Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3-nitrophenol (8.1 g, 38 mmol) and 2-(chloromethyl)quinoline (6.0 g, 38 mmol) in DMF (100 mL) were added K2CO3 (21 g, 153 mmol) followed by KI (317 mg, 1.9 mmol). The mixture was stirred at 50° C. for 5 h. The mixture was cooled to RT, water (100 mL) was added, and the mixture was extracted with EtOAc (3×150 mL). The organics were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=9, 1H), 8.15 (d, J=9, 1H), 7.87 (d, J=9, 1H), 7.80-7.72 (m, 2H), 7.65-7.56 (m, 2H), 7.32-7.26 (m, 1H), 7.23-7.16 (m, 1H), 5.44 (s, 2H).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[OH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[C:8]#[N:9].[OH-].[Na+].C(=O)=O>O.COCCOC>[F:3][CH:2]([F:4])[O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[C:8]#[N:9]
Reactant: FC(F)Cl
Reactant: N#Cc1c(O)cccc1F
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(F)cccc1OC(F)F
Reaction time: 1 h
Yield: 47.7 %

Procedure:
6.3 g of chlorodifluoromethane were passed into a stirred mixture of 10.0 g of 2-hydroxy-6-fluorobenzonitrile, 50 ml of 1,2-dimethoxyethane and 25 ml of NaOH (33%) at 75° C. (the reflux condenser was cooled with dry ice), and stirring was continued for one hour at 70-75° C. After cooling, the batch was diluted with 300 ml of water and extracted three times using in each case 150 ml of tert-butyl methyl ether. After the solvent had been evaporated, 6.5 g of the desired product were obtained as an oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH:26]=3)=[N:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:45]=CC=C[CH:41]=1.C(O)(C)C>ClCCl>[CH:40]([O:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:32][CH2:33][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]4)[CH:26]=3)=[N:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:45])[CH3:41]
Reactant: CC(C)N1CCN(c2cc(-c3ncc(-c4cccc(O)c4)[nH]3)ccn2)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Oc1cccc(-c2cnc(-c3ccnc(N4CCN(C(C)C)CC4)c3)[nH]2)c1
Yield: 33 %

Procedure:
Diethyl azodicarboxylate (0.22 mL) was added via syringe to a solution of 1-{4-[5-(3-Hydroxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (304 mg) and triphenylphosphine (0.371 g) in a 1:1 mixture of isopropanol and dichloromethane (13 mL). The resultant solution was stirred at ambient temperature for 3 days and then washed with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (5% methanol in dichloromethane) to provide 1-{4-[5-(3-Isopropoxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (0.112 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13](=O)[CH3:14])[O:12][C:7]=2[CH:6]=1.Cl.[NH2:31][OH:32].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13](=[N:31][OH:32])[CH3:14])[O:12][C:7]=2[CH:6]=1
Reactant: NO
Reactant: CC(=O)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
7-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-acetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 93) (0.3 g) obtained in Example 15 was dissolved in ethanol (10 ml), and hydroxylamine hydrochloride (0.1 g) and 1N-sodium hydroxide (0.8 ml) were added, followed by stirring at 90° C. for 2 hours. The reaction mixture was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=2/1) to give 0.3 g of the title compound (colorless crystals).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:7](Cl)=[O:8].[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13].ClCCCl.C(=O)([O-])O.[Na+]>ClCCCl>[Cl:1][CH2:2][C:3]([NH:5][C:7](=[O:8])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:4]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(=O)CCl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
To a suspension of 2-chloroacetamide (25 g, 267 mmol) in 1,2-dichloroethane (125 mL) was added dropwise oxalyl chloride (28 mL, 321 mmol) at 0° C. After heating under reflux for 3 hr, the mixture was cooled to 0° C., tert-butyl alcohol/1,2-dichloroethane (75 mL, 1/1) was added to the mixture, and the mixture was stirred for 20 min. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with 1,2-dichloroethane. After washing with saturated aqueous sodium hydrogencarbonate solution and water, the extract was dried over anhydrous magnesium sulfate and filtrated. The solvent was evaporated under reduced pressure, and the residue was recrystallized from cyclohexane to give the title compound (25.6 g, 49%) as white crystals.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)N1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 90.8 %

