Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]C(P(O)O)(C)CCCC.C1(O)C=CC=CC=1.CN(C1C=CC=CN=1)C.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1.CCOCC>[CH:36]1([NH:35][C:34]([NH:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:1])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCCCC(C)(O)P(O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1-Hydroxy-1,4-dimethylbutylphosphonous acid (0.166 g., 0.001M), phenol (0.094 g., 0.001M) and dimethylaminopyridine 0.01 g.) are stirred in tetrahydrofuran (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g. 0.001M) is added portionwise over 2 hours. On completion of the reaction (31P NMR) ether (10 ml.) is added and the dicylohexyl urea formed is filtered off. Evaporation of the filtrate gives an oil which is purified on silica using 5% methanol in chloroform as eluant. There is obtained phenyl (1-hydroxy-1,4-dimethylbutyl)phosphinate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[CH2:28][CH2:27]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Temperature: 80 °C
Yield: 63 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (160 mg, 0.72 mmol), 5-methoxy-3-(piperidin-4-yl)-1H-indole (obtained as described in PCT Int. Appl. WO 2004006922, Intermediate 37) (166 mg, 0.72 mmol) and DIPEA (0.138 mL, 0.79 mmol) in DMF (2 mL) were stirred and heated at 80° C. for 1 hour. The resulting mixture was cooled to room temperature and quenched in water (10 mL) to give a precipitate. The solid was collected by filtration, washed sequentially with water, acetonitrile and ether, and air dried to give 6-[4-(5-methoxy-1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (189 mg, 63%) as a colourless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:4]=2[N:5]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:7]=1>[Pd].CCOC(C)=O>[O:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:6]2[N:7]=[CH:2][C:3]3[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:4]=3[N:5]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)[C@H]1CCc2c(Cl)nc(NC3CCOCC3)nc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCc2cnc(NC3CCOCC3)nc2O1
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A solution of 404 (0.525 g, 1.23 mmol) and EtOAc (15 mL) was subjected to vacuum/nitrogen purge cycles then Pd/C (0.392 g, 0.369 mmol, 10% Degussa) was added and the solution stirred for 2 h under H2 (H2 balloon). The mixture was filtered and the solid washed with EtOAc and the filterate passed through a 0.45 micron frit and then concentrated. The crude product was purified by SiO2 chromatography eluting with MeOH/DCM (5:95) to afford 0.32 g (77%) of (R)-ethyl 2-(tetrahydro-2H-pyran-4-ylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-7-carboxylate (406) as a clear oil: MS m/z (APCI-pos) M+1=308.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:24])=[C:13]2[C:17]=1[N:16]([CH3:18])[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14]2)C1C=CC=CC=1>[Pd].O1CCCC1>[Cl:24][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:17]2[C:13]=1[CH:14]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]2[CH3:18]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccccc3)c2n1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 18 b) except for using 7.71 g (22.4 mmol) of ethyl 7-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate, 0.50 g of 10% palladium/carbon and 150 ml of tetrahydrofuran. Ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate was thus obtained in the yield of 4.70 g (82.6%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([O-:5])=[O:4].I[CH3:16]>C1COCC1>[CH3:16][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0° C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.F[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1S(C)(=O)=O>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(F)c(S(C)(=O)=O)c1
Product: CCOC(=O)c1ccc(Oc2ccc(C(=O)OC)cc2)cc1
Reaction time: 336 h

Procedure:
By reacting ethyl 4-hydroxybenzoate with methyl 4-fluoro-3-methylsulfonylbenzoate in analogy with the protocol given under 14 d) methyl 4-(4-ethoxycarbonylphenoxy)-benzoate was obtained as a colorless to pale-yellow oil which was hydrolyzed, without any further purification steps, in analogy with the manner indicated in protocol 16 c), to give 4-(4-carboxyphenoxy)-3-methylsulfonyl-benzoic acid.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][Si:7]([CH3:16])([CH3:15])[C:8]1[O:9][CH:10]=[C:11]([CH:13]=[O:14])[CH:12]=1.IC>CCCCCC.O1CCCC1>[CH3:1][C:10]1[O:9][C:8]([Si:7]([CH3:16])([CH3:15])[CH3:6])=[CH:12][C:11]=1[CH:13]=[O:14]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)c1cc(C=O)co1
