Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[N:5][N:6]([CH2:8][C:9]2[NH:10][C:11](=[O:19])[C:12]3[CH:17]=[C:16]([CH3:18])[S:15][C:13]=3[N:14]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[CH3:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([CH2:8][N:6]3[CH:7]=[C:3]([CH2:2][NH:1][C:33](=[O:35])[CH3:34])[C:4]([C:20]([F:22])([F:21])[F:23])=[N:5]3)[NH:10][C:11](=[O:19])[C:12]=2[CH:17]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(CN)c(C(F)(F)F)n3)nc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1cn(Cc2nc3sc(C)cc3c(=O)[nH]2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-(aminomethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.087 mmol, 30 mg) and DIPEA (0.175 mmol, 0.029 ml, 22.59 mg) in DCM (1 mL) was added acetyl chloride (0.175 mmol, 0.012 ml, 13.72 mg). The whole was stirred at room temperature overnight before the reaction mixture was concentrated under reduced pressure and the residue purified by reverse phase HPLC to give a white solid (8.7 mg, 23 mmol. 25.8%)
Reaction SMILES: [CH2:1]([O:9][C:10](=[O:20])[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10](=[O:20])[CH:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][O:13][C:27](=[O:29])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCOC(=O)C(CO)c1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)C(COC(C)=O)c1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
To 60.4 g of 3-hydroxy-2-phenyl-propionic acid octyl ester in 150 ml of toluene is added at 4° C. 22.9 g (290 mmol) of pyridine followed by 22.8 g (290 mmol) of acetyl chloride dissolved in 50 ml of toluene. The reaction mixture is stirred for 2 hours at 4° C. The white precipitate is filtered off and washed with 100 ml of toluene to afford 70.5 g of 3-acetoxy-2-phenyl-propionic acid octyl ester used as crude material in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:26]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH2:2][C:3]2[CH:23]=[CH:22][C:6]([CH2:7][N:8]3[CH2:13][CH2:12][C:11]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14]4)[CH2:10][CH2:9]3)=[CH:5][CH:4]=2)[CH:28]=[CH:27][C:26]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: BrCc1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN3CCC4(CCc5ccccc54)CC3)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 1′-[4-(bromomethyl)benzyl]-2,3-dihydrospiro[indene-1,4′-piperidine] (0.35 g, 0.94 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.2 g, 0.94 mmol) and K2CO3 (0.32 g, 2.3 mmol) in DMF (15 mL) is stirred overnight at room temperature. The reaction mixture is diluted with cold water and extracted with DCM (3×50 mL). The combined organic layer is washed with brine solution, dried over Na2SO4, and concentrated under vacuum. The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2) to give the title compound as an off-white solid (0.22 g, crude). ESI/MS 502 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:31]=3)[CH2:26][CH2:25]2)=[O:19])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)CC(=O)N1
Product: CC1=C(C(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)C(c2ccc(F)c(F)c2)CC(=O)N1

Procedure:
Prepared by Procedure AC and Scheme AM using 4-(3,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:15][CH2:16][CH2:17][N:18]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:19][CH2:20][C:21](O)=[O:22])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:27]([O:26][C:24]([N:18]1[CH2:19][CH2:20][C:21](=[O:22])[N:15]([C@H:4]([C:3]([O:2][CH3:1])=[O:34])[CH2:5][CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:16][CH2:17]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Reaction time: 15 h