Procedure:
Add acetic anhydride (0.084 ml, 0.89 mmol) to a solution of (2R,3S,5R)-5-[(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (400 mg, 0.85 mmol) in dry dichloromethane (9 mL). Add triethylamine (0.179 mL, 1.27 mmol), stir 1 hour at room temperature, concentrate and purify (silica gel cartridge chromatography, eluting with 1:1 hexanes:ethyl acetate) to give the title compound as a white solid (397 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.C([Li])(C)(C)C.[CH2:20]([N:23]1[C@@H:28]([CH3:29])[CH2:27][O:26][C:25](=[O:30])[CH2:24]1)[CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([C:25]3([OH:30])[O:26][CH2:27][C@H:28]([CH3:29])[N:23]([CH2:20][CH2:21][CH3:22])[CH2:24]3)=[CH:3][CH:4]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1ccc(Br)cn1
Reactant: CCCN1CC(=O)OC[C@@H]1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN1CC(O)(c2ccc(-n3c(C)ccc3C)nc2)OC[C@@H]1C

Procedure:
5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (1.5 g 5.9 mmol) was azeotroped with toluene and dissolved in THF (20 ml). This mixture was cooled to −78 C. and t-butyllithium (1.7M in pentane, 7 ml, 11.9 mmol) was added maintaining the temperature below −70 C. The material from example 62 was dissolved in THF (20 ml) and added to the mixture immediately on completion of the t-butyllithium addition. The mixture was allowed to stir at −78° C. for 30 minutes at which time NH4Cl (10% aq, 150ml) was added and the mixture extracted into EtOAc (200 ml), dried with magnesium sulphate, filtered and evaporated. Flash chromatography on SiO2 eluting with a stepped gradient from 25% EtOAc/pentane to 50% EtOAc/pentane gave the title compound as mixture of diastereoisomers in approximately 3.5:1 ratio as a yellow oil (480 mg).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[OH2:9]>C(O)(=O)C>[CH3:5][C:6]1[CH2:7][C:8](=[O:9])[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: O
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: CC1=NN(c2ccccn2)C(=O)C1

Procedure:
0.5 g (4.44 mmol) of 2-hydrazinopyridine and 0.58 g (4.44 mmol) of acetoacetic ester are stirred in 15 ml of glacial acetic acid for 2 hours at 90° C. The mixture is then diluted with water and the precipitated crystals are filtered off with suction, washed again with water and dried under reduced pressure.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:29][C@H:28]([OH:30])[CH2:27][C@H:19]1[C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:29][C:28](=[O:30])[CH2:27][C@H:19]1[C:20]([NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
A solution of 1.21 g (15.51 mmol) of dimethyl sulfoxide in 5 ml of methylene chloride was added to a solution of 0.98 g (7.72 mmol) of oxalyl chloride in 20 ml of methylene chloride at -50° to -60° C. After 5 minutes, a solution of 2.0 g (7.00 mmol) of (4R)-1-t-butoxycarbonyl-4-hydroxy-N-t-butyl-L-prolinamide (prepared as described in Preparation 5) in 40 ml of methylene chloride was added to the resulting mixture. The mixture was stirred for 15 minutes, after which 3.5 g (35.00 mmol) of triethylamine were added, and the mixture was stirred for a further 5 minutes. The temperature of the reaction mixture was then allowed to rise to room temperature, and the mixture was stirred for a further 1 hour. At the end of this time, the reaction mixture was poured into ice-water and extracted with methylene chloride. The organic extract was washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 1.47 g of the title compound as colorless crystals, melting at 147°-149° C.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH2:11].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:11][CH2:18][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[OH:10].[CH2:1]([Sn:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1
Reactant: CCCC[Sn](=O)CCCC
Reactant: O
Product: CCCC[Sn]CCCC
Product: OC[C@@H]1CCCC[C@H]1O
Temperature: 25 °C

