Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[N:27]([CH3:28])[C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:20]([C:23]2[N:27]([CH3:28])[C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)n1C

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with methyl 5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.37 (dd, J=1.8 & 10.5 Hz, 1H), 7.29 (m, 2H), 7.12-6.94 (m, 4H), 5.87 (dt, J=1.8, 8.4 & 17.4 Hz, 1H), 5.56 (br s, 1H), 3.65 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCSCc1cnccn1
Product: CNC(=O)NCCSCc1cnccn1

Procedure:
By the procedure of Example 24, 2-[(2-aminoethyl)-thiomethyl]pyrazine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [CH3:1][NH2:2].Cl.[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH:19]=O)[CH:15]=[CH:16][C:9]=12.O>CO>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH2:19][NH:2][CH3:1])[CH:15]=[CH:16][C:9]=12
Reactant: COc1ccnc2c1ccn2C(CC=O)c1ccccc1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNCCC(c1ccccc1)n1ccc2c(OC)ccnc21
Reaction time: 0.33 h
Yield: 20.8 %

Procedure:
To a RT solution of MeNH2.HCl (2.17 g, 31.9 mmol) in MeOH (40 mL) was added NaOH (319 mg, 7.98 mmol). The resulting mixture was stirred for 20 min. Then a solution of 3-(4-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propionaldeyde (2.0 mmol) in MeOH (20 mL) was added, and the resulting mixture was stirred for 2 h. To this solution was added NaCNBH4 (125 mg, 2.0 mmol), and the mixture was stirred for 1 h, poured into water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, concentrated, and purified via preparative TLC, affording [3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine (123 mg, 21% 3 steps yield). This compound was dissolved in EtOAc, and converted into the corresponding hydrochloride salt by the addition of 1 equivalent of HCl (1 M in Et2O) to give 107 mg of the corresponding HCl salt.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([CH:10]2C(=O)OC(C)(C)O[C:11]2=[O:19])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][NH2:21]>C(O)C>[CH:1]1([CH2:6][CH2:7][C:8]2[CH2:10][C:11](=[O:19])[NH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: CC1(C)OC(=O)C(C(=O)CCC2CCCC2)C(=O)O1
Solvent: CCO
Product: O=C1CC(CCC2CCCC2)=NN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
A solution of 5-(3-cyclopentylpropionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (900 mg, 3.3 mmol) in ethanol (5 ml) containing hydrazine (0.43 ml, 8.84 mmol) was stirred at ambient temperature for 20 minutes followed by stirring for 2 hours at 75° C. The volatiles were removed under vacuum and the residue was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 3-(2-cyclopentylethyl)-4,5-dihydro-1H-pyrazol-5-one (250 mg, 42%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:11]Br)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:11][NH:4][CH2:3][CH2:2][OH:1])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrCC1CCCCC1
Reactant: NCCO
Product: OCCNCC1CCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.[CH2:14]([Mg]Br)[CH:15]=[CH2:16]>O1CCCC1.CCOCC>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]=[C:7]2[CH2:16][CH:15]=[CH2:14]
Reactant: O=C1CCCc2c(F)cc(F)cc21
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1=CCCc2c(F)cc(F)cc21

