Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](O)([C:12]([F:15])([F:14])[F:13])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([C:12]([F:15])([F:14])[F:13])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2ccc(Cl)nn12
Temperature: 85 °C

Procedure:
A mixture of 3-chloro-6-hydrazinylpyridazine (3.3 g, 22.8 mmol) in TFA (60 mL) was heated to 85° C. for 18 h. The reaction mixture was cooled to room temperature and TFA was removed in vacuo. The residue was partitioned between DCM and saturated aqueous sodium bicarbonate and the organic layer was washed with a saturated solution of sodium bicarbonate (3×), dried over sodium sulfate, and evaporated to dryness to afford 2.8 g of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)n1
Yield: 88.3 %

Procedure:
Reaction of the above carbamate (300 mg, 0.542 mmol) with an excess of TFA (2 mL) in CH2Cl2 (10 mL) at room temperature for 3 hrs, followed by treatment with aq. NH3 gave 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]aniline (217 mg, 88%), which was used in the next step without further purification: 1H NMR (DMSO-d6) δ 8.17 (d, J=8.7 Hz, 2H), 8.05 (dd, J=8.3, 0.4 Hz, 1H), 7.80 (t, JHF=52.9 Hz, 1H), 7.47 (t, J=8.2 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 2H), 6.05 (s, 2H), 4.01 (br s, 2H), 3.99 (s, 3H), 3.88 (br s, 2H), 3.75 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[CH3:20][CH:19]([CH3:21])[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC(C)C(=O)O
Product: CC(C)C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 78.8 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8.8 mg (0.10 mMol) isobutyric acid, 11.8 mg (79%) of the title compound were recovered.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22](=[O:24])[CH3:23]>CC(=O)CC>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[O:1][C:21]([C:22](=[O:24])[CH3:23])=[CH:4][C:3]=2[CH:6]=1
Reactant: COc1cc(O)c(C=O)cc1OC
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc2cc(C(C)=O)oc2cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a solution of 2-hydroxy 4,5-dimethoxybenzaldehyde (2 g, 10.98 mmol) in butane-2-one (15 ml) added K2CO3 (6.07 g, 43.95 mmol) and then stirred at 0° C. for 10 min added bromoacetone (2.24 g, 16.47 mmol) and refluxed at 90° C. for 4 hr. After completion of the reaction butane-2-one was distilled off and water was added and extracted by ethylacetate twice. The EtOAc phase was dried over Na2SO4, Chromatography of the residue on silica gel (3:7 EtOAc/hexane) afforded the ketone A2 (1.69 g) in 70% yield pale yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.29 (s, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 2.30 (s, 3H) ppm. Mass: ESI [M+Na]+: 243.07; Elemental anal. calcd. for C12H12O4; C, 65.45; H, 5.49. found C, 65.20; H, 5.25.
Reaction SMILES: [OH-].[K+].C([O:6][C:7]1[C:16]([S:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=[O:19])=[O:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)C.Cl>C(O)C>[CH2:20]([S:17]([C:16]1[C:7]([OH:6])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:19])=[O:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCS(=O)(=O)c1cc2ccccc2cc1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCS(=O)(=O)c1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
To a solution of 25 g potassium hydroxide in 500 ml ethanol was added 25 g (0.050 mole) 3-octadecanesulfonyl-2-naphthyl acetate. The mixture was stirred at room temperature in a nitrogen atmosphere for 1.5 hr. then acidified with 5% hydrochloric acid. The solid was collected, dried, and recrystallized from hexane-ethyl acetate to give 18 g of white product, m.p. 98°-99° C.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Fc1ccc(CBr)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3Cc2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-fluorobenzyl bromide. The title compound was obtained in 5% yield as yellow oil. MS (m/e): 514.3 (MH+, 100%).
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11](I)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>>[C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[C:36]([O:37][CH3:38])[CH:35]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(=O)N1c2ccc(I)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1
Product: COc1ccc(-c2ccc3n(c2=O)[C@H](c2ccc(Cl)cc2)[C@H](c2ccc(Cl)cc2)N3C(C)=O)cc1OC