Procedure:
A solution of 4.40 g (8.64 mmol) of (S)-4-benzyloxy-2-{2-[benzyloxycarbonyl-(2-carboxy-ethyl)-amino]-ethylamino}-butyric acid methyl ester; hydrochloride in 85 ml dichloromethane was treated with 1.20 (8.64 mmol) of triethylamine and at 0° C. with 1.99 g (10.37 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. The cooling bath was allowed to come to room temperature and after 15 h the reaction was extracted with 10% aq. potassium hydrogensulfate solution/diethyl ether (3×). The organic phases were washed with 10% aq. potassium hydrogensulfate solution, 10% sodium chloride solution and dried over Na2SO4 to yield after evaporation of the solvent 3.74 g (95%) of the title compound as a light yellow oil. MS: 455.2 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:4].S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([Cl:19])=[O:9])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C(=O)Oc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
6 g (27 mmol) of 2-(2,2-dimethylpropionyl-oxy)benzoic acid are dissolved in 60 ml of dichloromethane with a few drops of pyridine. 2.4 ml (32 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. 6.8 g of 2-(chlorocarbonyl)phenyl 2,2-dimethylpropanoate are obtained in a quantitative yield.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Cl.Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][N:30]=2)[N:3]=1
Reactant: FC(F)(F)c1ccc(CCl)nc1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccc(C(F)(F)F)cn1
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
To a round bottom flask was added 3-iodo-4-nitro-1H-indazole (0.580 g, 2.01 mmol) and CH3CN (10 mL). 2-tert-Butyl-1,1,3,3-tetramethylguanidine (0.890 mL, 4.41 mmol) was added and the mixture was stirred for 5 minutes. 2-(Chloromethyl)-5-(trifluoromethyl)pyridine hydrochloride (0.512 g, 2.21 mmol) was added as a CH3CN solution (4 mL) and the mixture was stirred at ambient temperature overnight. The mixture was concentrated and diluted with saturated aqueous NH4Cl (20 mL) and EtOAc (60 mL). The layers were mixed and separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (50% EtOAc/hexane) to provide 0.490 g (54%) of the product as an orange solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:30][CH2:31][CH:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:27][CH2:28]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: COc1ccccc1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccccc1C1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-(2-methoxy-phenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=413.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([NH2:17])[N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[CH:21][CH:20]=3)[CH:12]=2)=[CH:7][CH:6]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:32][C:28]1[CH:27]=[C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:13]3[CH:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:6][CH:7]=4)[N:16]=[C:15]([NH2:17])[N:14]=3)=[CH:20][CH:21]=2)[CH:31]=[CH:30][N:29]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(OCCBr)cc4)nc(N)n3)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(OCCN5CCCC5)cc4)nc(N)n3)cc2)ccn1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step 3 (1 equiv), pyrrolidine (2 equiv) and K2CO3 (8 equiv) in DMF is stirred at 65° C. overnight. The solvent is removed and the residue is dissolved in EtOAc. The organic solution is washed with water, dried, and evaporated to dryness. The residue is purified by chromatography on a silica column to afford the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:5])[CH3:4].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23](Cl)=[O:24])[S:22][C:15]=12>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([O:1]/[N:2]=[C:3](\[NH2:5])/[CH3:4])=[O:24])[S:22][C:15]=12
Reactant: CC(N)=NO
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C/C(N)=N/OC(=O)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
A 100 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 6 drops of DMF. Oxalyl chloride (0.248 ml, 2.85 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours then concentrated in vacuo to yield 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride as a brown solid. This material was suspended in chloroform (5 mL). N′-hydroxyacetamidine (0.186 g, 2.50 mmol), triethylamine (0.347 ml, 2.50 mmol), and chloroform (15 mL) were stirred together in a 50 mL flask to form a slurry, which was slowly added to the 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride suspension, then stirred for 1.5 hours at room temperature. The reaction mixture was diluted with chloroform (50 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was triturated with toluene, and the precipitate collected to obtain the title compound (0.282 g, 46% yield) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](Br)=[O:21].O>CN(C)C=O>[Br:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]2[O:11][CH2:19][C:20](=[O:21])[NH:1][C:2]=2[C:7]=1[CH3:8]
Reactant: O=C(Br)CBr
Reactant: Cc1c(Br)cc(F)c(O)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(F)c2c1NC(=O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
An ice cold suspension of 2-amino-4-bromo-6-fluoro-3-methylphenol (647 mg) and potassium carbonate (1.526 g, 11.04 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was treated by dropwise addition of 2-bromoacetyl bromide (0.320 mL, 3.67 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was treated slowly with water (10 mL+10 mL), then poured into water (50 mL) and stirred to form a suspension which was passed through a fine glass frit and dried in vacuo to give the crude product as a yellow solid. The solid was washed with cold isopropanol and dried in vacuo to provide 6-bromo-8-fluoro-5-methyl-2H-benzo[b][1,4]oxazin-3(4 H)-one (510 mg) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) d=7.83 (br. s., 1 H), 7.10 (d, J=9.6 Hz, 1 H), 4.65 (s, 2 H), 2.30 (s, 3 H). LC/MS (m/z) ES+=259.99 (M+1).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.[C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[CH:16][CH2:15][CH2:14]2)#[N:10].O>CS(C)=O.C(Cl)Cl>[C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[CH:16][CH2:15][CH2:14]2)(=[O:2])[NH2:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(c1)CCC=C2n1ccnc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c(c1)CCC=C2n1ccnc1
Reaction time: 24 h