Procedure:
A solution of 5, 7-difluoro-1-tetralone [110931-79-8] (prepared in accordance with DE-A 3702039) in tetrahydrofuran is added to an equimolar amount of an allylmagnesium bromide solution in ether at 0° C. The reaction mixture is subjected to conventional aqueous acidic workup (Mohammadi et al., J. Lab. Cpd. Radiopharm. XXIV, 317 (1987)) and distillation. The 5,7-difluoro-1-(1-propen-3-yl)-3,4-dihydronaphthalene obtained is reacted with an equimolar amount of thexyl-borane in terahydrofuran to give B-thexyl6,8-difluoro-2,3,4,4a,9,9a,10-octahydro-1-boraphenanthrene which is reacted with equimolar amounts of sodium cyanide at room temperature without further characterization. After 2 h, an equimolar amount of trifluoroacetic anhydride (TFAA) is added dropwise at −75° C., and the mixture is brought to room temperature with stirring. 3 equivalents of NaOH are added and the mixture is oxidized with 50% H2O2, finally at 50° C.; extraction and chromatography yield 1-keto6,8-difluoro-1,2,3,4,4a,9,9a,10-octahydrophenanthrene. As described by Mohammadi et al., J. Lab. Cpd. Radiopharm. XXIV, 317 (1987), this product can be converted into 1-keto-6,8-difluoro-2-propyl-1,2,3,4,4a,9,9a,10-octahydrophenanthrene by reacting with lithium diisopropylamide (LDA) followed by addition of n-propyl bromide. This product can be converted into 6,8-difluoro-1,2,3,4,4a,9,9a,10-octahydrophenanthrene by reducing with triethylsilane in trifluoroacetic acid. 6,8-Di-fluoro-7-pentyl-2-propyl-1,2,3,4,4a,9,9a,10-octahydrophenanthrene is obtained by ortho metalation using “Schlosser base” (i.e. butyllithium and potassium tert-butylate; see, for example: F. Mongin, M. Schlosser, Tetrahedron Lett. 1996, 37, 6551-6554) at −75° C., quenching with n-pentyl bromide and conventional workup by hydrolysis, extraction, chromatography (silica gel, dichloromethane) and repeated recrystallization (to increase the proportion of the desired isomer, among other things).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:13]=1)(C)(C)C.O1CCOCC1>Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([NH2:7])[CH:9]=[N:10][C:11]=2[O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
[5-(4-Chloro-phenyl)-6-cyclobutoxy-pyridin-3-yl]-carbamic acid tert-butyl ester (1.042 g, 2.78 mmol) was dissolved in 4M HCl in dioxane (10.4 ml, 41.7 mmol). The reaction mixture was a light yellow solution and was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and 1M Na2CO3 solution. The organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 5% to 75% ethyl acetate in heptane) to give 0.358 g (46.9%) of the title compound as light red oil; LC-MS (UV peak area/ESI) 94.3%, 275.0950 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(C)C=CC=CC=1>ClCCl.[Cu]I>[CH3:1][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Reactant: C1CNCCN1
Agent: [Cu]I
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)c1ccc(N2CCNCC2)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
4.2 g of 2-methyl-1-[4-fluorophenyl]-2-morpholinopropan-1-one (0.0167 moles), 5.75 g of piperazine (0.0669 moles), 0.063 g of copper (I) iodide and 15 ml of toluene were mixed in a three necked flask equipped with a stirrer, nitrogen inlet, condenser, nitrogen outlet and a temperature probe. The mixture was heated to reflux for a total of 24 hours under a constant flow of nitrogen gas. The mixture was then cooled to room temperature, after which it was dissolved in 75 ml of dichloromethane. The mixture was then extracted with 100 ml of a saturated aqueous sodium chloride solution and then with 2×100 ml of water. The dichloromethane layer was then dried using anhydrous magnesium sulphate. The magnesium sulphate was removed by filtration and the organic solvent was then removed on a rotary evaporator to yield the product.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4].[CH3:38][C:39]1([CH3:42])[CH2:41][O:40]1.CCN(C(C)C)C(C)C>CC#N>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][N:22]([CH2:38][C:39]([CH3:42])([OH:40])[CH3:41])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Reactant: CC1(C)CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 90 °C
Yield: 34.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (150 mg, 0.27 mmol), 2,2-dimethyloxirane (242 μL, 2.73 mmol) and DIPEA (187 μL, 1.09 mmol) in MeCN (3 mL) was heated at 70° C. r.t. for 3 h before further 2,2-dimethyloxirane (242 μL, 2.73 mmol) was added and the mixture heated at 90° C. for 6 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 791 (51 mg, 34%). LCMS (method I): RT 2.72 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.03-8.02 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 4.26 (4 H, brd s), 4.08 (1 H, s), 3.91 (3 H, s), 3.79 (4 H, t, J=4.72 Hz), 3.27-3.26 (2 H, m), 3.20-3.15 (1 H, m), 3.06 (3 H, s), 3.01-2.97 (1 H, m), 2.69-2.61 (1 H, m), 2.46-2.38 (1 H, m), 2.25 (2 H, s), 2.17-2.14 (1 H, m), 1.92-1.75 (3 H, m), 1.33 (3 H, t, J=7.43 Hz), 1.03 (3 H, s), 0.94 (3 H, s)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Yield: 86.6 %

