Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[C:42]([O:45][CH2:46][CH3:47])(=[O:44])[CH3:43]>C1COCC1>[C:42]([O:45][CH2:46][CH3:47])(=[O:44])[CH3:43].[CH2:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C1CCCCC1

Procedure:
The amine AM17 (1 eq.) was initially introduced into the flask together with the corresponding acid (1 eq.) under nitrogen. TBTU (1 eq.) and HOBT (1 eq.) were then added and the solids were dissolved in THF (8.5 ml/mmol of amine). N-ethyldiisopropylamine (2 eq.) was added to this mixture with constant stirring and the mixture was subsequently stirred at room temperature overnight. Ethyl acetate was added to the reaction solution and the mixture was washed with sat. NaCl solution, NaHCO3 solution, NaCl and with NH4HSO3 solution and evaporated to dryness with nitrogen and the residue was dried overnight using an oil pump. It was possible to obtain the desired product by means of flash column chromatography (mobile phase: ethyl acetate/cyclohexane, 1:5).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+].Br[CH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:22]=1[C:23]([O:25][CH3:26])=[O:24].O>CN1C(=O)N(C)CCC1.C1COCC1>[CH3:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: OCCCOCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cccc1COCCCOCc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-(Quinolin-2-ylmethoxy)-propan-1-ol (4.6 g, 21.2 mmol, EXAMPLE 3a) is dissolved in 20% DMPU in THF (50 mL) and cooled to 0° C. Sodium hydride (60%, 920 mg, 23 mmol) is added portionwise, and the contents are allowed to stir for 15 min. at 0° C. Methyl 2-bromomethyl-6-methyl-benzoate (77%, 7.25 g, 23 mmol, EXAMPLE 2a) is added and the reaction is allowed to warm to r.t. and continue to stir overnight. The reaction is poured into water (600 mL) and extracted with ethyl acetate (3×200 mL). The organic fractions are pooled and washed with water (3×250 mL) and brine (2×300 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material is purified by flash chromatography (silica, 2% methanol in dichloromethane) to give the title compound. MS (ESI) 380 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[SH:4][C:5]1[N:10]=[C:9](S)[CH:8]=[C:7]([CH3:12])[N:6]=1>C(O)C>[NH:2]([C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]([SH:4])[N:10]=1)[NH2:3]
Reactant: NN
Reactant: Cc1cc(S)nc(S)n1
Solvent: O
Solvent: CCO
Product: Cc1cc(NN)nc(S)n1

Procedure:
Hydrazine monohydrate (6.4 ml) was added dropwise to a suspension of 2,4-dimercapto-6-methylpyrimidine (7.0 g) in 100 ml of ethanol at room temperature, the mixture was refluxed for two hours, and the crystals formed upon cooling were collected by filtration and washed with 100 ml of ethanol, giving 6.4 g of the objective compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([NH2:20])=[C:15]([CH3:21])[C:14]=1[CH2:22][O:23]C(=O)C)[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])C.COC(=O)[C@@H](CC1C(CO)=C2C(=CC=1)N[N:42]=C2)CC(OC)=O>>[CH3:19][C:17]1[CH:18]=[C:13]([CH2:12][C@@H:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:4]([O:3][CH3:1])=[O:27])[C:14]([CH2:22][OH:23])=[C:15]2[C:16]=1[NH:20][N:42]=[CH:21]2
Reactant: CCOC(=O)C[C@H](Cc1cc(C)c(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Product: COC(=O)C[C@H](Cc1cc(C)c2[nH]ncc2c1CO)C(=O)OC
Yield: 98 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-5-methyl-3-methyl-benzyl)-succinic acid diethyl ester (230 mg, 0.59 mmol) was converted to the title compound in a manner analogous to the preparation of 2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethyl ester. Material was obtained as off-white solid in 98% yield. MS m/e (M−H)−=319.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl.[Cl:74][C:75]1[CH:80]=[CH:79][C:78]([N:81]2[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]2)=[CH:77][CH:76]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:84]3[CH2:83][CH2:82][N:81]([C:78]4[CH:77]=[CH:76][C:75]([Cl:74])=[CH:80][CH:79]=4)[CH2:86][CH2:85]3)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(c4ccc(Cl)cc4)CC3)c1)C(C)(C)C2
Temperature: 120 °C
Reaction time: 12 h
Yield: 24.8 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (410 mg, 1 mmol), palladium acetate (6.73 mg, 0.03 mmol), cesium carbonate (0.65 g, 2 mmol), xantphos (23 mg, 0.04 mmol) and 1-(4-chloro-phenyl)piperazine hydrochloride (350 mg, 1.5 mmol) in toluene (10 mL) was stirred at 120° C. for 12 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 6-chloro-2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.13 g, 25%) as a white solid: LC/MS m/e calcd for C29H31C12N3O2 M+: 524.5, observed: 524.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]23)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:31]N1C(=O)CCC1=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=3)[N:11]3[C:28]([I:31])=[CH:29][N:30]=[C:10]23)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2nccn21
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(I)n21
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.5 %