Procedure:
Potassium carbonate and 30% aqueous H2O2 solution are added several times, within a period of 24 hours, to 6-cyano-1-(1-imidazolyl)-3,4-dihydronaphthalene (Example 1) in DMSO and CH2Cl2. Finally, water is added and the solid is filtered off, yielding the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[Na].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(Cl)n1
Agent: [Na]
Product: Nc1nc(N)c([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 160 °C

Procedure:
2,4-Diamino-6-chloro-5-nitropyrimidine (O'Brien et. al., J. Med. Chem., 9, 573-575 (1966)) (1.0 g, 5.28 mmol) was added to a solution of sodium (0.14 g, 6.008 mmol) in benzyl alcohol (9 mL). The solution was heated in a 160° C. oil bath for 3.5 h and the solvent was evaporated under reduced pressure to provide a yellow solid. This solid was washed with water, and air dried. Crystallization from benzene/ether gave a pale yellow filamentous solid: yield, 0.69 g (50%); mp 194-195° C. (171° C.; Kosary et. al., Acta. Pharm. Hung., 49, 241-247 (1989)); UV (pH 1) λmax 236 nm (sh) (ε=1.452×104), 264 (0.522×104), 321 (1.294×104); (pH 6.9) 242 (sh) (0.965×104), 337 (1.493×104); (pH 13) 242 (sh) (0.952×104), 338 (1.479×104); 1H NMR δ 5.43 (s, 2H, ArCH2), 7.26 (br s, 2H, NH2, exchange with D2O), 7.33-7.51 (m, 5H, ArH), 7.93 (br s, 2H, NH2, exchange with D2O); MS (EI) calcd. m/z for C11H11N5O3 261.0861, found 261.0866; Anal. (C11H11N5O3).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:29][C:28]=4[CH3:42])[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])C.[OH-].[Na+]>CCO>[CH3:42][C:28]1[CH:29]=[C:30]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=[C:32]([CH3:33])[C:27]=1[C:25]1[N:26]=[C:21]2[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:13]3[CH:12]=[CH:11][C:10]([C@@H:6]([C:7]#[C:8][CH3:9])[CH2:5][C:4]([OH:43])=[O:3])=[CH:15][CH:14]=3)=[CH:23][N:22]2[N:24]=1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4C)nn3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCc2ccc3nc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4C)nn3c2)cc1
Temperature: 50 °C
Yield: 54.7 %

Procedure:
To a solution of (S)-3-(4-{2-[4-(3-methanesulfonyl-propoxy)-2,6-dimethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester (0.145 g, 0.238 mmol) in EtOH (5 mL) is added 5 N NaOH solution (0.14 mL, 0.715 mmol) at room temperature and the reaction mixture is heated at 50° C. for 30 minutes. The reaction mixture is evaporated and the residue is dissolved in water (5 mL), washed with ether (2×5 mL), and acidified with aqueous citric acid solution (pH-6) at 0° C. The precipitate solid is filtered and dried to give the title compound as an off-white solid (0.075 g, 55%). LCMS m/z 576 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21]2)=[O:6]
Reactant: c1ccc2c(c1)CCCO2
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)CCCO2)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (1.0 g, 3.06 mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl chloride (0.44 mL, 4.59 mmol) at 0° C. After complete addition, the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure, and the crude product was dissolved in DCM (4 mL) and added to chroman (488 mg, 3.67 mmol) which had been cooled to 0° C. To this mixture was added aluminum chloride (488 mg, 3.67 mmol) in portions. After stirring for 4 h, the reaction was quenched by pouring it into crushed ice. This was extracted with dichloromethane (50 mL×2). The dichloromethane layers were combined and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL×2), and brine (20 mL), then dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to furnish (2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[C@H:10]([OH:32])[CH2:11][NH:12][C@@H:13]2[C:22]3[C:17](=[C:18](Cl)[N:19]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=3)[O:16][C:15]3([CH2:31][CH2:30][CH2:29]3)[CH2:14]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.[F:73][C:74]([F:78])([F:77])[CH2:75][OH:76]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:20]1[CH:21]=[C:22]2[C@@H:13]([NH:12][CH2:11][C@@H:10]([OH:32])[C@@H:9]([NH:33][C:34](=[O:38])[CH2:35][O:36][CH3:37])[CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:14][C:15]3([CH2:31][CH2:30][CH2:29]3)[O:16][C:17]2=[C:18]([O:76][CH2:75][C:74]([F:78])([F:77])[F:73])[N:19]=1
Reactant: OCC(F)(F)F
Reactant: COCC(=O)N[C@@H](Cc1cccc(F)c1)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COCC(=O)N[C@@H](Cc1cccc(F)c1)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2OCC(F)(F)F
Temperature: 110 °C

