Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Zn+])=[CH:6][CH:5]=1.Br[C:13]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[N:23][C:24]=3[CH2:25][CH2:26][C:17]=2[CH:16]=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:13]2[C:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[N:23][C:24]=4[CH2:25][CH2:26][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: Brc1cccc2c1-c1cccnc1CC2
Agent: [Cl-]
Product: COc1ccc(Cc2cccc3c2-c2cccnc2CC3)cc1
Yield: 85 %

Procedure:
The title compound is prepared from 4-methoxybenzylzinc chloride and 10-bromo-5,6-dihydro-benzo[f]quinoline following a procedure analogous to that described in Step 1 of Intermediates 21 and 22. Yield: 85% of theory; LC (method 1): tR=3.09 min; Mass spectrum (ESI+): m/z=302 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:18])=[C:12]([CH2:14][CH2:15][CH2:16][OH:17])[N:13]=2)=[CH:5][CH:4]=1.O[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=[O:31])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([CH3:18])=[C:12]([CH2:14][CH2:15][CH2:16][O:17][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([CH:30]=[O:31])=[CH:22][CH:21]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(CCCO)c(C)o2)cc1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(CCCOc3ccc(C=O)c4ccccc34)c(C)o2)cc1
Reaction time: 3 h

Procedure:
g of the above prepared 3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propan-1ol (4.04 mmol) was dissolved in 21 ml of toluene and treated successively at 0° C. with 0.696 g of 4-hydroxy-naphthalene-1-carbaldehyde (4.04 mmol), 1.061 g of triphenylphosphine (4.04 mmol), and 0.818 g (4.04 mmol) of DIAD. The cooling bath was then removed and stirring continued for 3 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with 3N NaOH and water, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=7/3) left finally 1.084 g of the title compound as light yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH3:17])([CH3:18])[CH2:14][CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCCC(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 3.0 g of N-(3,5-dichlorophenyl)-N'-(1,1-dimethylbutyl)thiourea produced in Example A-3 in 50 ml of dichloromethane were added 5.2 g of triphenylphosphine, 3.1 g of carbon tetrachloride and 2.0 g of triethylamine. The mixture was refluxed for 6 hours, and then evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-(1,1-dimethylbutyl)carbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 1.6 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 6 hours, cooled to room temperature and poured into 400 ml of water. The resulting crystals were filtered off, washed with small amount of cyclohexane, and purified by silica gel column chromatography using chloroform as a solvent to give 1.2 g of the title compound. Recrystallization from cyclohexane gave 1.1 g of colorless platelets melting at 115.0°-117.0° C.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=[CH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:29][CH:28]=2)=[CH:43][CH:44]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: Cc1ccc(CC=CC(C)Cc2ccc(C(C)(C)C)cc2)cc1
Yield: 41.5 %

Procedure:
Starting from p-methylphenethyltriphenylphosphonium bromide (5.04 g, 9.91 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 6.2 mL, 9.91 mmol, 1.0 equiv.) and 3-(4-tert-butylphenyl)-2-methylpropanal (3.04 g, 14.9 mmol, 1.5 equiv.), 1.26 g (42%) of the title compound as a light yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10](Cl)=[N:9][N:8]=1.Br.[C:25](=[O:28])([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:6]([CH2:5][CH2:4][CH2:25][OH:28])[CH3:7])=[N:9][N:8]=[C:7]2[NH:6][CH2:5][C:4]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(Cl)cc23)cc1Cl
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nnc(N(C)CCCO)c3ccc(Cl)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 7.5 h
Yield: 6.5 %

Procedure:
The compound (1.0 g, 2.7 mmol) prepared in Example 27 was dissolved in 9 ml of N-methyl-2-pyrrolidone, followed by the addition of 0.7 g (4.1 mmol) of N-methylpropanolamine hydrobromide and 1.14 g (8.2 mmol) of anhydrous potassium carbonate. The obtained mixture was stirred at 170° C. for 7.5 hours, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by distillation. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (20:1)] and crystallized from dichloromethane/ether to give 37 mg of the title compound as white needles.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[CH3:16][O:17][C:18]1[CH:19]=[C:20](OB(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=3)[CH:3]=[C:4]2[C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: COc1cccc(OB(O)O)c1
Reactant: COc1ccc2cc(Br)cc(C#N)c2c1
Product: COc1cccc(-c2cc(C#N)c3cc(OC)ccc3c2)c1
Reaction time: 24 h
Yield: 53 %