Procedure:
A solution of (R)-1-(3,5-dichloro-phenyl)-3-methyl-3-(4-trifluoromethoxy-benzyl)-1H-imidazo[1,2-a]imidazol-2-one (Example 1) (1.54 g, 3.38 mmol) in 30 mL of THF was treated with N-iodosuccinimide (0.846 g, 3.76 mmol) and pyridinium p-toluenesulfonate (0.086 g, 0.37 mmol). The mixture was stirred at room temperature for 17 h, then diluted with EtOAc and washed with 10% Na2S2O3 solution and water. The combined aqueous layers were extracted with 10 mL of EtOAc. The combined organic phases were washed with 25 mL of brine, dried over Na2SO4, filtered and concentrated. The crude orange oil was purified by silica gel chromatography to provide 1.27 g (65%) of (R)-1-(3,5-dichloro-phenyl)-5-iodo-3-methyl-3-(4-trifluoromethoxy-benzyl)-1H-imidazo[1,2-a]imidazol-2-one as an off-white oil (582.0, M+1).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41]C(=O)OC(C)(C)C)[CH2:36]2)=[C:27]2[CH2:33][CH2:32][C:31](=[O:34])[C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH2:41])[CH2:36]2)=[C:27]2[CH2:33][CH2:32][C:31](=[O:34])[C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (2.0 mg, 0.0029 mmol) in DCM (0.009 mL) was treated with TFA (0.01 mL, 0.1 mmol). The reaction mixture was stirred at room temperature for 1 h, concentrated and then diluted with MeOH and neutralized with NH4OH. After filtration, the crude was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the title compound as white powder (1.3 mg, 92%). LCMS calc. for C23H23F2N6O2S (M+H)+: m/z=485.2. Found: 485.1.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9](OC)=[O:10]>CO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([NH:1][NH2:2])=[O:10]
Reactant: NN
Reactant: COC(=O)c1cncc(Cl)c1
Solvent: CO
Product: NNC(=O)c1cncc(Cl)c1
Temperature: 70 °C
Yield: 50 %

