Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl>[C:10]1([CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCCCOCCc1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Product: c1ccc(CCOCCCCCNCc2ccccc2)cc1

Procedure:
[2-[(5-Bromopentyl)oxy]ethyl]benzene (10.0 g) was added over 1 h to benzylamine (30 ml) at ca. 120° under nitrogen. After 2 h at 120° the reaction mixture was added to 2N hydrochloric acid (200 ml), the mixture was extracted with ethyl acetate (2×250 ml) and the combined organic extracts were washed with 2N sodium carbonate, water and brine, dried and concentrated in vacuo to give the title compound as a pale yellow oil (8.6 g), t.l.c. (ethyl acetate-triethylamine 99:1) Rf 0.78
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][CH2:24][CH:25]3[O:29][CH2:28][CH2:27][O:26]3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCCC1OCCO1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(CCC3OCCO3)c3cc(F)ccc23)CC1
Reaction time: 15 h
Yield: 117.7 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.1 g (0.37 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.081 g (0.45 mmol) of 2-(2-bromo-ethyl)-[1,3]dioxolane. 0.170 g (quantitative yield) of 4-[1-(2-[1,3]dioxolan-2-yl-ethyl)-6-fluoro-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([N:8]([C:20](=[O:24])[CH2:21][C:22]#[N:23])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.C1(C)C=CC=CC=1>C(O)C.O>[NH2:23][C:22]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)[C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20](=[O:24])[CH:21]=1
Reactant: CSc1cccc(NC(=O)N(Cc2ccccc2)C(=O)CC#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1cccc(-n2c(N)cc(=O)n(Cc3ccccc3)c2=O)c1
Reaction time: 1 h

Procedure:
1-Benzyl-1-(cyanoacetyl)-3-[3-(methylthio)phenyl]urea (14.9 g) was suspended in ethanol (150 ml) and to this was added a solution of sodium hydroxide (2.34 g) in water (30 ml). This was stirred for 1 h then allowed to stand overnight at room temperature. The mixture was filtered to remove a dark impurity and the filtrate carbon treated. This solution was then evaporated to remove ethanol then diluted with water. It was extracted with ethyl acetate (150 ml) and the extracts washed with water (2×75 ml) then dried and evaporated to give a foam. This was taken up in a 1:1 mixture of ethyl acetate and toluene (100 ml). After standing for 1 h the product had precipitated. It was filtered off and washed with 1:1 toluene/hexane (50 ml) then dried to constant weight. Yield=9.06 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([SH:21])[CH2:19][SH:20]>>[OH:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]2[S:21][CH2:18][CH2:19][S:20]2)=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: SCCS
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C2SCCS2)cc(C(C)(C)C)c1O

Procedure:
Molar amounts of 3,5-di-tert.butyl-4-hydroxy benzaldehyde and 1,2-ethane dithiol are condensed by the method described in Example 1 to yield the 2-(4'-hydroxy-3', 5'-di-tert.butyl phenyl)-1,3-dithiolane of formula VII, ##SPC6##
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3ccc(OC)c(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.7 %

Procedure:
To a solution of ethyl 3-(5-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methoxyphenyl)propanoate (200 mg) in methanol (3.0 mL) was added a solution of sodium hydroxide (100 mg) in water (3.0 mL), and the mixture was stirred at room temperature for 15 hr. 2N Hydrochloric acid was added to the reaction mixture to adjust to pH<2, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (143 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])=[C:4]([CH3:15])[CH:3]=1.OS(O)(=O)=O.[CH3:21][CH2:22]O>>[F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([O:14][CH2:21][CH3:22])=[O:13])=[C:4]([CH3:15])[CH:3]=1
Reactant: CCO
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1CC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
2-(4-Fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g, 86.5 mmol, 1.00 eq) and cone. H2SO4 (4.00 ml) were combined in EtOH (300 ml) and stirred with heating at 85° C. After 2.5 h, the completed reaction was cooled to RT and concentrated as completely as possible. The residue was dissolved in MTBE (250 ml) and washed with H2O (2×) and brine (2×), dried (MgSO4), filtered and evaporated to afford ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)acetate (16.79 g, 81% yield) as a dark orange oil which was used as is in the next reaction. MS (ESI) m/z: 242.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nc(C)cc(C)n4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nc(C)cc(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.56 g) in methylene chloride (16.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.22 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. The mixture was allowed to be warmed up to 0° C., and an aqueous solution of saturated sodium thiosulfate was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 230) (165 mg).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>O1CCOCC1.C(OCC)(=O)C.O>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.2 %