Procedure:
The dibutyltin intermediate was prepared by a synthetic procedure reported in the literature. The diol 4(80.4 g, 0.61 moles) was dissolved in 1 L toluene and transferred to a three-neck, 2-L flask fitted with a mechanical stirrer, thermometer, Dean Stark trap with extension adapter, and a reflux condenser. To the stirred reaction mixture was added 153.8 g 98% purity di-n-butyltin oxide, (Bu)2SnO. The mixture was then heated to reflux to azeotrope off the water of reaction. Initially, considerable foaming resulted and care was taken to prevent overflow into the Stark trap. The last traces of H2O were slowly removed at reflux (4 to 5 hr); total H2O collected: ˜11 mL. The mixture (a deep orange-brown color) was cooled to room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[C:19](Cl)(=[O:23])[C:20](Cl)=O.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:11][C:10]2[CH:9]=[CH:8][C:28]([C:29]([O:23][CH2:19][CH3:20])=[O:25])=[CH:27][CH:26]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (600 mg), oxalyl chloride (260 μL), tetrahydrofuran (10 mL) and N,N-dimethylformamide (2 drops) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated and diluted with N,N-dimethylacetamide (10 mL). Ethyl 4-aminobenzoate (482 mg) was added and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into a 0.1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate, and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from acetone-hexane to give ethyl 4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzoate (810 mg, yield 84%) as colorless needle crystals. melting point: 202-203° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][CH2:23][C@@H:24]([OH:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: NC[C@@H](O)c1ccccc1
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NC[C@@H](O)c3ccccc3)cnc21

Procedure:
Intermediate 48 was prepared from Intermediate 17 and (1S)-2-amino-1-phenylethanol (commercially available from Fluka) using an analogous method to that for Intermediate 42. LCMS showed MH+=410; TRET=2.62 min.
Reaction SMILES: [Pd:1].[C:2]([OH:5])(=[O:4])[CH3:3]>O>[C:2]([O-:5])(=[O:4])[CH3:3].[Pd+2:1].[C:2]([O-:5])(=[O:4])[CH3:3]
Reactant: CC(=O)O
Reactant: [Pd]
Solvent: O
Product: CC(=O)[O-]
Product: [Pd+2]
Yield: 95 %

Procedure:
The procedure of Example 6 was followed except that the reaction mixture was made up of 0.2 g. of palladium sponge, 42 g. of glacial acetic acid and 2 drops of distilled water. The reaction temperature was from 65°-70° C. and NO was bubbled slowly through the mixture under these conditions over a 20-25 minute period, during this time the mixture was periodically flushed with oxygen. All the palladium sponge dissolved during this time to give an orange-red solution which upon concentration afforded orange-red crystals of trimeric palladium acetate in 95% yield. The crystals were soluble in benzene and toluene and showed a sharp infrared band at 1600 cm-1.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]([SH:12])=[N:6][C:7]([SH:11])=[N:8][C:9]=1[NH2:10].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.O>CO>[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:11][C:7]1[N:8]=[C:9]([NH2:10])[C:4]([NH2:3])=[C:5]([S:12][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[N:6]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1nc(S)nc(S)c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc(SCc2cccc(F)c2F)nc(SCc2cccc(F)c2F)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of potassium hydroxide powder (7.72 g) in methanol (250 ml) was added first 5,6-diamino-2,4-pyrimidinedithiol (10.9 g) followed by 2,3-difluorobenzyl bromide (22.5 g). The reaction mixture was stirred for one hour at room temperature then poured into water (500 ml), giving a brown precipitate. This was isolated by filtration, washing with isopropanol and diethyl ether, to give the subtitled compound as a pale brown solid (15.0 g).
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8]([CH2:19][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[OH:29]>CO>[C:27]([O:25][CH2:24][C:21]([NH:20][CH2:19][C:8]1[CH:7]=[C:6]2[C:15](=[C:14]3[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:16]=[CH:17][C:18]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=1)([CH3:26])[CH2:22][OH:23])(=[O:31])[CH:28]([CH3:30])[OH:29]
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CC(O)C(=O)O
Solvent: CO
Product: CC(O)C(=O)OCC(C)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Yield: 44.1 %

Procedure:
A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol free base (1D) (3.45 g, 10 mmol) and lactic acid (Fisher Scientific Co., 711 Forbes Ave., Pittsburgh, PA, 15219, 85% liquid, 1.04 g, 10 mmol) in CH3OH (500 mL) was brought to reflux and filtered through a glass fritted funnel. The solvent was removed by rotary evaporation to give a crude white solid. This was crystallized (CH3OH/Et2O) 3x to give 1.84 g (42.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol lactate mp 163°-164°. (C,H,N).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[NH:23][CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1.N[C@H:27](C(O)=O)CCSC>CN(C=O)C.O>[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[N:23]([CH3:27])[CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc2[nH]ccc12
Reactant: CSCC[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(NC(=O)c3c(N)nn4cc(F)cnc34)cncc21
Yield: 19 %