Procedure:
Hydrazine (17.93 mg, 0.560 mmol) was added to methyl 5-chloronicotinate (80 mg, 0.466 mmol) in methanol (8 mL) and heated overnight at 70° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the compound was purified by column chromatography affording the title compound (40 mg). 1H NMR (400 MHz, CD3OD): δ 8.85 (d, 1H, J=2.0 Hz), 8.70 (d, 1H, J=2.4 Hz), 8.22 (t, 1H, J=2.0 Hz). ESI-MS: 172.0 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C(N(CC)CC)C.Br[CH2:34][CH2:35][OH:36]>CN(C=O)C>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:34][CH2:35][OH:36])[CH2:19][CH2:20]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: OCCBr
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CCO)CC3)c(F)c21
Temperature: 90 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (0.3 g), triethylamine (0.2 g), 2-bromoethanol (0.15 g), and DMF (5 ml) was heated with stirring at 90° C. for 3 hours. After the solvent evaporated, the residue was dissolved in 2N sodium hydroxide solution, neutralized with aqueous acetic acid, and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The solid was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[4-(2-hydroxyethyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (0.08 g), mp 225°-228° C.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].C(O)(=O)C>O1CCCC1.CO>[CH3:1][C:2]([CH3:30])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
In tetrahydrofuran (0.85 mL) and methanol (0.85 mL) was dissolved methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate (85 mg), 2N aqueous sodium hydroxide solution (1013.35 μL) was added to the solution, and the mixture was stirred at room temperature overnight. Acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. To the residue were added acetic acid, water, and a phosphate buffer (pH 6.8), and after stirring the mixture, the organic layer was separated and concentrated under reduced pressure. After purification of the residue by LC-MS, it was dissolved in water and ethyl acetate, and the liquids were separated by adding 0.1 N phosphate buffer (pH 7.0). The organic layer was separated and concentrated under reduced pressure, and the obtained residue was pulverized by cooled ethyl acetate and collected by filtration to obtain 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoic acid (29.3 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH3:27])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(C)C2=O)CC1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and methyl iodide, to give the desired product as a colorless solid (22%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](N(OC)C)=[O:15])=[N:13][N:7]3[C:6]=2[CH:30]=1.[CH3:31][Li]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](=[O:15])[CH3:31])=[N:13][N:7]3[C:6]=2[CH:30]=1
Reactant: [Li]C
Reactant: CON(C)C(=O)C1=NN2c3cc(F)ccc3OCC2C1(CCCO)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C1=NN2c3cc(F)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: -78 °C

Procedure:
8-Fluoro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-7; a racemic mixture, 2.6 g, 6.29 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −78° C. Methyllithium (11.8 mL, 3M in diethylether, 18.9 mmol) was added and the reaction stirred to 25° C. Upon completion the reaction was quenched by the addition of NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography (ISCO Redisep 0-100% EtOAc/hexanes gradient) provided 1-[8-fluoro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone (5-8; a racemic mixture). 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 4H), 7.07 (m, 2H), 6.78 (dd, J=8.9, 5.1 Hz, 1H), 6.58 (ddd, J=8.9, 8.2, 3.1 Hz, 1H), 4.15 (dd, J=10.5, 3.5 Hz, 1H), 3.75 (m, 2H), 3.71 (dd, J=10.8, 3.5 Hz, 1H), 2.95 (t, J=10.8 Hz, 1H), 2.55 (dt, J=13.0, 4.0 Hz, 1H), 2.55 (s, 3H), 2.37 (dt, J=13.0, 4.0 Hz, 1H), 1.74 (m, 1H), 1.42 (m, 1H); MS (M+H+, C21H21FN2O3) 369.3 found 369.4 required. This compound was resolved on the Chiracel OD column using MeOH as eluant into its separate enantiomers.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[N:15]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[O:11]=[CH:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[N:15]1
Reactant: COC(=O)c1cccc2cnn(CCO)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2cnn(CC=O)c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
To a stirred solution of DMSO (0.4 mL, 5.2 mmol) and methylene chloride (2 mL) at −78° C. was added oxalyl chloride (0.3 mL, 3.1 mmol) dropwise. After 20 min, a solution of methyl 1-(2-hydroxyethyl)-1H-indazole-7-carboxylate (0.6 g, 2.6 mmol) from Step D above in methylene chloride (17 mL) was added and the mixture was stirred at −78° C. for 1.5 h. After N,N-diisopropylethylamine was added, the reaction was cooled to 0° C. and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with methylene chloride and the organic extracts were dried (Na2SO4), filtered, concentrated under reduced pressure and purified by preparatory thin layer chromatography (30% ethyl acetate in hexanes) to give methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate (0.3 g, 53%): 1H NMR (500 MHz, CDCl3) δ 9.79 (s, 1H), 8.16 (s, 1H), 8.10-8.09 (m, 1H), 7.99-7.97 (m, 1H), 7.25-7.21 (m, 1H), 5.61 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Product: CC(=O)OC(C)(C)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Exampe 68) and 2-acetoxyisobutyryl chloride. m.p.: 228-229° C. (recrystallized from ethyl acetate) IR(KBr)ν: 3500, 3250, 1740, 1710, 1620, 1600, 1570, 1540, 1480, 1350, 1230, 1180, 1150, 740 cm−1.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[Cl:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[C:7]([Cl:24])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1ccc(N2CCC(c3ccccc3)CC2)cc1=O
Solvent: ClCCl
Product: CCCCn1ccc(N2CCC(c3ccccc3)CC2)c(Cl)c1=O
Yield: 80.8 %