Procedure:
The compound is prepared by the reaction of 3-bromo-7-methoxy-1-naphthonitrile (1.4 g, 1.76 mmol, 1 eq) with 3-methoxyphenylboric acid (320 mg, 2.11 mmol, 1.2 eq) according to method A in 24 h. Purification by column chromatography with hexane/ethyl acetate 9/1 as the eluent yielded the desired compound in a yield of 53%, 300 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH2:11].[Si]([C:16]([F:19])(F)[F:17])(C)(C)C.[Na+].[I-]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:11][C:16]1([F:19])[F:17]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=Cc1ccc(OC)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2CC2(F)F)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The solution of 2-chloro-4-methoxy-1-vinylbenzene (290 mg, 1.72 mmol) in dry THF (4 mL) was degassed, and then TMS-CF3 and NaI were added. The mixture was stirred at 80° C. overnight. TLC (100% Hexane) showed the reaction as complete. The mixture was diluted with hexane (20 mL). The inorganic salt was removed by filtration. The filtrate was concentrate in vacuo. The residue was purified via Isolera One (Hexane=100%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:54][NH2:55]>C1COCC1>[CH3:54][NH:55][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([O:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([NH:12][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)=[O:29])[CH2:14][CH2:15]2)=[CH:28][CH:27]=1
Reactant: CN
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(O[C@H]2CC[C@H](NC(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1728 (0.22 g, 0.5 mmol), EDC HCl (0.12 g, 0.63 mmol), HOBT (0.09 g, 0.63 mmol), TEA (0.17 mL, 0.63 mmol) in THF (10 mL) was added 2M MeNH2 in THF (1.25 mL, 2.5 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature overnight. The solvent was removed in vacuo and then purified by recrystallization with EtOAc/Hexanes gave the title compound, 0.16 g (71%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.28 (q, J=4 Hz, 1H), 7.77 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 6.99 (d, J=9 Hz, 2H), 6.21 (d, J=8 Hz, 1H), 4.49-4.36 (m, 1H), 3.62-3.45 (m, 1H), 2.75 (d, J=4 Hz, 3H), 2.11-1.87 (m, 4H), 1.57-1.25 (m, 4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:11](=[O:17])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[I:18]I>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[I:18][C:10]1[C:11](=[O:17])[N:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:9]=1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nccc(-c2cc(=O)n3n2CCC3)n1
Reactant: II
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1nccc(-c2c(I)c(=O)n3n2CCC3)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 20, (4.7 g, 19.1 mmol), in carbon tetrachloride/pyridine (140 mL of 1:1 mixture) is added dropwise a solution of iodine in carbon tetrachloride/pyridine (80 mL of 1:1 mixture). After stirring at 0° C. for 30 min, the ice-bath is removed at the mixture was stirred at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was poured into aqueous saturated Na2S2O3. The aqueous phase is extracted with EtOAc (×3). The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The resulting yellow solid is purified by silica gel chromatography (5% MeOH/chloroform) to afford 4.2 g of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=5.1 Hz, 1H), 7.97 (d, J=5.1 Hz, 1H), 4.31 (t, J=6.9 Hz, 2H), 4.10 (t, J=6.9 Hz, 2H), 2.74 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.62 (s, 3H); ESI+ MS: m/z (rel intensity) 375.0 (100, M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:44]=[CH:43][C:35]([O:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][C:33]=1[O:45][CH3:46])=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:44]=[CH:43][C:35]([O:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][C:33]=3[O:45][CH3:46])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cc(OCCCC(=O)O)ccc1C=O
Product: COc1cc(OCCCC(=O)O)ccc1CNc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(4-formyl-3-methoxy-phenoxy)-butyric acid according to the procedure of Example 66. MS (ESI) m/z 613.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)[N:5]=2.C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[F:62][C:63]([F:72])([F:71])[C:64]1[CH:65]=[C:66]([CH:68]=[CH:69][CH:70]=1)[NH2:67].[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:67][C:66]1[CH:68]=[CH:69][CH:70]=[C:64]([C:63]([F:62])([F:71])[F:72])[CH:65]=1)=[O:16])[N:5]=2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Nc1nc2ccc(-c3cccc(C(=O)O)c3)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2ccc(-c3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
To a solution 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoic acid (310 mg, 1.14 mmol) in DMF (5.0 mL) was added N,N-diisopropylethylamine (0.56 mL, 3.42 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (649 mg, 1.71 mmol) and 3-(trifluoromethyl) aniline (0.28 mL, 2.28 mmol). The reaction mixture was stirred at room temperature for 16 h. The crude product was diluted with satd. NH4Cl solution (10 mL). The resulting brown solid was collected and washed with water and dried to give 320 mg (67% yield) of the 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)-N-(3-(trifluoromethyl)phenyl)benzamide.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)=[O:19])=[CH:14][CH:13]=3)=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:2]1.C(N(CC)CC)C.N1([C:41](=[O:43])[CH3:42])C=CN=C1.C1COCC1>CN(C=O)C>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[C:5]([CH:3]3[CH2:4][N:1]([C:41](=[O:43])[CH3:42])[CH2:2]3)=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: CC(=O)n1ccnc1
Reactant: O=C(c1ccc(Oc2ncccc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.3 %