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1oc([Si](C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (a 1.6 M solution in hexane; 2.04 ml, 3.28 mmol) was added dropwise to a solution of N,N'N'-trimethylethylenediamine (0.46 ml, 3.56 mmol) in tetrahydrofuran (7 ml) at-78 degrees under argon. After 15 minutes, a solution of 2-trimethylsilyl-4-furaldehyde (Compound 30, 0.5 g, 2.98 mmol) in tetrahydrofuran (2 ml) was added, followed by n-butyl lithium (3.72 ml, 5.94 mmol) after 15 minutes. Iodomethane (1.12 ml, 17.9 mmol) was then added and the mixture was allowed to warm to room temperature gradually over 1/2 hour. The mixture was quenched with brine and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by flash chromatography using 10% ethyl ether/hexane. Fractions with Rf of about 0.22 on evaporation afforded the title methylfuran as a light yellow oil
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH3:17])([CH3:16])[CH:4]=1)#[N:2].[ClH:18].[CH2:19]([OH:21])[CH3:20]>>[ClH:18].[CH2:19]([O:21][C:1]([C:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH3:17])([CH3:16])[CH:4]=1)=[NH:2])[CH3:20]
Reactant: CCO
Reactant: CC1(C)C=C(C#N)c2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Product: CCOC(=N)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21

Procedure:
To a mixture of 1.04 g of 4-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran and 20 ml of ethyl alcohol was added hydrogen chloride with stirring and cooling with ice. After being saturated with hydrogen chloride, the mixture was further stirred at 5° C. for 6 days. The reaction mixture was concentrated, and to the residue was added a 1:1 mixture of diethyl ether and ethyl alcohol. After trituration, the crystal was collected by filtration, washed with a mixture of ethyl alcohol and diethyl ether, and dried to obtain 1.13 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic acid ethyl ester hydrochloride. A mixture of 0.94 g of the resulting compound, 0.31 g of triethylamine, 0.13 g of cyanamide, and 7 ml of ethyl alcohol was stirred at room temperature for 6 hours, followed by concentration. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was washed with 2N hydrochloric acid, dried over magnesium sulfate, and subjected to silica gel column chromatography (AcOEt:n-hexane=1:1) to isolate three components having different polarity. The component of the lowest polarity was recrystallized from a mixture of diethyl ether and n-hexane to obtain 0.15 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester represented by formula shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([CH3:14])=[CH2:13])=[C:6](I)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][C:12]([CH2:14][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH3:13])[C:6]=2[CH:5]=1)=[O:16]
Reactant: C=C(C)COc1ccc(C(=O)OC)cc1I
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C(C)(Cc1ccccc1)CO2
Temperature: 115 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 3-Iodo-4-(2-methyl-allyloxy)-benzoic acid methyl ester (455 mg, 1.37 mmol) in DMF (15 mL) were added Potassium carbonate (379 mg, 2.74 mmol), Tetrabutylammonium chloride (380 mg, 1.37 mmol), a solution of Palladium acetate (25.6 mg, 0.136 mmol) in DMF (5 mL) and Phenylboronic acid (200 mg, 1.64 mmol). The resulting mixture was stirred for 3 h at 115° C., cooled to room temperature, filtered over silica, washed with water, dryed over MgSO4 and concentrated. Column chromatography (silica gel, heptane/CH2Cl2: 4/6) afforded 202 mg (52%) of the title compound as a slight brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.C[O:12][C:13](=[O:20])[C:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17].C[Si](C)(C)Cl.Cl>O1CCCC1.C(OCC)(=O)C.CN1CCCN(C)C1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([CH3:18])([CH3:17])[CH2:15][C:14](=[O:19])[C:13]([OH:20])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: COC(=O)C(=O)C=C(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: COc1cccc(C(C)(C)CC(=O)C(=O)O)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