Procedure:
A solution of intermediate D19 (0.43 g, 1.40 mmol) and N-chlorosuccinimide (0.19 g, 1.40 mmol) in DCM (10 ml) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by column chromatography (silica gel; 0-3% methanol/DCM as eluent). The desired fractions were collected and evaporated in vacuo and the resulting solid was recrystallized from diethyl ether to yield compound E2 (0.39 g, 82%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[O:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]([OH:28])[CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:13]>CCN(CC)CC.C(Cl)Cl>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][N:18]1[CH2:17][CH:16]([OH:28])[CH2:15][NH:14][C:12](=[O:13])[CH2:11][O:10][C:9]1[CH:29]=[CH:30][CH:31]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reaction time: 2 h

Procedure:
MsCl (23 mg, 0.2 mmol) was added to a cooled 0° C. stirred solution of 2-(3-aminophenoxy)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)acetamide (71 mg, 0.2 mmol) in Et3N (0.1 mL) and DCM (10 mL). After stirred for 2 h, the solvent was removed by concentration. The residue was purified by prep-HPLC to afford the title compound. 1H NMR (400 MHz, MeOD): δ 7.26-7.22 (m, 1H), 7.11-7.01 (m, 4H), 6.91-6.85 (m, 2H), 6.71-6.68 (m, 1H), 4.53 (s, 2H), 4.03-4.00 (m, 1H), 3.69 (s, 2H), 3.43-3.88 (m, 1H), 3.13-3.12 (m, 1H), 2.96 (s, 3H), 2.89 (d, J=6 Hz, 1H), 2.82 (d, J=5.6 Hz, 1H), 2.57 (t, J=6 Hz, 1H) ppm; ESI-MS (m/z): 434.1 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]([O:33]C)=[O:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.CO>O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]([OH:33])=[O:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Yield: 94.9 %

Procedure:
A mixture of methyl {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate (0.250 g, 0.559 mmol), prepared in the previous step, and 1N NaOH (0.84 mL, 0.84 mmol) in 1:1:1 THF:MeOH:water (30 mL) was stirred at ambient temperature for 10 minutes. The volatiles were removed under reduced pressure (without the application of heat). The residue was partitioned between 0.1N HCl and EtOAc. The layers were separated and the aqueous layer was extracted one time with EtOAc. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound as a pale-yellow solid (0.23 g, 95%), mp 171–172° C. Elemental Analysis for C29H23NO3.0.17 H2O Calc'd: C, 79.79; H, 5.39; N, 3.21. Found: C, 79.88; H, 5.37; N, 2.96.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1(=[O:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.[C:21](C(OCC(F)(F)F)=O)(F)(F)F.[NH4+].[Cl-]>C1COCC1>[CH2:21]=[C:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]1=[O:20]
Reactant: O=C1CCc2ccccc21
Reactant: O=C(OCC(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a 0° C. solution of LiHMDS (0.65 mL, 0.6 M in THF) was added a solution of 1-indanone (26 mg, 0.19 mmol) in THF (1.0 mL). The reaction mixture was allowed to warm to room temperature over 20 min, and then CF3CO2CH2CF3 was added (55 μL, 0.41 mmol). After an additional 20 min at room temperature, saturated aqueous NH4Cl (5 mL) was added, and the resulting mixture was extracted with EtOAc (3×5 mL). The organics were dried over Na2SO4 and concentrated under reduced pressure. Without purification, the crude mixture was immediately subjected to general procedure B. SiO2 flash chromatography (25% EtOAc in hexanes) afforded the 2-methlyene-1-indanone as a yellow oil (28 mg) in 98% yield.