Procedure:
Combine triethylamine (15.8 mL, 111.0 mmol) and 2,6-diaminopyridine (6.5 g, 59.6 mmol) in dioxane (200 mL). Add 4-fluorobenzoyl chloride (5.46 mL, 44.7 mmol) in small increments. After complete addition, stir at room temperature for 18 hr. Pour into water and dilute with ethyl acetate and water. Separate and extract twice the aqueous layer with CH2Cl2, combine the organic fractions, dry over MgSO4, and concentrate. Chromatograph on silica gel, eluting with a gradient of 0%–10% (2M NH3 in methanol) in CH2Cl2 to give the title intermediate (8.91 g, 86.3%): mass spectrum (ion spray): m/z=232.3 (M+1); Analysis calc'd for C12H10N3OF.0.1H2O: C, 61.85; H, 4.41; N, 18.03. Found: C, 61.75; H, 4.08; N, 17.66.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:25][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:25][C:19]=2[CH:18]=1)=[O:16]
Reactant: COCCOCCOc1ccc2sc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Yield: 62.8 %

Procedure:
A solution of 80 mg (0.164 mmol) of [2-({5-[2-(2-Methoxy-ethoxy)-ethoxy]-benzo[b]thiophene-2-carbonyl}-amino)-phenyl]-carbamic acid tert-butyl ester (28) in 1.0 ml trifluoroacetic acid was stirred for 45 min at room temperature and then added to an aqueous solution of sodium bicarbonate. After extraction with ethyl acetate and removal of the solvent the residue was recrystallized from ethyl acetate/heptane to yield 40 mg (0.103 mmol) of the desired product (27) as white crystals, mp. 167–168° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]([SH:15])=[N:13][N:12]=[C:11]3[C:16]3[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:17]=3O)=[CH:7][CH:8]=2)[CH2:3][C:2]21[O:30]CCO2.O.CC1C=CC(S(O)(=O)=[O:40])=CC=1>CC(C)=O>[OH:22][C:21]1[CH:20]=[C:19]([OH:40])[C:18]([CH:23]([CH3:24])[CH3:25])=[CH:17][C:16]=1[C:11]1[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][C:2](=[O:30])[CH2:3]3)[C:14]([SH:15])=[N:13][N:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)c1ccc(O)c(-c2nnc(S)n2-c2ccc3c(c2)CC2(C3)OCCO2)c1O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1cc(-c2nnc(S)n2-c2ccc3c(c2)CC(=O)C3)c(O)cc1O
Temperature: 25 °C
Yield: 902.9 %

Procedure:
Compound 10 (160 mg, 0.38 mmol) was stirred in acetone (7 mL) and water (2 mL) at 63° C. in the presence of p-TsOH (5 mg, cat. amount) for 2 h. After cooled to room temperature, water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. Purification of the concentrated crude product by column chromatography (EtOAc:Hexane=1:1) afforded the title product as a white solid (100 mg, 69%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([CH2:20][CH3:21])[CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[CH2:20]([CH:7]([CH2:8][NH2:9])[CH2:6][NH2:5])[CH3:21]
Reactant: CCC(CN1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Product: CCC(CN)CN
Yield: 100 %

Procedure:
A mixture consisting of 1,3-diphthalimido-2-ethylpropane (25 g, 69 mmol) concentrated hydrochloric acid (700 mL), and ethanol (700 mL) was refluxed for 6 days with additional concentrated hydrochloric acid being added at the indicated time; 3 days (300 mL), 4 days (200 mL), 5 days (200 mL). The reaction was evaporated to dryness and the residue was diluted with water (200 mL), chilled, and filtered. The filtrate was washed with ethyl acetate (5×500 mL) and evaporated to leave 12 g (100%) of 2-ethyl-1,3-propanediamine dihydrochloride as a thick oil.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH:11]([C:13](OC)=[O:14])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[C:1]1([CH:7]2[NH:12][CH:11]([CH2:13][OH:14])[CH2:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCCC(c2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCCC(c2ccccc2)N1
Yield: 29.9 %

Procedure:
A solution of methyl 6-phenylpipecolinate (0.23 g) in THF (15 mL) was treated with 1M lithium aluminum hydride in ether (10 mL) at room temperature for 2 h. The reaction mixture was quenched with EtOAc, then MgSO4 was added and the mixture was filtered. The filtrate was concentrated to give a residue, which was purified by chromatography on silica gel plates (2, 1000 μm) using EtOAc:hexane 1:1 as the eluent, to give (6-phenyl-piperidin-2-yl)-methanol as a white solid (0.06 g).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O.BrCC1C=C2C(=CC=1)N=CC=N2.CC1C=C2C(=CC=1)N=CC=N2>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1nc(C)nc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: BrCc1ccc2nccnc2c1
Agent: Cc1ccc2nccnc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(CBr)nc2ccccc12

Procedure:
By brominating 2-methyl-4-methoxy-quinazoline [Recl. Trav. Chim. Pays-Bas 76, 401 (1957)] with N-bromosuccinimide in carbon tetrachloride in an analogous manner to the procedure described for the preparation of 6-bromomethylquinoxaline [J. Het. Chem. 11, 595(1974)] from 6-methylquinoxaline there was obtained 2-bromomethyl-4-methoxy-quinazoline as a light yellow solid; MS: 252, 254 (M)+.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])([CH3:3])[CH3:2].CO.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccccc1C(=O)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Sc1ccccc1C=O
Reaction time: 0.5 h

