Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[Cl:31])[CH:19]=[CH:18][C:17]=2[F:32])([CH2:14][F:15])[N:13]=1)(C)(C)C>Cl.O1CCOCC1.Cl.CO>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]2[CH:19]=[CH:18][C:17]([F:32])=[C:16]([C:12]3([CH2:14][F:15])[CH2:11][O:10][CH2:9][C:8]([NH2:7])=[N:13]3)[CH:21]=2)=[C:25]([Cl:31])[CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cc(NCc3ccc(Br)cc3Cl)ccc2F)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1=NC(CF)(c2cc(NCc3ccc(Br)cc3Cl)ccc2F)COC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
{5-[5-(4-Bromo-2-chloro-benzylamino)-2-fluoro-phenyl]-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl}-carbamic acid tert-butyl ester (82 mg, 0.151 mmol) were suspended in 1.1 ml HCl/Dioxane (4M). A few drops HCl/MeOH (3M) were added and the mixture was stirred at 50° C. for 2 h. The mixture was evaporated, taken up in 10% aq soda, extracted with DCM and dried with Na2SO4. The title compound was purified via chromatography on silica gel [DCM/1-5%(MeOH/DCM 10:90)]. The product was dissolved in Et2O and precipitated as its hydrochloride salt by adding 1N HCl/Et2O.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14].[Br:17]Br.[O-]S([O-])=O.[Na+].[Na+]>[Fe].C(Cl)Cl>[CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([Br:17])[CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COc1ccccc1OCC(C)C
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)COc1ccc(Br)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,2-Bis(-2-methylpropyloxy)benzene (359.61 g, 1.62 mol) and 500 ml of CH2Cl2 were placed in the reaction vessel and admixed with a little iron powder. While cooling, bromine (266.88 g, 1.78 mol) (mixed with about 200 ml of CH2Cl2) was slowly added dropwise. The mixture was stirred for about 20 hours at room temperature. For the work-up, the mixture was stirred with aqueous Na2SO3 solution and the iron powder was subsequently filtered off. The organic phase was then shaken twice with NaHCO3 solution and subsequently washed with water until neutral. After drying, the organic phase was evaporated.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[N:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=[O:33])[CH:26]=[C:27]([Cl:29])[CH:28]=1>C1COCC1.C1CCCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[C:31]([CH:32]([OH:33])[CH:1]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:34][CH:35]=[CH:36][N:37]=2)[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: O=Cc1cccnc1-c1cc(Cl)cc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OC(c1cccnc1-c1cc(Cl)cc(Cl)c1)C(c1cccnc1)c1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,3′-methylenedipyridine (340 mg, 1.99 mmol) in THF (20 mL) at −78° C. was treated with lithium diisopropylamide (2.65 mL of a 1.5 M solution of the mono-THF complex in cyclohexane, 3.98 mmol) dropwise. After stirring at −78° C. for 30 min, 2-(3,5-dichlorophenyl)nicotinaldehyde (500 mg as a solution in 6 mL THF, 1.99 mmol) was added dropwise via syringe. The reaction mixture was stirred for 1 h at −78° C., warmed to 0° C. over 5 min, then quenched with the addition of 100 mL H2O. The mixture was extracted with EtOAc (3×60 mL) and organic extracts were pooled, dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (40 g SiO2, 0-10% MeOH/CH2Cl2 gradient elution) to provide racemic 1-[2-(3,5-dichlorophenyl)pyridin-3-yl]-2,2-dipyridin-3-ylethanol. Resolution was performed by HPLC using a chiral stationary phase (ChiralPak AD, 5 cm×50 cm, 20μ, 40-100% i-PrOH/hexanes gradient elution modified with 1 mL/L diethylamine, 80 mL/min) and provided the title compound.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41](S([O-])(=O)=O)C>>[C:1]1([CH:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH2:8][CH3:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCS(=O)(=O)[O-]
Reactant: CC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1

Procedure:
7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-phenyl-ethyl)-amide, ethanesulfonate;
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[O:4].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CCN(CC)CC>CC(C)=O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:17]1[CH:18]=[CH:19][C:20]([O:23][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[CH:21][CH:22]=1)[N:5]([C:3](=[O:4])[C:2]([F:1])([F:24])[F:25])[CH2:14][CH2:13]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(O)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 115.4 %

Procedure:
A solution of 2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (3.387 g, 9.64 mmol), p-toluenesulfonyl chloride (2.206 g, 11.6 mmol) and Et3N (1.6 ml, 11.6 mmol) in acetone (50 ml) was refluxed under N2 for 5 hr, then concentrated in vacuo. The remaining residue was suspended in H2O (100 ml) and extracted with CHCl3 (4×75 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give 5.622 g of orange oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 4.383 g (90% yield) of white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[N:30]1[CH:35]=[C:34]([CH:36]=O)[CH:33]=[N:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:36][C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: O=Cc1cncnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(Cc5cncnc5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (45 mg, 0.1 mmol) and pyrimidine-5-carbaldehyde (32 mg, 0.3 mmol) in DCM (1.5 mL) was added NaBH(OAc)3 (64 mg, 0.3 mmol), followed by addition of AcOH (12 uL). After stirring at room temperature in a sealed vial for 16 h, the reaction was quenched with EtOAc (50 mL). The reaction mixture was sequentially washed with water (10 mL), brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica chromatography (0-10% MeOH in EtOAc gradient with 1% NH3 in MeOH additive) to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(pyrimidin-5-ylmethyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; 1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 8.81 (s, 2H), 8.00 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz, 1H), 6.23 (br s, 1H), 3.65 (s, 2H), 3.03 (m, 2H), 2.76 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.25 (m, 2H), 1.80-1.68 (m, 4H); ESMS m/z 508.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=1.O>CS(C)=O>[CH3:1][C:2]1[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2ccnc2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
In DMSO (5 mL) was dissolved 2-methyl-1H-imidazole (575 mg, 7.00 mmol). To the solution 60% sodium hydride (in oil) (323 mg, 8.08 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 minutes. Ethyl 6-chloronicotinate (1.00 g, 5.39 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=97/3) to give ethyl 6-(2-methyl-1H-imidazol-1-yl)nicotinate (455 mg, 37% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].S(=O)(=O)([OH:35])N.Cl([O-])=O.[Na+]>O.C1COCC1.CCOCC>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:15])=[O:16])[C:10]([OH:35])=[O:11]
Reactant: COC(=O)c1cc(C=O)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)O)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of 317 mg (0.7 mmol) of the product of Example 268 and 102 mg (1.05 mmol) of sulfamic acid in 40 ml of water:THF (3:1) was added 98 mg (1.08 mmol) of sodium chlorite. The resulting mixture stirred for 2 hr, diluted with ether, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 325 mg (99%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec 468 (M-H).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:31])([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH3:20]>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:31])([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH3:20])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=NC(C)(C)c1ccc2ccccc2c1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccc3ccccc3c2)CO1
Yield: 37.6 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g), N-methylene-1-methyl-1-(2-naphthyl)ethylamine (0.60 g) and xylene (3 ml) was heated at reflux for 20 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.40 g).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:16][CH2:15]2)=[C:9]([Br:17])[CH:8]=1)=[O:6])C.[OH-].[Na+].O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:17][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[C:4]([OH:18])=[O:3])[CH:12]=[CH:11][C:10]=1[S:13][CH:14]1[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(=O)c1ccc(SC2CC2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)C(=O)c1ccc(SC2CC2)c(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A solution of ethyl[3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetate (30 g) in toluene (60 mL) was heated to 50° C., and a 3 M aqueous sodium hydroxide solution (36 mL) was added thereto at an internal temperature of 60° C. or lower, followed by stirring at 50° C. for 1 hour. After leaving it to be cooled at room temperature, water (150 mL) and ethyl acetate (100 mL) were added to the reaction mixture. To the aqueous layer was added concentrated hydrochloric acid (12 mL) under ice-cooling, followed by extraction with ethyl acetate (100 mL×3). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was sequentially washed with hexane/ethyl acetate (19/1, 200 mL) and diethyl ether/hexane (1/2, 200 mL) to obtain [3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetic acid (14.7 g) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:27]([OH:29])=[O:28])(O)=[O:2].FC1C=C2[C:37](=CC=1)[N:36](CC1C3C(=CC=C(F)C=3)C=CC=1)[C:35]1C(=O)OC(=O)CC2=1.CNC>>[CH3:35][N:36]([CH3:37])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:27]([OH:29])=[O:28])=[O:2]
Reactant: O=C1Cc2c(n(Cc3cccc4ccc(F)cc34)c3ccc(F)cc23)C(=O)O1
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccc(F)cc12
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
3-Carboxymethyl-5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (from Example 97) was converted to 6-fluoro-9-(7-fluoro-naphthalen-1-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was converted according to Example 68.2. but using dimethyl amine to give the title compound as a white solid. MS: 421.0 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:24]=[CH:25]/[CH2:26][OH:27])[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][C:16]=1[CH3:17])[CH3:11]>[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([C:12]1[N:13]=[C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:15][C:16]=1[CH3:17])[CH3:11])[CH:24]=[CH:25][CH:26]=[O:27]
