Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][C:13](=[O:16])[C:12]=2[CH:17]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=[O:16])[C:12]=2[CH:17]=1
Reactant: CCOC(=O)Cl
Reactant: O=C1COc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1Oc2ccc(Br)cc2C1=O

Procedure:
Potassium carbonate (1.66 g, 12 mmol) is added to a solution of 5-bromo-1-benzofuran-3(2H)-one (2.13 g, 10 mmol) in acetone (25 mL). The stirred mixture is treated dropwise with ethyl chloroformate (1.05 mL, 11 mmol). The mixture is then heated at reflux for 18 h. The solids are filtered off and the filtrate concentrated in vacuo. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the organic layer washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([Br:12])[CH:11]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[O:13][C:8]1[CH:9]=[C:10]([Br:12])[CH:11]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:7]=1
Reactant: Cc1ccccc1N=C=O
Reactant: COC(COc1cc(O)cc(Br)c1)OC
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(COc1cc(Br)cc(OC(=O)Nc2ccccc2C)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethoxy)-5-bromophenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 2-Methylphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-bromophenyl] N-2-methylphenylcarbamate as the residue.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)[CH2:33]1>CN(C)C=O.C(#N)C>[CH3:48][N:45]1[CH2:44][CH2:43][N:42]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:39]=2[CH2:40][CH2:41][C@@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:33]3)[CH2:47][CH2:46]1
Reactant: CN1CCN(c2cccc3c2CC[C@@H](N)C3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN1CCN(c2cccc3c2CC[C@@H](NC(=O)c2ccc(N4CCOCC4)cc2)C3)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of 4-morpholinobenzoic acid (110 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1,1′-carbonyldiimidazole (87 mg, 0.54 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at 70° C. for 18 h and the solvent was evaporated in vacuo. The residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave after crystallization from acetonitrile, 65 mg (30% yield) of the title compound as white crystals: mp 127-128° C.; [α]21D +51° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (14, M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCCCC.[C:17]([N:24]1[CH2:27][C:26](=[O:28])[CH-:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[NH4+]>C(OCC)C>[F:9][C:4]1[CH:3]=[C:2]([C:26]2([OH:28])[CH2:25][N:24]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:27]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1[CH-]C(=O)C1
Reactant: Fc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)c(F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
To a solution of 4-bromo-1,2-difluorobenzene (1.35 g, 7.01 mmol) in dry diethylether (50 ml) at −78° C. under nitrogen was added n-hexyllithium (2.3 M in hexane, 3.0 ml, 7.01 mmol) dropwise. The mixture was stirred for 10 min after which a solution of 1-Boc-azetidone (1.0 g, 5.85 mmol) in dry diethyl ether (10 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 10 min and then brought to ambient temperature and stirred for 10 min. Saturated aqueous ammonium chloride (50 mL,) was added and the mixture was extracted with tert-butyl methyl ether (2×50 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethylacetate/isooctane 1:1) to give the title compound (1.06 g). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 156 (60), 141 (43), 127 (80), 57 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([O:23]C)=[O:22])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:32]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(C(=O)OC(C)(C)C)cc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a solution of 2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid dimethyl ester (1.63 g) in THF (16 ml) were added methanol (16 ml) and 8N-aqueous sodium hydroxide solution (0.8 ml) at room temperature, and the mixture was stirred for 18 hrs. The reaction mixture was concentrated under reduced pressure and water and 1N-hydrochloric acid (7 ml) were added to the residue. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methylene chloride was added to the residue and insoluble material was removed from the mixture. The filtrate was concentrated and recrystallized (ethyl acetate-hexane) to give the title compound (1.16 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[S:41])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC(=S)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of 14.8 g (33.9 mmol) of 4-benzyl 1-tert-butyl N-[(1-tert-butoxyformamido)acetyl]-L-aspartate and 6.9 g (17 mmol) of Lawesson reagent in 140 ml of dry toluene is heated to 100° for 2.5 hours. Thereafter, the solvent is distilled off under reduced pressure and the residue is boiled up three times with 500 ml of a 9:1 mixture of hexane and ether. The combined organic phases are evaporated and, for purification, the residue is chromatographed on silica gel using a 9:1 mixture of hexane and ether as the eluent, whereby there is obtained 4-benzyl 1-tert-butyl N-[(1-tert-butoxyformamido)thioacetyl]-L-aspartate as a viscous oil; MS: 452 (M)+.
Reaction SMILES: [ClH:1].Cl.[C:3]([N:6]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][C:29]([C:35](=[NH:37])[NH2:36])=[CH:30][CH:31]=4)[CH:26]=3)[C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)(=[NH:5])[CH3:4]>Cl>[ClH:1].[ClH:1].[C:3]([N:6]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][C:29]([C:35](=[NH:36])[NH2:37])=[CH:30][CH:31]=4)[CH:26]=3)[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)(=[NH:5])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCN(C(C)=N)C2)cc1
Agent: Cl
Product: CC(=N)N1CC[C@H](Oc2ccc(C(Cc3ccc4ccc(C(=N)N)cc4c3)C(=O)O)cc2)C1
Reaction time: 232 h
Yield: 198.4 %