Procedure:
rac-cis-1-Acetyl-2,3-bis-(4-chloro-phenyl)-6-(3,4-dimethoxy-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-1-acetyl-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-6-iodo-1H-imidazo[1 2-a]pyridin-5-one with 3,4-dimethoxyphenylboronic acid The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 535.16; the expected mass is 534.1. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=C[C:29](C#N)=[C:28](N)[CH:27]=1)=[O:4].[N:35]1[CH:40]=[N:39][CH:38]=[N:37][CH:36]=1.CC(O)=O>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:12])=[O:13])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[C:36]2[C:29]([C:40]([NH2:35])=[N:39][CH:38]=[N:37]2)=[CH:28][CH:27]=1)=[O:4]
Reactant: c1ncncn1
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 38.9 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (42 mg, 0.08 mmol), EXAMPLE 99, 1,3,5-triazine (40 mg, 0.48 mmol), and glacial HOAc (30 mg, 0.48 mmol) in absolute EtOH (1 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated and then dissolved in water/CH3CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 17 mg (32%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C([O:25][C:26]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:27])C>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:33]=[CH:34][C:29]([CH2:28][C:26]([OH:27])=[O:25])=[CH:30][CH:31]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CC(=O)O)cc4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 4-(ethoxycarbonylmethyl)phenyl boronic acid following a procedure analogous to that described for Intermediate 63. LC (method 5): tR=1.58 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([Cl:5])=[O:4].[CH2:6]([NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([NH:13][C@H:14]([CH3:17])[CH2:15][O:16][CH2:2][C:3]([Cl:5])=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@H](CO)NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H](COCC(=O)Cl)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroacetyl chloride (11.6 mL, 120 mmol) was added dropwise at 0° C. to a solution of (R)-2-(benzylamino)propan-1-ol (19.9 g, 120 mmol) and triethylamine (30.5 mL) in toluene (600 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure and the recovered solids dissolved in EtOAc (500 mL) and then washed with saturated bicarbonate (2×250 mL), H2O (250 mL) and saturated brine (250 mL). The organic phase was then dried (Na2SO4), filtered and concentrated to afford (R)-2-(2-(benzylamino)propoxy)acetyl chloride: MS consistent.
Reaction SMILES: C(O)[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])O)O.[C:13]([O-])(O)=O.[Na+].I([O-])(=O)(=O)=O.[Na+]>C(Cl)Cl>[C:4](=[C:6]([OH:7])[CH:8]([OH:9])[CH:10]=[O:11])([CH3:2])[CH3:13]
Reactant: O=C([O-])O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)=C(O)C(O)C=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The mannitol derivative of Example 7(a) (81 g, 0.311 mol) was suspended in CH2Cl2 (1.1 L) and saturated NaHCO3 (40 mL) and stirred at ambient temperature. Sodium periodate (100 g, 0.47 mol) was added in four portions over 20 minutes and the solution was stirred vigorously at 0° C. for 3 hours. The solvent was decanted off and the remaining solid was stirred in CH2Cl2 and then filtered to remove the excess solid. The two organic portions were combined and concentrated in vacuo. The resulting oil was distilled at reduced pressure to give the title product as a clear, viscous oil. Yield (59 g, 75%). 1H NMR (CDCl3) δ4.3 (t, 1 H), 3.9 (m, 2 H), 1.4 (d, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:30]=[C:31]1[CH2:36][S:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][CH2:41][C:39]3[CH:38]=[CH:37][C:34]4[S:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=4[N:40]=3)[CH2:14][CH2:13]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(N3CCN(CCN)CC3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(N3CCN(CCNCc4ccc5c(n4)NC(=O)CS5)CC3)c2n1
Reaction time: 12 h
Yield: 29.7 %

Procedure:
To a solution of (2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amine (155 mg, 0.508 mmol) in DCM-EtOH (5 mL, 1:1) were added Na2SO4 (144 mg, 1.02 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (99 mg, 0.508 mmol). After 12 h at 25° C., the imine was quenched by addition of NaBH4 (29 mg, 0.762 mmol) in one portion. After an additional 1 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (73 mg, 30%) as a light yellow solid: LCMS (ES) m/e 484 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.46 (d, J=4.8 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.13 (d, J=9.1 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 4.06 (s, 3H), 3.92 (s, 2H), 3.83 (bs, 4H), 3.54 (bs, 2H), 2.88 (s, 2H), 2.66-2.72 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13].COC1C=CC([NH2:44])=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:44][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])=[CH:22][C:21]=2[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:13])[CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2ccc3ccccc3c2O)c(C(C)(C)CC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
1-Hydroxy-N-[4-(2,4-di-t-pentylphenoxy)-butyl]-2-naphthamide was coupled with a diazotized p-anisidine ##STR29## The azo group of the compound thus prepared was then reduced with sodium dithionite (Na2S2O4) to the corresponding amine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23](C4C=CN=CC=4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=NN([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)C=2)O1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccncc3)c2)c2ccc(F)cc21
Reactant: CC1(C)OB(c2cnn(-c3ccccn3)c2)OC1(C)C
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccccn3)c2)c2ccc(F)cc21
Yield: 62 %

Procedure:
Following the general method as outlined in Intermediate 10, starting from 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine (Intermediate 14; 485 mg; 1.80 mmol), 234 mg (62%) of the title compound was obtained as a yellow solid after purification by a silica gel chromatography (petroleum ether/EtOAc=1/1).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][NH:9][C:10]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:41]=[CH:40][C:25]([O:26]C2C=CC(C#N)=C(OCC(F)F)N=2)=[CH:24][C:23]=1[CH:42]=[O:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:16]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19])[N:17]=2)=[CH:24][C:23]=1[CH:42]=[O:43]
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OCC(F)F
Reactant: CC(C)(C)[Si](C)(C)OCCNc1nc(Cl)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNc1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Yield: 75.6 %