Procedure:
NaH (3.958 mg, 0.09894 mmol) was added to a suspension of 2-amino-6-fluoro-N-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (28 mg, 0.08995 mmol) (synthesized according to a procedure similar to Example 1 or Example 3a) and Met (11.49 mg, 5.039 μL, 0.08096 mmol) in DMF (3 mL) under N2. The suspension was stirred at RT for 5 h before water (2 drops) was added. The crude mixture was purified by fractionlynx HPLC. Clean fractions were liophilized to yield 2-amino-6-fluoro-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (5 mg, 16%). MS (ES+) 326.1.
Reaction SMILES: [I-:1].[CH2:2]1[CH2:28][O:27][CH:5]([CH2:6][CH2:7][P+:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([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)[CH2:4][O:3]1.[CH2:29]([Li])CCC.[I-].[PH4+].C1COC(CC=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CO1.CI>O1CCCC1.CCCCCC>[I-:1].[CH2:2]1[CH2:28][O:27][CH:5]([CH2:6][CH:7]([P+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:29])[CH2:4][O:3]1
Reactant: c1ccc([P+](CCC2COCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: [Li]CCCC
Agent: C(CC1COCCO1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [PH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(CC1COCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
1.51 G (3.0 mmol) of finely powdered (4-ethylenedioxybutyl)-triphenyl-phosphonium iodide are suspended in 10 ml of tetrahydrofuran and treated dropwise with a solution of 4.5 mmol of butyl-lithium in hexane. The solution turns red as the phosphonium iodide goes into solution as (4-ethylenedioxy-butylidene)-triphenyl-phosphorane. After approximately 10 minutes, 0.25 ml (4.5 mmol) of methyl iodide are added to this solution, which thereby becomes lighter, and the (4-ethylenedioxy-1-methylbutyl)-triphenyl-phosphonium iodide which is formed partially precipitates as an oil. After 10 minutes, 3.0 mmol of butyl-lithium in hexane are added dropwise and the solution thereby again becomes dark red.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]([C:18]2[C:19]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=3[CH:37]=2)[CH:13]=[CH:14][C:15]=1[O:16]C.B(Br)(Br)Br.O>ClCCl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[O:25][C:21]3[CH:20]=[C:19]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:40])=[O:41])[C:18]([C:12]4[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([C:2]5[NH:1][C:9]6[C:4]([CH:3]=5)=[CH:5][CH:6]=[CH:7][CH:8]=6)[CH:11]=4)=[CH:37][C:22]=3[C:23]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:27][CH:28]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(-c4cc5ccccc5[nH]4)c3)cc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5ccccc5[nH]4)c3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.1 %

Procedure:
To a solution of 5-(3-(1H-indol-2-yl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 g, 0.16 mmol) in dichloromethane (2 mL) was added dropwise BBr3 (0.2 mL) at 0° C., Then warmed up to room temperature and stirred for 5 hours. Water was added, extracted with dichloromethane and washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using Prep-TLC to provide the product of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(1H-indol-2-yl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 31%). 1H-NMR (CDCl3, 400 MHz) δ 9.30 (s, 1H), 8.75 (s, 1H), 7.79˜8.30 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.37 (d, J=1.6 Hz, 1H), 6.91˜7.19 (m, 7H), 6.65 (d, J=1.2 Hz, 1H), 6.01 (d, J=4.4 Hz, 1H), 2.95 (d, J=4.8 Hz, 3H), 2.61 (s, 3H), 2.43 (s, 3H). MS (M+H)+: 584.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:35](=[O:36])[O:37][CH3:38])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(NC(=O)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg, 0.24 mmol) and triethylamine (0.10 mL, 0.72 mmol) in tetrahydrofuran (5.0 mL) was added methyl chloroformate (0.0377 mL, 0.488 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 35-65% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (31.5 mg, 0.067 mmol, 28%) as colorless crystals.