Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=4)[CH2:18][CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1>C(Cl)Cl>[O:64]1[CH2:65][CH2:66][CH2:67][CH2:68][CH:63]1[O:62][NH:61][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:21]=3[CH2:20]2)=[N:27][CH:26]=1)=[O:29]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc(N2CCc3c(n(CCN4CCCCC4)c4ccccc34)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(CCN4CCCCC4)c4ccccc34)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a solution of the acid 2-[9-(2-piperidin-1-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylic acid (200 mg, 0.49 mmol) in DCM (20 mL) was added EDCI (140 mg, 0.73 mmol), HOBT (99 mg, 0.73 mmol), DIEA (183 mg, 1.46 mmol) and NH2OTHP (57 mg, 0.48 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-(2-piperidin-1-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (80 mg). 1H NMR (200 MHz, CDCl3) ppm: 8.75 (s, 2H), 7.50 (d, 1H, J=7.0 Hz), 7.30 (m, 1H), 7.16 (m, 2H), 5.13 (s, 2H), 5.04 (s, 1H), 4.24 (m, 4H), 4.00 (m, 1H), 2.91 (m, 2H), 2.70 (m, 2H), 2.49 (m, 4H), 1.85-1.45 (m, 11H); m/e=504 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([NH2:29])=[N:13][CH2:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18](O)=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:30][NH:31][O:32][CH3:33].Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:17]([C:18]([N:31]([O:32][CH3:33])[CH3:30])=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:29])[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: CNOC
Reactant: Cc1ccc(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
To a suspension of Boc-Arg(Tos)- OH (2 g, 4.7 mmol) in DMF (20 mL) at 0° C. was added MeNHOMe·HCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution was stirred at 0° C. for 10 hours. DMF was evaporated by vacuum. The oily residue was dissolved in EtOAc (200 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3, water (20 mL), 1 M HCl (10 mL) and sat. NaCl (2×20 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a suspension. The suspension was filtered, and the solid was washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70% yield).
Reaction SMILES: C(OC(=O)NC1C=CC=C([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31](Cl)[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.C(Cl)(=O)C(Cl)=O.NC1C=CN([CH2:54][C:55](C)([OH:57])[CH3:56])N=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:24]1([CH2:23][C@H:22]([C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C:55]([OH:57])([CH3:56])[CH3:54])[N:16]=2)=[O:40])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 3, 60 mg, 0.20 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 117 μL, 0.23 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 1 h at 25° C. After this time, the reaction was concentrated in vacuo to ⅙ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 34 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. After addition was complete, the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (65 mg, 75%) as a white foam: [α]30589=−20.0° (c=0.13, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; H1-NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.10 (m, 2 H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.08 (m, 1H, CH), 3.18 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.1 Hz, 1H, Ar), 7.50 (d, J=2.1 Hz, 1H, Ar), 7.64 (d, J=8.2 Hz, 2H, Ar), 7.88 (d, J=8.2 Hz, 2H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: O[C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13]3[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]=1.BrBr.[C:25]([NH2:28])(=[S:27])[CH3:26]>C(Cl)(Cl)Cl.C(O)C>[CH3:26][C:25]1[S:27][C:3]2[CH2:4][CH2:5][C:6]3[C:11](=[N:10][C:9]([NH:12][C:13]4[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[N:8][CH:7]=3)[C:2]=2[N:28]=1
Reactant: CC(N)=S
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)C(O)=CCC3)c1
Agent: BrBr
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 3-(8-hydroxy-5,6-dihydro-quinazolin-2-ylamino)benzenesulfonamide (100 mg, 0.314 mmol) in chloroform (1 mL) was treated with a solution of bromine (32 μl, 0.628 mmol) in chloroform (1 mL) and the mixture stirred at room temperature for 2 hours giving an insoluble black residue. The solvent was decanted and the residue treated with thioacetamide (47 mg, 0.6 mmol) in ethanol (3 mL). The mixture was stirred at 80° C. for 3 hours and filtered to give a black solid (75 mg). The solid was dissolved in DMSO and purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100 A column, gradient 10%-100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to give a yellow solid (6.9 mg) which was further purified by flash chromatography on silica gel eluting with ethyl acetate to afford the title compound (1.9 mg) as a pale yellow solid. MS (ES+) 374, (ES−) 372. δH (CD3OD) 2.78 (3H, s), 3.01-3.07 (2H, m), 3.10-3.16 (2H, m), 7.46 (1H, t), 7.53 (1H, d), 7.65 (2H, s, partially exchanged), 7.83 (1H, d), 8.27 (1H, s), 8.48 (1H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10].[CH3:14][O:15][C:16](=[O:45])[N:17]=[C:18]([S:43][CH3:44])[C:19]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[C:35]([OH:41])[C:34]=1[F:42])=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH3:14][O:15][C:16](=[O:45])[N:17]=[C:18]([S:43][CH3:44])[C:19]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[C:35]([O:41][CH2:8][C:9](=[O:10])[N:11]([CH3:13])[CH3:12])[C:34]=1[F:42])=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[CH:23][CH:22]=1
Reactant: CCc1cc(O)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
After adding 0.163 g of potassium carbonate and 0.14 ml of 2-chloro-N,N-dimethylacetamide to a solution of 0.41 g of {2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 15 ml of DMF, the reaction mixture was stirred at room temperature for 60 hours, and then 200 ml of ethyl acetate and 100 ml of water were added. The organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.41 g) as a light yellow solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH:24]([N:31]([CH3:33])[CH3:32])[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19]>CCOCC>[C:8]([O:29][CH2:28][CH2:27][CH2:26][C:25](=[O:30])[CH:24]([C:20]1([C:15]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=2)[CH2:23][CH2:22][CH2:21]1)[N:31]([CH3:33])[CH3:32])(=[O:10])[CH3:9]
Reactant: CN(C)C(C(=O)CCCO)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OCCCC(=O)C(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
Triethylamine and then a solution of acetyl chloride in ether were added dropwise to a solution of the product of Example 45 in ether and the mixture was heated under reflux for 90 minutes, cooled and filtered. The filtrate was diluted with water and extracted with ether. The extract was washed, dried and evaporated to give an oil which was distilled on a Buchi Kugelrohr apparatus (200°/0.5 mm) to give 5-[1-(3,4-dichlorophenyl)cyclobutyl]-5-dimethylamino-4-oxopentyl acetate.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[I-].[K+].C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][CH:2]([F:5])[CH2:3][NH:4][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NCC(F)F
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNCC(F)F
Temperature: 25 °C
Reaction time: 25 h