Procedure:
3-Hydroxyphenylacetonitrile (834 mg, 6.26 mmol) was dissolved in DMF (10 ml), and to this solution were successively added benzyl bromide (0.82 ml, 6.89 mmol, 1.1 eq) and anhydrous potassium carbonate (1.30 g, 9.40 mmol, 1.5 eq). The mixture was stirred under heating at 90° C. for 1.5 hours. This reaction mixture was cooled to room temperature, and water (20 ml) was added. The mixture was extracted twice with ethyl acetate (40 ml). The organic layers were combined, washed with saturated brine (80 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give (3-benzyloxyphenyl)acetonitrile (1.21 g, 86.8%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:13]=[N:14][CH:15]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2cncc(-c3ccc(C(C)C)cc3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(-c2cncc(-c3cccc(C(=O)O)c3)c2)cc1
Temperature: 45 °C
Yield: 87.1 %

Procedure:
Part C. A solution of ethyl 3-[5-(4-isopropyl-phenyl)-pyridin-3-yl]-benzoate (100 mg) in methanol-water (3 mL/1 mL) is treated with lithium hydroxide hydrate (50 mg), and the solution is heated to 40-50° C. for 12 h. After cooling, the solution is neutralized to pH 7 with 3 N HCl and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound as a powder (80 mg, 87%), m.p. 155-156° C. 1H NMR (300 MHz, CDCl3): δ 8.93-8.90 (2H, m), 8.44 (1H, s), 8.21-8.19 (2H, m), 7.89 (1H, d, J=7 Hz), 7.64 (1H, t, J=8 Hz), 7.61 (2H, d, J=9 Hz), 7.39 (2H, d, J=9 Hz), 3.00 (1H, heptet, J=7 Hz), 1.30 (6H, d, J=7 Hz). MS (ES+): m/e 319 (22), 318 (100).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:1]([NH:17][C@H:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: C[C@@H](NCc1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirred solution of benzaldehyde (1.58 mL, 15.5 mmol) in 10 mL of absolute ethanol at room temperature under nitrogen was added (R)-α-methylbenzylamine (2.0 mL, 15.51 mmol, 99% ee.). The reaction mixture was stirred for 3 hours. The reaction solution was then dried over magnesium sulfate and diluted to a 60 mL volume with EtOH. Ethanol washed Raney nickel Ni (~1.5 g) was added and the resulting suspension was treated with 58 psi of hydrogen in a Parr Type Shaker. After 1 day, additional Raney nickel (~1 g) and 30 mL of ethanol were added and the hydrogenolysis continued for 3 days. The reaction mixture was filtered through Celite to remove the catalyst and concentrated to afford 3.11 g (95%) of N-benzyl (R)-α-methylbenzylamine as a pale yellow oil contaminated with~5% of benzyl alcohol and (R)-α-methylbenzylamine; 1H NMR (DMSO-6, 250 MHz) δ7.1-7.5 (m, 10H, Ar), 3.68 (q, 1H, J=6.6 Hz), 3.48 (dd, 2H, J1 =13.6 Hz, J2 =20.5 Hz), 1.26 (d, 3H, J=6.6 Hz, CH3); 13C NMR (DMSO-d6) δ146.1, 141.0, 128.2, 128.0, 127.8, 126.5, 126.4, 56.7, 50.6, 24.5. This mixture was used directly in the next reaction.
Reaction SMILES: N#N.[NH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[N:3]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCNC1
Reactant: OCCOCCCl
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: OCCOCCN1CCCC1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of pyrrolidine (0.35 mL, 4.22 mmol) and 2-(2-chloroethoxy)ethanol (0.45 mL, 4.22 mmol) in dry toluene (7 mL) was added K2CO3 (3.21 g, 23.20 mmol) at rt followed by KI (70 mg, 0.42 mmol). The reaction mixture was stirred at reflux for 15 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give crude 2-(2-(pyrrolidin-1-yl)ethoxy)ethanol as a yellow oil. TLC:rf (90:10:0.5 CH2Cl2-MeOH—NH4OH)=0.17.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]1([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)[CH2:22][CH2:21]1.S(O)(C1C=CC(C)=CC=1)(=O)=O>CC(O)C>[CH:20]1([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)=[CH:25][C:24]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)[CH2:22][CH2:21]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Reactant: Nc1ccc(C2CC2)c(-n2cnnn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3ccc(C4CC4)c(-n4cnnn4)c3)ncc2F)CC(C)(C)N1
Temperature: 100 °C