Procedure:
To a solution of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-6-chloro-nicotinonitrile (4, 1.1 g, 3.5 mmol) in DMF (80 mL) were added 2-bromo-5-hydroxy-benzaldehyde (5, 0.75 g, 3.7 mmol) and K2CO3 (0.97 g, 7.05 mmol). The reaction was heated at 80° C. for 24 h. The DMF was removed in vacuo. Purification was accomplished by Biotage silica gel chromatography with 1%-3% EtOAc/hexanes gradient to afford 1.26 g (75% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:2].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[S:32])[NH2:18])=[CH:15][CH:16]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:23]
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(C(N)=S)cc1)(NC(C)=O)C(=O)OCC
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a solution of 10.0 g (30 mmoles) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester and 3.5 g (35 mmoles) of triethylamine in 250 ml of pyridine, hydrogen sulfide gas is introduced until the solution is saturated. The reaction mixture is then stirred at 25° for 18 hours, followed by evaporation of the solvent. The residue is slurried with 50 ml of carbon disulfide for 1 hour and the resulting crystalline solid recovered by filtration to yield 8.7 g (24 mmoles, 80 %) of N-acetyl-α-ethoxycarbonyl-4-thiocarbamoylphenylalanine ethyl ester, m.p. 168°-172°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:28]([NH2:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:28]([NH:30][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:29]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (77 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100 mg), ethylamine (2 M in THF, 254 uL), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 421.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.46 (bs, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.74 (s, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 3.66 (bs, 3H), 3.30 (q, 2H), 1.13 (t, 3H).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].[O-]CC.[Na+].[C:15](OC)(=[O:18])[CH:16]=[CH2:17].Cl>>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N:3]2[CH2:17][CH2:16][C:15](=[O:18])[NH:4]2)[CH:6]=1
Reactant: NNc1cccnc1
Reactant: C=CC(=O)OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: O=C1CCN(c2cccnc2)N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a four-neck round bottomed flask (250 mL) which contained 3-hydrazinopyridine dihydrochloride (18.2 g, 0.100 mol) was added sodium ethoxide (21 wt % in ethanol, 107 g, 0.330 mol). The temperature of the slurry rose to 33° C. over 5 minutes. The mixture was stirred at room temperature for 1.25 hours. To the light red tinted slurry was added methyl acrylate (18.0 mL, 0.200 mol) over 10 minutes, with the temperature rising from 25° C. to 35° C. The color of the slurry changed from light red to brown/green. The mixture was heated at 55° C. for 3 hours. After stirring at room temperature overnight, the mixture was neutralized to pH ˜7 with hydrochloric acid (4 M in 1,4-dioxane, 32.6 g, 0.130 mol). The dark gray slurry was concentrated to a dark, paste like solid.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[C:20]([C:29]#[N:30])[CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([C:20]1[CH:19]=[C:18]([N:17]=[C:8]=[S:9])[C:27]([CH3:28])=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)#[N:30]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)cc(C#N)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)cc(C#N)c2cccnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (1.22 g) and 4-dimethylaminopyridine (0.08 g) in methylene chloride (60 mL) is added dropwise a solution of 7-amino-5-cyano-8-methylquinoline (1.22 g) in methylene chloride (80 mL). The mixture is stirred for 4 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane to afford 5-cyano-8-methyl-7-quinolinylisothiocyanate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)cc(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of dimethyl 5-bromoisophthalate (5.4 g, 20 mmol) in methanol (300 mL) at 0° C. was slowly added sodium tetrahydroborate (10 g, 0.28 mol). The mixture was stirred at rt for 3 h, and then treated with water (300 mL). The volatiles were removed in vacuo and the aqueous phase was extracted with CH2Cl2 (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting oil was purified by flash chromatography to afford the title compound.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:23]=2)[CH:18]=[CH:17]1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:21]1[CH:20]=[C:19]2[CH:18]=[CH:17][NH:16][C:24]2=[N:23][CH:22]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Product: c1ccc2c(c1)OCCc1cc(-c3cnc4[nH]ccc4c3)sc1-2

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine from Example 73 was reacted with 7-azaindole-5-boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on prep HPLC gave 136. 1H NMR (400 MHz, CDCl3): 3.30 (2H, t), 4.40 (2H, t), 6.56-6.58 (1H, m), 7.05-7.07 (2H, m), 7.15-7.18 (2H, m), 7.36 (1H, t), 7.75 (1H, d), 8.16 (1H, d), 8.63 (1H, d). MS: (ESI+) 318