Reactant: COc1cc(/C=C/CO)ccc1OC(C)c1nc(-c2ccccc2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Product: COc1cc(C=CC=O)ccc1OC(C)c1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Reference Example 35, (E)-3-[3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propen-1-ol was subjcted to oxidation reaction with activated manganese dioxide to yield 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamaldehyde, which was recrystallized from acetone-isopropyl ether to give colorless needles, m.p.152-153° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>C(Cl)Cl>[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)=[O:20])([O-:15])=[O:14]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
Under an inert atmosphere, to a stirred solution of methyl 4-(aminomethyl)benzoate (50 g, 0.436 mol) and TEA (210 mL, 1.5 mol) in anhydrous DCM (1.0 L) was added a solution of freshly prepared 3-nitro benzoyl chloride (0.59 mol) in DCM (250 mL). The resulting mixture was allowed to stir for 2 hrs. The reaction was quenched with a 10% aqueous solution of sodium hydrogenocarbonate. The organic layer was washed with a 1.5N HCl solution and water. After drying over MgSO4 and evaporation of the solvent in vacuo, a solid was obtained and purified by flash chromatography to give the title compound (50 g) in a 52% yield as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].CC1C=CC(S(O[CH2:35][C@H:36]2[CH2:40][CH2:39][CH2:38][O:37]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:35][C@H:36]5[CH2:40][CH2:39][CH2:38][O:37]5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione was obtained (32%) as a colorless solid: mp>250° C. (toluene/hexanes); 1H NMR (300 MHz, CDCl3) δ7.38-7.29 (m, 1H), 7.17-7.03 (m, 3H), 6.90-6.85 (m, 1H), 6.40-6.28 (m, 1H), 4.99-4.92 (m, 1H), 4.75-4.67 (m, 1H), 4.36-4.25 (m, 1H), 4.01-3.67 (m, 4H), 3.25-3.21 (m, 3H), 2.14-1.85 (m, 3H), 1.79-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.6, 157.0, 156.9, 155.0, 143.5 (2C), 143.1, 142.6, 132.2, 131.9, 129.3, 129.2, 126.2, 124.1, 123.8, 123.6, 109.8, 109.8, 103.1, 103.0, 94.7 (2C), 80.5, 80.4, 77.1, 76.3, 68.4, 68.2, 58.2 (2C), 45.0, 44.7, 29.3, 29.2, 28.3, 28.2, 25.7; MS (ES+) m/z 393.0 (M+1).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH2:2]([N:9]([CH2:21][CH:22]([OH:20])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1ccccc1OCC1CO1
Reactant: Oc1ccc(OCCNCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Oc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2F)cc1

Procedure:
A mixture of N-benzyl-2-p-hydroxyphenoxyethylamine hydrochloride (5.6 g), 1,2-epoxy-3-o-fluorophenoxypropane (3.6 g) and anhydrous potassium carbonate (2.7 g) was heated under reflux in propan-2-ol (100 ml) for 24 hours. The reaction mixture was cooled, the solid removed by filtration and the solvent evaporated from the filtrate. The residual oil was purified by chromatography on silica eluting with 1% v/v methanol in dichloromethane to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-3-o-fluorophenoxy-2-hydroxypropylamine as a colourless oil; NMR: 2.27-3.15 (m, 4H, CH2NCH2), 3.8 (dd, 2H, NCH2Ph), 3.9-4.2 (m, 5H, OCH2.CHOH, o-F-Ph.OCH2), 6.7 (s, 4 aromatic H), 6.8-7.1 (m, 4 aromatic H), 7.3 (m, 5H, CH2Ph).
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:41]([NH:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)C#Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (12 mg, 0.026 mmol) in CH2Cl2 (1 mL) was added triethylamine (50 μL) and acetic anhydride (10 μL) and trace DMAP. After 30 min, the reaction mixture was filtered and purified by reverse phase HPLC (MeCN/H2O w/0.1% TFA) to give 10 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 7.27 (s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.90 (s, 3H), 1.61 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33ClNO4: 506.2; found: 506.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:20][CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 998.8 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.11 g, 10 mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (50 ml) was added with N*1*,N*1*-dimethyl-ethane-1,2-diamine (968 mg, 11 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (5 g, 26 mmol) and 1-hydroxybenzotriazol (1.5 g, 11 mmol) in an ice-water bath. Upon completion of the addition, the mixture was stirred at room temperature overnight, added with cold water (50 ml) and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated sodium bicarbonate solution (50 ml), water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[(2-dimethylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (28.1 g, 90.9%) as a colorless oil which was used as such.
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH2:37][CH2:36][C:31]6(OCC[O:32]6)[CH2:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[C:13]=2[CH3:38])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH2:37][CH2:36][CH:31]([OH:32])[CH2:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[C:13]=2[CH3:38])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCC(O)CC3)cc12

Procedure:
A mixture of Example 27 (450 mg, 0.832 mmol) and TFA (6 ml) in DCM (30 ml) was stirred at r.t. for 6 hrs. The solvents were removed in vacuo and the crude product was purified by flash chromatography (silica gel, EtOAc/MeOH/NH4OH gradient) to yield Intermediate 19.