4.2 ml of a 0.6 m solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran is mixed at −70° C. with 257 mg of copper bromide-dimethylsulfide complex and then stirred at −40° C. for 20 minutes. It is cooled again to −70° C., and 0.33 ml of 1,3-dimethyl-tetrahydro-2-1H-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs Annalen [Liebigs Annals] 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran are slowly added. It is stirred for one hour at −70° C. and then heated to room temperature. Then, 2N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethane. After 200 mg of tetrabutylammonium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethane phase is dried (Na2SO4) and concentrated by evaporation. After chroma-tography on silica gel with hexane/ethyl acetate (97:3), 63 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid-methyl ester, which is mixed with 1 ml of potassium hydroxide in methanol (10%), is obtained. After 45 minutes, it is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase is dried (Na2SO4) and concen-trated by evaporation. 50 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6]2[C:8]([N:10]=[C:11]([NH2:13])[NH:12][C:5]=2[NH:4][CH2:3]1)=[O:9].BrBr.SCCO>CO>[CH3:1][C:2]1([CH3:14])[CH2:3][NH:4][C:5]2[C:6]([C:8](=[O:9])[N:10]=[C:11]([NH2:13])[N:12]=2)=[N:7]1
Reactant: CC1(C)CNc2[nH]c(N)nc(=O)c2N1
Agent: BrBr
Agent: OCCS
Solvent: CO
Product: CC1(C)CNC2=NC(N)=NC(=O)C2=N1

Procedure:
Quinoid-6,6-Me2PH2 is an intermediate in the synthesis of 6,6-Me2PH4 (see above). It can also be prepared quantitatively by bromine oxidation of 6,6-Me2PH4. The properties of q-6,6-Me2PH2 were determined on material made by the latter route. 6,6-Me2PH4 dihydrochloride, 0.1 mmoles, was dissolved in 3 ml methanol, and 22 mg Br2 (0.14 mmoles) was added. Removal of solvent by rotary evaporation left a dark orange film. The sample was repeatedly redissolved in 3 ml fresh methanol and evaporated to dryness for a total of 6 times, until the film was light yellow and no odor of bromine could be detected. Failure to remove the excess bromine resulted in complex absorbance changes that hindered spectral studies of q-6,6-Me2PH2. The quantitative yield was established by reduction back to 6,6-Me2PH4 using 2-mercaptoethanol, which resulting in full recovery of the original material.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH3:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C.CC(N(C)C)=O>[CH2:13]([O:12][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[CH:19][N:20]([CH3:22])[CH3:21])[CH:11]=1)[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCOc1cc(N)c(C(=O)OC)cc1OC
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1OC
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of 15.056 g (66.9 mmol) methyl 2-amino-4-ethoxy-5-methoxybenzoate and 14.1 ml (100 mmol) N,N-dimethylformamide dimethylacetal was heated to 100° C. under N2. At 4.5 hours added 4.7 ml (33.3 mmol) more DMF/DMA and removed heat at 5 hours. Stripped solvent, azeotroped with toluene, and dried in vacuo, giving 18.211 g of grey-brown solid: mass spectrum (electrospray m/e): M+H=281.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C@@H:15]([CH3:19])[C:16](N)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl.CC#N.O.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C@@H:15]([O:14][CH3:13])[CH3:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CO[C@@H](C)C(N)=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.5 g, 2.17 mmol; Example 1, Step H), (S)-2-methoxypropanamide (0.471 g, 4.56 mmol), BOP-Cl (1.16 g, 4.56 mmol), and triethylamine (1.51 mL, 10.9 mmol) were placed in DCM (10 mL) and stirred for 18 hours at room temperature, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95% CH3CN/water) to give (S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 87% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:58]=[CH:57][C:12]([CH2:13][N:14]([CH2:22][C:23]2[O:27][CH:26]=[C:25]([C:28]3[CH:56]=[CH:55][C:31]4[N:32](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:33](=[O:35])[O:34][C:30]=4[CH:29]=3)[CH:24]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:22][C:23]2[O:27][CH:26]=[C:25]([C:28]3[CH:56]=[CH:55][C:31]4[NH:32][C:33](=[O:35])[O:34][C:30]=4[CH:29]=3)[CH:24]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:57][CH:58]=1
Reactant: CN1CCC(N(Cc2ccc(F)cc2)Cc2cc(-c3ccc4c(c3)oc(=O)n4C(c3ccccc3)(c3ccccc3)c3ccccc3)co2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(N(Cc2ccc(F)cc2)Cc2cc(-c3ccc4[nH]c(=O)oc4c3)co2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
1 mL of 95% aqueous TFA was added to a solution of 6-(5-{[(4-fluoro-benzyl)-(1-methyl-piperidin-4-yl)-amino]-methyl}-furan-3-yl)-3-trityl-3H-benzooxazol-2-one (64 mg, 0.09 mmol) in 2 mL of dichloromethane, and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed to afford the crude product. Purification was achieved via flash silica gel chromatography (elution with DCM:MeOH:AcOH:water). The pooled fractions were combined and the solvent was removed in vacuo with co-evaporation of residual AcOH using toluene to give 16 mg of product. LC/MS (long run): Retention time, 3.83 min; (M+H)=436.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:23]([O:25]C)=[O:24]>CO.CN(C=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][N:2]([CH3:3])[CH3:1])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:23]([OH:25])=[O:24]