Procedure:
To a flame-dried microwave vial under Ar gas was added N-((1S,2R)-1-((3-fluorophenyl)methyl)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide (100 mg, 182 μmol), cesium carbonate (357 mg, 1095 μmol), DavePhos (79 mg, 201 μmol), palladium(II) acetate (41 mg, 182 μmol) were added and vial was flushed with N2 5×, then 2,2,2-trifluoroethanol (332 μl, 4561 μmol) and toluene (1 mL) were added simultaneously. The reaction was heated in the microwave at 110° C. for 30 min. The reaction mixture was filtered through a small plug of silica gel, and the residue purified by reverse phase HPLC to give the title compound as a tan amorphous solid. MS m/z: 612.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(O)[C:11]3[CH:10]=[C:9]4[C:27]5[C:32]([C:33]([CH3:35])([CH3:34])[C:8]4=[CH:7][C:6]=3[C:5]([C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][CH:38]=3)(O)[C:4]=2[CH:3]=1)=[CH:31][CH:30]=[CH:29][CH:28]=5.[I-].[K+].[PH2]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][CH:38]=3)[C:6]3[CH:7]=[C:8]4[C:33]([CH3:35])([CH3:34])[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:9]4=[CH:10][C:11]=3[C:12]=2[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)C(O)(c1cccc2ccccc12)c1cc(Br)ccc1C3(O)c1cccc2ccccc12
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2cc3c(-c4cccc5ccccc45)c4ccc(Br)cc4c(-c4cccc5ccccc45)c3cc21
Reaction time: 5 h
Yield: 57.7 %

Procedure:
9-bromo-13,13-dimethyl-6,11-di(naphthalen-1-yl)-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (11.87 g, 0.018 mol), potassium iodide (29.88 g, 0.18 mol), and sodium hypophosphite (35.63 g, 0.297 mol) were placed in a flask, and were suspended in acetic acid (300 ml). The reaction mixture was stirred for five hours while heating. After the reaction was terminated, the reaction solution was added to an excess of distilled water. The resultant solid was washed with distilled water, filtered, and purified by column chromatography to give 9-bromo-13,13-dimethyl-6,11-di(naphthalen-1-yl)-13H-indeno[1,2-b]anthracene (6.5 g, yield=57%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=3[C:6]=2[CH:17]=1.CO[C:20]1([CH:27](OC)OC)[CH2:24][CH2:23][CH:22](OC)[O:21]1>C(O)(=O)C>[CH:22]([C:23]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]3[CH:14]=[CH:13][C:12]4[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=4[C:6]=3[CH:17]=2)[CH:27]=[CH:20][CH:24]=1)=[O:21]
Reactant: Nc1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Reactant: COC1CCC(OC)(C(OC)OC)O1
Solvent: CC(=O)O
Product: O=Cc1cccn1-c1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Yield: 26.6 %

Procedure:
7.0 g (30.8 mmol) of 9-aminobenzo[f]quinoxaline-2,3(1H,4H)-dione and 6.4 g (30.8 mmol) of 2,5-dimethoxy-2-(1,1-dimethoxymethyl)tetrahydrofuran were refluxed in 170 ml of glacial acetic acid for 30 minutes. The precipitate was filtered off with suction and purified by chromatography on silica gel (mobile phase: toluene/acetone/glacial acetic acid=10/10/1). 2.5 g (27%) of the product were obtained. Melting point >250° C.