Procedure:
In a 100 mL round bottom flask to a solution of 2-chloro-5-fluoro-N-(2,2,6,6,-tetramethylpiperidin-4-yl)pyrimidin-4-amine (Compound 15; 0.18 g, 0.63 mmol) in 10 mL iPrOH, 4-cyclopropyl-3-(1H-tetrazol-1-yl)benzeneamine (0.18 g, 0.88 mmol) and TosOH (0.095 g, 0.50 mmol) were added. The reaction mixture was heated at 100° C. for 3 hours. LCMS analysis indicated the complete consumption of the mono-SNAr product and appearance of Compound III-118. The reaction mixture was then cooled to room temperature and volatiles were removed under reduced pressure. The crude reaction mixture was purified by column chromatography using DCM/2 M NH3 in MeOH to get tan solid that was further purified by tituration using DCM/hexanes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([CH3:35])([CH3:36])[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 192 mg (0.380 mmol) of tert-butyl 3-(4-{[(2-(2,4-dimethylphenyl)-amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate (Example 1-1) in 1 ml of dichloromethane is treated with 1 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The mixture is then concentrated under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed 2× with water, 1× with 20% strength sodium acetate solution, 1× with water and 1× with sat. NaCl solution, dried over sodium sulphate and freed from the solvent under reduced pressure. Chromatographic purification of the residue on silica gel (dichloromethane→dichloromethane/methanol 20:1) gives 150 mg (88%) of 3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionic acid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:16][CH2:15]2)[N:7]=1)C.[ClH:25].O1CCOCC1>C(O)C>[ClH:25].[CH3:23][O:22][CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:8]2[N:7]=[C:6]3[CH2:5][C:4](=[O:3])[NH:12][C:11]3=[CH:10][CH:9]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)Cc1nc(OC2CCN(CCOC)CC2)ccc1N
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COCCN1CCC(Oc2ccc3c(n2)CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5 (0.483 mmol) in ethanol (5 mL) was added 4M HCl/Dioxane (15 mL). The solution was agitated at room temperature for 18 hours. All components in reaction are extremely polar and elute with solvent front. By LCMS, 6 was the major observed ion. The crude material was concentrated and taken directly on to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([N+:23]([O-])=O)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([NH2:23])=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc([N+](=O)[O-])sc2-c2ccc(F)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Yield: 81.5 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-nitrothiophene (3.6 g), iron powder (3.6 g) and ammonium chloride (0.36 g) in ethanol (58 ml) and water (22 ml) was stirred and refluxed for 1 hour. The insoluble was filtered and washed with N,N-dimethylformamide (40 ml). The filtrate was concentrated. The residue was triturated with water, filtered, and washed with water and ethanol to give a pale yellow powder of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (2.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:32][CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: CSc1sc(-c2cc(Nc3cccc(O)c3)ccc2C)c(-c2cccnc2)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1sc(-c2cc(Nc3cccc(OCCCO)c3)ccc2C)c(-c2cccnc2)c1C#N
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 5-[5-(3-hydroxyphenylamino)-2-methyl-phenyl]-2-methylsulfanyl-4-pyridin-3-yl-thiophene-3-carbonitrile (330 mg, 0.77 mmol) in DMF (anhydrous, 5 mL) was added 3-bromo-propan-1-ol (214 mL, 1.54 mmol). The reaction was stirred at 70° C. in the presence of excess K2CO3 overnight then cooled to ambient temperature and partitioned between water and DCM. The mixture was extracted with DCM (30 ml×3) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (2% MeOH-DCM) afforded desired product (370 mg, 99%). 1H NMR (CDCl3): δ 8.6 (d, 1H), 8.5 (d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 (s, 1H), 7.3–7.2 (m, 3H), 7.0 (d, 1H), 6.6 (d, 1H), 4.1 (t, 2H), 3.9 (t, 2H), 2.7 (s, 3H), 2.0 (m, 2H), 1.5 (s, 3H)
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:29])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2)([CH3:4])[CH3:3].[Cl:30]N1C(=O)CCC1=O.C(O)(=O)C.[OH-].[Na+]>O>[Cl:30][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]([OH:29])[CH2:6][NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:28])[NH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 8.6 g of 1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-3-(1H-indol-4-yl)-1-propanone, 3 g of N-chlorosuccinimide and 170 ml of acetic acid was stirred at room temperature for 2 hours and was then diluted with water. The mixture was made alkaline by addition of sodium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 6.37 g of 3-(3-chloro-1H-indol-4-yl)-1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-1-propanone.