Procedure:
While keeping the inner temperature at -5° C. or below, 110.1 g of ethyl (+)-2-[4-[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-3-(7-amidino-2-naphthyl)propionate dihydrochloride was dissolved in 3,300 ml of concentrated hydrochloric acid, and the resulting solution was allowed to stand still for 232 hours at 5° C. The resulting reaction solution was concentrated by distilling off hydrochloric acid and water under a reduced pressure. The resulting residue was purified by subjecting it to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with a small amount of dilute hydrochloric acid, and then concentrated to dryness. In this way, 103.6 g of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([S:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:16]2[CH:15]=[N:14]1.Cl[C:30]1[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:36]([C:33]1[CH:32]=[N:31][C:30]([N:26]2[CH2:25][CH2:24][CH:23]([S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]4[N:13]([C:4]5[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=5[F:2])[N:14]=[CH:15][C:16]=34)[CH2:28][CH2:27]2)=[N:35][CH:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(Sc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
A mixture of 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (250 mg, 0.56 mmol), 2-chloro-5-ethyl-pyrimidine (680 μL, 5.6 mmol), and triethylamine (315 μL, 2.24 mmol) in isopropanol (4 mL) was heated under microwave irradiation for 15 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound A237 as a white solid (100 mg, 35%). 1H NMR (CDCl3, 400 MHz) δ 1.18 (t, 3H), 1.82-1.94 (m, 2H), 2.28-2.37 (m, 2H), 2.53 (q, 2H), 3.06 (s, 3H), 3.55-3.64 (m, 2H), 4.41-4.55 (m, 3H), 7.82 (m, 3H), 8.24 (s, 1H), 8.37 (s, 2H), 8.74 (s, 1H). Exact mass calculated for C23H24FN7O2S2 513.61, found 514.4 (MH+).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH2:3]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)[C@@H:4]([C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH3:12])=[O:9])[CH2:3]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)CCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)CCN2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound (D133) (62 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-((2R)-4-fluoropiperidine-2-carboxamido)ethyl)benzoate (D95) (75 mg) and 4-(trifluoromethyl)-benzylbromide (0.045 ml). (Cs2CO3: 1.3 eq; reaction time: 18 hrs; RT).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([O-])(O)=O.[Na+].[Cl:18][CH2:19]OS(Cl)(=O)=O.C(Cl)Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O>[Cl:18][CH2:19][O:11][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(=O)(Cl)OCCl
Reactant: CCCCCCCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Decanoic acid (0.2 gm, 1.2 mmol) was treated with 4 eq NaHCO3, 0.1 eq Bu4NHSO4 and, 1.2 eq ClCH2OSO2Cl in 1:1 CH2Cl2:H2O. The reaction was stirred vigorously at 0° C. for 30 min then room temperature (“RT”) for 3 hrs. Aqueous workup yielded chloromethyldecanoate (yield 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[S:35])[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2c(Cl)cccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2c(Cl)cccc2c1=S
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl-8-chloro-1-(4-iodobenzyl)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (736 mg, 1.57 mmol) and Lawesson's Reagent (445 mg, 1.10 mmol, 0.7 equiv) were combined in toluene (8 mL) and placed into an oil bath preheated at 105° C. for 15 minutes. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 40:60; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1Oc1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C