Procedure:
2,2-difluoroethylamine (4.0 g) was added to a suspension of ethyl bromoacetate (5.4 mL), potassium iodide (0.82 g), diisopropylethylamine (9.8 mL) in acetonitrile (100 mL) and the mixture was stirred at RT for 25 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the sub-title compound (7.0 g) as a colorless oil; 1H NMR (300 MHz, CDCl3); 5.82 (1H, tt), 4.18 (2H, q), 3.46 (2H, s), 3.00 (2H, dt), 1.26 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43][NH2:44].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([NH:44][CH2:43][C:42]1[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=1[F:40])=[O:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1F
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(O)cc2)C(=O)CCC(=O)O)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(O)cc2)C(=O)CCC(=O)NCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A mixture of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl)succinamic acid (0.67 g, 1.2 mmols), 2-fluorobenzylamine (0.16 ml, 1.4 mmols), diethyl cyanophosphate (0.20 ml, 1.4 mmols), triethylamine (0.20 ml, 1.4 mmols) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an amorphous solid of N-[2-[3(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl)-N′-(2-fluorobenzyl)succinamide (0.69 g, 97%).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][C:14]=2[Cl:21])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[OH-:28].[K+].[OH2:30]>C(O)C>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:30])=[O:28])=[CH:15][C:14]=2[Cl:21])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCc1c(OCCCOc2ccc(C#N)cc2Cl)ccc(C(C)=O)c1O
Reactant: O
Agent: [K+]
Solvent: CCO
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Cl)ccc(C(C)=O)c1O

Procedure:
A mixture of 1-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-3-(2-chloro-4-cyanophenoxy)propane (1 g), potassium hydroxide (2 g), water (5 ml) and ethanol (10 ml) was refluxed for 4 hours, then concentrated, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried over sodium sulfate, the solvent was distilled off and the residue was recrystallized from ethyl acetate to give 4-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3-chlorobenzoic acid as crystals (780 mg). Melting point 171°-172° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C[N:16](C)C=O.N>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([NH2:16])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc2c(c1)OCO2
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a suspension of 50.0 g (260 mmol) 3-Benzo[1,3]dioxol-5-yl-acrylic acid in 300 ml tetrahydrofurane and 3.0 ml N,N-dimethyl formamide 44.5 ml (350 mmol) oxalyl chloride was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 750 ml of an 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 49.5 g (99%) 3-Benzo[1,3]dioxol-5-yl-acrylamide were obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: O=C(O)c1[nH]ccc1Cl
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.0289 g, 0.199 mmol) nd diisopropylethylamine (0.052 mL, 0.298 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.018 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80 (br. s., 1H), 8.29-8.40 (m, 1H), 7.91-8.04 (m, 2H), 7.57-7.69 (m, 3H), 7.51 (dd, 1H), 7.35 (t, 2H), 6.93 (t, 1H), 6.52 (d, 1H), 6.19 (t, 1H), 4.54 (d, 2H). ES MS: m/z 429 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:21]=1)[CH3:2].C([O-])(=O)C.[NH4+:30].C(OCC)C>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH2:30])[C:8]=2[N:21]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CC(C)C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOCc1nc2c(N)nc(C)cc2n1CC(C)C
Temperature: 150 °C
Reaction time: 36 h

