH:32][N:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cc1nc(C(F)(F)F)n[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C(F)(F)F)n[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 15 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (5-trifluoromethyl-2H-[1,2,4]triazol-3-yl)-acetic acid methyl ester with heating for 5 days to afford the title compound as tan solid (24 mg, 15%). LC/MS (Method B) 3.94 min, [M+1]+ 530.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[C:18][C:21]4[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3cncc(S(N)(=O)=O)c3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (270 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (example B.1) (216 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (20 mg, 5%). MS (ISP) 495.0 [(M+H)+], 497 [(M+2+H)+]; mp 282° C.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+]([O-])=O)[CH:8]=2)[N:3]=1.ClC1C(Cl)=NC2C(=CC=CC=2)N=1.[K][S:29][C:30](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[S:31][K]>>[S:29]1[C:11]2=[N:10][C:9]3[C:4]([N:3]=[C:2]2[S:31][C:30]1=[C:33]([C:36]#[N:37])[C:34]#[N:35])=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Agent: Clc1nc2ccccc2nc1Cl
Product: N#CC(C#N)=C1Sc2nc3ccccc3nc2S1
Yield: 69 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 3.0 g of 2,3-dichloroquinoxaline and 3.95 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a light tan powder weighing 2.8 g with a calculated overall yield of 69 percent and has a melting point greater than 320° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C@@H:24]([NH:34][C:35](=[O:45])[O:36][C@H:37]1[C:41]([CH3:43])([CH3:42])[CH2:40][O:39][C:38]1=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([NH:32][CH3:33])=[O:31])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].C(N(CC)CC)C>ClCCl>[CH3:33][NH:32][C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]([NH:34][C:35](=[O:45])[O:36][C@H:37]1[C:41]([CH3:42])([CH3:43])[CH2:40][O:39][C:38]1=[O:44])[C:12](=[O:11])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])=[O:31]
Reactant: CNC(=O)NCCCC[C@H](NC(=O)O[C@@H]1C(=O)OCC1(C)C)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NCCCC[C@H](NC(=O)O[C@@H]1C(=O)OCC1(C)C)C(=O)C(=O)N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalylchloride (0.058 mL, 0.67 mmol) in anhydrous dichloromethane (2 mL) was cooled to −60° C. under nitrogen. Anhydrous dimethylsulfoxide (0.095 mL, 1.34 mmol) was then added dropwise, and the resulting solution was stirred for 10 min. A solution of (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate (150 mg, 0.30 mmol) in dichloromethane (3 mL) was then added. After 15 min, triethylamine (0.212 mL, 1.52 mmol) was added to the reaction mixture, which was kept cold for 2 min. and then allowed to warm to room temperature. After 40 min, the reaction mixture was subjected directly to column chromatography on silica gel. Elution with 10% acetone in ethyl acetate afforded (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl (1S)-5-{[(methylamino)carbonyl]amino}-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate as a colorless gum after drying under vacuum (82 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (d, J=8 Hz, 1H); 7.99 (d, J=8 Hz, 1H); 7.40-7.33 (m, 4H); 7.31-7.23 (m, 1H); 5.92-5.84 (m, 1H); 5.71-5.63 (m, 1H); 5.40 (s, 1H); 5.08-4.96 (m, 1H); 4.85-4.78 (m, 1H); 4.16 (1/2Abq, J=8 Hz, 1H); 4.06 (1/2Abq, J=8 Hz, 1H); 3.04-2.91 (m, 2H); 2.55 (part of d overlapping DMSO, 3H); 1.74-1.61 (m, 1H); 1.46 (d, J=7 Hz, 1H); 1.45-1.29 (m, 5H); 1.12 (s, 1H); 1.05 (s, 1H). ES-LCMS m/493 (M+H) HRMS C24H34N4O7 m/491.2505 (M+H)cal. 491.2490 (M+H)Obs.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[CH:12]=[N:11]1.[H-].[Na+].[H][H].Br[CH2:24][C:25]#[CH:26]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:26][C:25]#[CH:24])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[CH:12]=[N:11]1
Reactant: C#CCBr
Reactant: Cn1c(=O)cnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-n2ncc(=O)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Under a dry nitrogen atmosphere a solution of 1.0 g (0.003 mole) of 2-(2,4-dichloro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione in 15 mL of N,N-dimethylformamide was added slowly to a stirred mixture of 0.09 g (0.0037 mole) of sodium hydride in 15 mL of N,N-dimethylformamide. After complete addition, the mixture was stirred at 28° C. until hydrogen evolution ceased, then at 45° C. for 30 minutes. The reaction mixture was cooled to room temperature, and a solution of 0.57 g (0.0038 mole) of 3-bromo-1-propyne in 5 mL of N,N-dimethylformamide was added. The mixture was stirred at room temperature for approximately 18 hours, poured into water, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate by evaporation under reduced pressure to leave an oil. The oil was purified by preparative chromatography on silica gel, eluting with ethyl acetate:heptane (1:1), to yield 0.8 g of 2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (mp 119°-120° C.), Compound 20 in the tables.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1)(=[O:41])=[O:40]
Reactant: CC(Oc1ccc(CCCO)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(CCCOS(C)(=O)=O)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
A solution of (3R and 3S)-3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (0.092 g, 0.22 mmol) in dry dichloromethane (5 ml) was cooled to 0° C. and treated with triethylamine (0.07 ml, 0.5 mmol) followed by methanesulfonyl chloride (0.03 ml, 0.39 mmol). After 45 minutes at 0° C., the reaction mixture was quenched by addition of ethyl acetate (100 ml) and water. The organic phase was washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography of the residue on silica gel (elution toluene and ethyl acetate, 9:1) gave 0.090 g (82%) of the title material as an oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:29](OC)=[O:30])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]21.O1C[CH2:36][CH2:35][CH2:34]1>>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:29]([OH:30])([CH2:34][CH2:35][CH3:36])[CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reactant: C1CCOC1
Reactant: CCC[Mg]Br
Product: CCCC(O)(CCC)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
n-Propylmagnesium bromide (2.0 M solution in tetrahydrofuran, 1.2 mL, 2.4 mmol) was added to a stirred solution of methyl 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (200 mg, 0.471 mmol) in tetrahydrofuran (3.0 mL), and the mixture was stirred at 60° C. for 8 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 2-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (113 mg, 0.235 mmol, 50%).
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.F[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][S:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=2)(=[O:32])=[O:31])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(Cl)(Cl)Cl>[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][S:30]([CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N:18]5[CH2:19][CH2:20][C@H:16]([NH:15][C@@H:13]([C:3]6[C:12]7[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=7)[CH:6]=[CH:5][CH:4]=6)[CH3:14])[CH2:17]5)=[CH:37][CH:36]=4)(=[O:32])=[O:31])=[CH:24][CH:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(CCc1ccc(F)cc1)CCc1ccc(F)cc1
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: C[C@@H](N[C@H]1CCN(c2ccc(CCS(=O)(=O)CCc3ccc(N4CC[C@H](N[C@H](C)c5cccc6ccccc56)C4)cc3)cc2)C1)c1cccc2ccccc12
Temperature: 130 °C
Reaction time: 24 h
Yield: 73.7 %

Procedure:
To a solution of 150 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and 108 mg of 4-fluorophenylethylsulfone in 2 ml of DMSO was added 263 mg of potassium carbonate, and the reaction mixture was stirred at 130° C. for 1 day. To the reaction mixture was added water and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and evaporated, and then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=80:20→40:60) to obtain 132.5 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]phenylethylsulfone.