Procedure:
A mixture of 2-aminopyridin-3-ol (1.00 g, 9.08 mmol) and DMF (20 mL) was cooled in a 0° C. bath and sodium hydride (0.240 g, 9.49 mmol) was slowly added in portions with vigorous stirring (significant gas evolution). After the addition was completed, the mixture was stirred at ambient temperature for 30 minutes to ensure all the NaH was consumed (reaction becomes very viscous). The 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (1.17 mL, 8.26 mmol) was added and the mixture heated to 110° C. under nitrogen overnight. The reaction was cooled to ambient temperature and the DMF removed under reduced pressure. The resulting black sludge was quenched with 0.5 N NaOH (100 mL) and extracted with Et2O). The organic layer was washed with 1N NaOH and brine, dried over sodium sulfate, filtered and concentrated to afford a brown solid. The solids were purified on silica gel eluting with 40% EtOAc/Hexanes to afford 3-(2-bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine the title compound.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]3[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=3[Cl:33])=[O:27])[CH2:21][CH2:20]2)[N:18]=1)[C:12]([O:14]C)=[O:13].Cl>CN(C=O)C>[Cl:33][C:32]1[C:31]([Cl:34])=[C:30]([CH3:35])[NH:29][C:28]=1[C:26]([NH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]2[CH:16]=[C:11]([CH:10]=[C:9]([O:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[N:18]=2)[C:12]([OH:14])=[O:13])[CH2:20][CH2:21]1)=[O:27]
Reactant: CN(C)CCO
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(OCCN(C)C)n3)CC2)c(Cl)c1Cl

Procedure:
Sodium (155 mg, 6.74 mmol) and 2-(dimethylamino)ethanol (0.677 ml, 6.74 mmol) were stirred together in DMF (1.5 ml). Methyl 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinate (Example 333; 200 mg, 0.449 mmol) was added. The reaction mixture was refluxed overnight, then brought to room temperature and acidified with 10% HCl. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, then with brine, dried over sodium sulfate and concentrated to give the desired product. The crude product was purified by reversed phase HPLC eluting with water/acetonitrile/TFA mixtures to afford the desired product (60 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:20][CH2:19][C:15]([NH:21][C:22]2C=CC=CC=2)([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.C(OCC)(OCC)OCC.C1(C)C=CC=CC=1.[OH-].[NH4+]>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:13][CH2:14][C:15]2([NH:21][CH:22]=[N:18][C:16]2=[O:17])[CH2:19][CH2:20]1
Reactant: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1N=CNC12CCN(CC1=Cc3ccccc3CC1)CC2

Procedure:
A mixture of 1-[(3,4-dihydro-2-naphthalenyl)methyl]-4-anilino isonipecotamide (6.0 g), triethyl orthoformate (3.0 g), toluene (30 ml), and glacial acetic acid (1.5 ml) is refluxed under nitrogen for 38 hours. The reaction mixture is cooled and poured into aqueous ammonium hydroxide. The organic layer is separated, dried, and concentrated to give the crude product. Digestion of this material with benzene followed by filtration and concentration of the organic solution yields the title compound.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([O:20]C)=[O:19])=[CH:10]1.Cl>O1CCCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([OH:20])=[O:19])=[CH:10]1
Reactant: COC(=O)c1cn(-c2ccccn2)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccccn2)c2ncccc12

Procedure:
1.6 cm3 of 10N sodium hydroxide solution were added to methyl 1-(pyridine-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate in 15 cm3 of tetrahydrofuran. After stirring at reflux of the solvent for 200 h, the reaction mixture was acidified with 2 cm3 of 10N hydrochloric acid and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid in the form of a brown powder, characterized by LC/MS (m/z 240 [MH]+), which was used directly in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1)[CH2:27][NH:28][CH3:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:37]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([CH:26]([OH:25])[CH2:27][N:28]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[CH:17]=2)[CH3:29])=[CH:31][CH:32]=1)(=[O:39])[CH3:38]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1ccc(NC(C)=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1ccc(C(O)CN(C)Cc2cc3c(s2)c(=O)c(C(=O)NCc2ccc(Cl)cc2)cn3C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 58.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), N-{4-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (42 mg, 0.20 mmol) and diisopropylethylamine (40 μL, 0.23 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with 3 mL of warming acetonitrile, cooled to room temperature, diluted with 2 mL of water, and then cooled to 0° C. overnight) gave the title compound (42 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][OH:28])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][C:42]([F:45])([F:44])[F:43])[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][C:33]=1[O:41][C:42]([F:43])([F:44])[F:45])(=[O:39])=[O:38])[C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][OH:28])[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N[C@@H](CO)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N[C@@H](CO)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 0.88 g of the compound obtained in Step 65-3 and 0.649 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, respectively 140 mg (Isomer A, colorless amorphous) and 170 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Example 2.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(trifluoromethyl)phenylboronic acid (1.63 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.4 g, 17.2 mmol) and Pd(PPh3) 4 (0.497 g, 0.430 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (0.22 g, 0.739 mmol, yield 9%) as a brown solid.