Procedure:
A sealed glass tube containing 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.51 g) from Part E and ammonium acetate (25.1 g) was heated to 150° C. After 36 hours, TLC monitoring indicated that the reaction was complete. The resulting reaction mixture was cooled and then dissolved in ethyl acetate. The ethyl acetate solution was washed with 25% aqueous sodium hydroxide. The resulting organic layer was dried with magnesium sulfate, and concentrated under reduced pressure to an orange oil. The oil was put through a column using 95/5 ethyl acetate/methanol, providing good separation. The oil recovered from the product fraction was dissolved in isopropyl alcohol, to which 1M HCl in diethyl ether was added. A white solid formed. More diethyl ether was added, and the white solid was filtered and dried under vacuum at 80° C. for 5 hours. The resulting solid was dissolved in water (50 ml), and the pH was adjusted to 11 using sodium carbonate. An oil separated and was extracted with dichloromethane. The resulting dichloromethane solution was dried with magnesium sulfate and concentrated under reduced pressure to a clear oil. The oil was triturated with methanol, and the resulting solid was dissolved in diethyl ether. The diethyl ether solution was subjected to high vacuum at room temperature to dry the product. The resulting partially solidified product was solidified by cooling with an isopropyl alcohol/dry ice bath to provide 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 77.0-79.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].Br[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[C:22]([O:27][CH3:28])[CH:23]=[CH:24][CH:25]=2)[C:20]([CH:29]=O)=[CH:19][CH:18]=1.C(OCC)(OCC)OCC.[I-].[K+].[CH2:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][NH:44]1>CN(C=O)C>[CH2:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][N:44]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[C:22]([O:27][CH3:28])[CH:23]=[CH:24][CH:25]=2)[C:20]([CH:29]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cccc2c(OCCBr)ccc(C=O)c12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(OCC)OCC
Product: COc1cccc2c(OCCN3CCc4ccccc4C3)ccc(C=NNC(=O)c3ccc(O)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The above resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (2 g, 1.8 mmol) was swelled in DMF (25 mL) for 30 minutes and the above 4-(2-bromoethoxy)-8-methoxynaphthalene-1-carbaldehyde (1.7 g, 5.4 mmol) was added followed by triethyl orthoformate (1.2 mL) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was successively washed with DMF (3×25 mL), dichloromethane (4×25 mL) and N-methyl pyrrolidin-2-one (NMP) (2×25 mL). NMP (25 mL) was added followed by potassium iodide (0.6 g) and 1,2,3,4-tetrahydro-isoquinoline (2.25 mL, 18 mmol) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was successively washed with NMP (2×25 mL) and dichloromethane (6×25 mL). The compound was cleaved off the resin by addition of 50% TFA in dichloromethane (30 mL) and shaking at room temperature for 1 hour. After filtration followed by extraction of the resin with dichloromethane (2×30 mL) the combined filtrates were concentrated in vacuo. The residue was partitioned between ethyl acetate (80 mL) and saturated sodium hydrogen carbonate (100 mL). The aqueous phase was extracted with ethyl acetate (2×80 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (200 mL) eluting with a mixture of dichloromethane and methanol (9:1). This afforded 217 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:21]1([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CCCCCC>[C:21]1([N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:15]4[C:16]([C:13]=3[CH:14]=2)=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc(N(c3ccccc3)c3ccc4c(c3)c3ccccc3n4-c3ccccc3)cc2)cc1

Procedure:
The Rf values of the objective substance, 3-bromo-9-phenyl-9H-carbazole, and N-phenyl-N-(4-phenylphenyl)amine were respectively 0.65, 0.73, and 0.54, which were obtained by silica gel thin layer chromatography (TLC) (with a developing solvent containing ethyl acetate and hexane in a 1:5 ratio).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[CH:12]=[CH:11]C(C(F)(F)F)=[CH:9][N:8]=1.C([N:20](C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:9]1[N:8]=[CH:7][CH:12]=[CH:11][N:20]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: CNCCNc1ncccn1

Procedure:
A solution of 100 mg of N-methylethylenediamine, 245 mg of 2-chloro-5-trifluoromethylpyridine and 261 mg of diisopropylethylamine in toluene was heated at 110° C. for 18 h. The reaction mixture was concentrated, poured into water, and extracted with 10% IPA/chloroform. The organic extracts were dried over sodium sulfate, filtered, and concentrated to provide the desired title compound contaminated with <3% of the bis-substituted dimer. MS (M+H)+=220.2.