Procedure:
To a solution of 2-(isopropylthio)benzoic acid (0.98 g, 5 mmol) in THF (10 ml) was added dropwise borane-dimethyl sulphide complex (0.8 ml, 8 mmol) at 3° C. under argon with vigorous stirring. After continuing to stir in an ice bath for 30 min, the reaction was left to stand at RT for a further 24 h. Methanol (1.5 ml) was added cautiously and the reaction solution was concentrated under reduced pressure. The residue was taken up in diethyl ether (50 ml), and washed with saturated K2CO3 solution and NaCl solution. Aqueous solutions were additionally extracted with ether, the combined organic phases were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (30 ml), admixed cautiously with PCC (1.20 g, 5.6 mmol) and stirred at room temperature for 36 h. After solvent removal, the residue was purified by column chromatography on silica gel (10:1 hexane:ethyl acetate). Yield 0.69 g (76%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[F:35])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(Cl)c1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.060 g, 0.162 mmol) in dry THF (5 mL) was added DIPEA (3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0° C. and 2-fluorobenzoyl chloride (0.038 g, 0.243 mmol) was added and stirred for 3 h at room temperature. The reaction mass was quenched in water, extracted with DCM:MeOH and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.030 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 4.50-4.52 (d, J=8 Hz, 2H), 7.25-7.33 (m, 2H), 7.52-7.55 (m, 2H), 7.63-7.65 (m, 2H), 7.72-7.86 (d, J=2.4 Hz, 1H), 7.83-7.86 (d, J=11.6 Hz, 2H), 8.17-8.20 (d, J=11.6 Hz, 2H), 8.95-8.99 (t, 1H), 12.69 (br s, 1H); MS (m/z): 491.17 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg+].[Br-].[CH3:13][C:14]1([CH3:22])[C:16]([CH3:18])([CH3:17])[CH:15]1[C:19]([OH:21])=O.[Cl-].[NH4+]>C(OCC)C.S(Cl)(Cl)=O>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:19]([CH:15]2[C:16]([CH3:17])([CH3:18])[C:14]2([CH3:13])[CH3:22])=[O:21])=[CH:2]1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCCCn1cc(C(=O)C2C(C)(C)C2(C)C)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Indole 1 (11.7 g, 100 mmol) was dissolved in diethylether (100 ml) under nitrogen atmosphere and cooled to 0° C. 3M solution of MeMgBr (35 ml, 105 mmol) was added drop-wise and allowed to stir at room temperature for 3 hours. In the meantime, 2,2,3,3-tetramethylcyclopropane carboxylic acid (14.22 g, 100 mmol) was dissolved in thionyl chloride (100 ml) and refluxed for 90 min, then the solvent was removed under vacuo and the residue was dissolved in diethylether (100 ml). The resulting solution was added drop-wise to the indole reaction mixture at 0° C. and then allowed to stir at room temperature for 2 hours. A solution of ammonium chloride (200 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed by water, brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by column chromatography (silica gel: 10-30% ethyl acetate in hexane) to give 8.6 g (36%) of N-desalkyl UR-144 2 as a cream solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[S:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH:13]=2)[NH:8][C:7]=1[CH3:26])C.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CO>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH2:16][C:17]4[S:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([OH:3])=[O:27])=[C:7]2[CH3:26])=[CH:31][CH:30]=1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OCc3nc4ccccc4s3)cc12
Reactant: ClCc1ccc(Cl)cc1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
The title compound is prepared according to the method of Example 16 using 2-methyl-5-(2-benzothiazolylmethoxy)-1H-indole-3-acetic acid ethyl ester and 4-chlorobenzyl chloride; however, the hydrolysis is carried out in aqueous methanol. Recrystallization from acetonitrile affords white crystals, m.p. 175°-176° C.
Reaction SMILES: O=[C:2]1[N:10]2[C:6]([NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[C:5]([C:15]#[N:16])[C:4]2[CH2:17][CH2:18][S:19][CH2:20][C:3]1=2.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[C:5]([C:15]#[N:16])=[C:4]2[CH2:17][CH2:18][S:19][CH2:20][C:3]=12
Reactant: N#Cc1c2c(c(=O)n3c1[nH]c1ccccc13)CSCC2
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c2c(c(Cl)n3c1nc1ccccc13)CSCC2

Procedure:
Phosphorus oxychloride (50 ml) was added to 12-oxo-3,4,6,12-tetrahydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (16 g), followed by heating under reflux for 3 hours. The reaction liquid was concentrated under reduced pressure and the residue was poured into ice-water. The precipitate was collected by filtration and washed with water to obtain 12-chloro-3,4-dihydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (18 g).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH2:31].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH:31][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 130 °C
Reaction time: 24 h
Yield: 6.7 %

Procedure:
Compound D (202 mg, 650 μmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (357 mg) and sodium hydrogencarbonate (540 mg) were added to DMSO (3 ml), and the mixture was stirred at 130° C. for 24 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography (90 mg). This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-(pyridin-3-yl)nicotinonitrile dihydrochloride (22 mg).