Reactant: CNC
Reactant: COC(=O)c1cc2c(OCC3CO3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CC(O)COc1cccc2c1cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Dimethylamine in methanol (2.0 M, 2.14 ml) was added to a stirred solution of methyl N-(3,4-dichlorobenzyl)-4-(2,3-epoxypropyloxy)indole-2-carboxylate (87 mg) in DMF (5 ml) under an atmosphere of argon. The reaction was heated at 80° C. for 16 hours. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in THF (3 ml) and methanol (1.5 ml) and NaOH (2M, 3 ml) added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo and the residue dissolved in water. The solution was acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered, washed with water and dried in vacuo to give the desired end product as a white solid (50 mg, 54%, 2 steps); NMR d (CD3SOCD3) 2.85 (s, 6H), 3.22-3.40 (m, 2H), 4.01-4.14 (m, 1H), 5.81 (s, 2H), 6.01 (d, 1H), 6.60 (d, 1H), 6.88 (dd, 1H), 7.13 (d, 1H), 7.21 (t, 1H), 7.28 (d, 1H), 7.44 (s, 1H), 7.53 (d, 1H); M/z (−) 435 (M−H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]=2[CH:5]=[C:4]([F:23])[CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].[C:30](=O)(O)[O-].[Na+].CI>C1COCC1.O>[Br:1][C:2]1[C:10]2[O:9][C:8]([S:11]([CH3:30])(=[O:13])=[O:12])=[C:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]=2[CH:5]=[C:4]([F:23])[CH:3]=1
Reactant: O=S(=O)(Cl)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CS(=O)(=O)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-2-sulfonyl chloride (0.63 gm, 1.5 mmol) was dissolved in THF (5 ml) and added dropwise to a mixture of sodium sulfite (0.504 gm, 4 mmol) and sodium bicarbonate (0.336 gm, 4 mmol) in water (12 ml). The mixture was refluxed for three hours, cooled to room temperature, and methyl iodide (0.75 ml, 12 mmol) was added. The mixture was heated to 50° C. for two hours then cooled to room temperature and stirred for 16 hours. The mixture was diluted with water and extracted twice with dichloromethane. The solution was dried over magnesium sulfate and purified by preparative thin layer chromatography (1/4, ethyl acetate/hexanes) to give 7-bromo-5-fluoro-3-(3-fluoro-benzyl)-2-methanesulfonyl-benzofuran (0.35 gm, 58% yield), (M+H)+ 402.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19](=[O:21])[NH2:20])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=1)(=[O:21])[NH2:20]
Reactant: COc1ccc2c(C(N)=O)cn(CC(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(C(N)=O)cn(CC(=O)O)c2c1
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-6-methoxy-indol-1-yl)-acetic acid tert-butyl ester (300 mg, 0.99 mmol) in CH2Cl2 (9 mL) was added TFA (4.5 mL) at RT, and stirring was continued for 2 h. Methanol was then added to the reaction mixture, and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated under reduced pressure to afford the title compound as a grey solid: MS: 249 [M+H]+, 497 [2M+H]+; tR (HPLC conditions c): 2.86 min. The material thus obtained was used in the next reaction step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[C:11]([F:17])[CH:10]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:15][C:14]1[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[C:21]2[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=2)=[CH:10][C:11]([F:17])=[C:12]([NH2:16])[CH:13]=1
Reactant: Nc1cc(Cl)c(Oc2ccncc2Br)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: Cn1ccc(-c2cnccc2Oc2cc(F)c(N)cc2Cl)n1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
To a solution of 4-(3-bromopyridin-4-yloxy)-5-chloro-2-fluorobenzenamine, (0.300 g, 0.945 mmol) in n-butanol (5 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.236 g, 1.134 mmol), S-Phos (0.078 g, 0.189 mmol), Pd2(dba)3 (0.087 g, 0.094 mmol) and potassium phosphate (0.602 g, 2.83 mmol). The resulting mixture was degassed and heated in a sealed tube at 100° C. for 20 h. The solvent from the reaction mixture was completely evaporated. The residue was stirred in a mixture of CH2Cl2-MeOH (1:1), filtered, rinsed, dried and subjected to chromatography (50-100% EtOAc-hexanes) to provide 5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-yl)pyridin-4-yloxy)benzenamine, (0.148 g, 49.1% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.20 (m, 2H), 8.01 (s, 1H), 7.24 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.51 (d, J=5.6 Hz, 1H), 5.51 (s, 2H), 3.88 (s, 3H); MS (ESI) m/z: 319.1 (M+H+).