Procedure:
To a solution of (4-(3-(azetidin-3-yl)pyridin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone (279 mg, 0.753 mmol) in DMF (1.0 mL) is added triethylamine (0.386 mL, 3.01 mmol) and 1-(1H-imidazol-1-yl)ethanone (100 mg, 0.904 mmol). A solid crashed out, so THF (2 mL) was added to give a homogeneous solution and the reaction was stirred at rt 2 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated, then purified by RPHPLC to give 1-(3-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)azetidin-1-yl)ethanone (35 mg, 0.085 mmol, 11.27% yield over 2 steps) as a white solid. MS (ESI, pos. ion) m/z: 413.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:4](=[O:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CCC(CC)C(=O)Cl
Product: CCC(CC)C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-ethylbutyryl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (71% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 8.00, 7.00, 3.86-3.90, 3.76, 3.68, 3.57, 2.57, 1.70, 1.50-1.55, 0.90, 0.45, 0.10. MS (ES+) m/z 374 (M+1).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH2:22][CH3:23])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:22][CH3:23])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1nnc(-c2cc(C(=O)OC)c(CC)cc2C2CCC2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nnc(-c2cc(C(=O)O)c(CC)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a round-bottom flask was added a solution of methyl 4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate (compound 181.8, 360 mg, 1.15 mmol, 1.00 equiv) in methanol (20 mL). A solution of sodium hydroxide (460 mg, 11.5 mmol, 10.0 equiv) in water (10 mL) was added to the reaction mixture. The resulting solution was stirred at 25° C. for 15 h. The organic solvent was then removed under reduced pressure. The pH value of the remaining aqueous phase was adjusted to 2-3 with hydrogen chloride (aq., 2 M). The resulting precipitate was collected by filtration and dried under high-vacuum to yield 320 mg (93%) of the title compound as a white solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH3:22])[C@H:6]([C@H:15]1[CH2:19][O:18]C(C)(C)[O:16]1)[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[N+:2]=[N-:3].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[N:1]([CH2:4][C@H:5]([CH3:22])[C@@H:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C@H:15]([OH:16])[CH2:19][OH:18])=[N+:2]=[N-:3]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O)CO
Temperature: 80 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of ((1R,2S)-3-azido-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)(tert-butyl)dimethylsilane (1.0 equiv.) in MeOH (0.1 M) was added PPTS (1.0 equiv.) and the mixture was stirred at rt for 14 hours, 50° C. for 2 hours and 80° C. for 1 hour. The volatiles were removed under vacuo and the residue was purified via silica gel column chromatography (10-25% EtOAc/n-heptanes) yielding (2R,3R,4S)-5-azido-3-(tert-butyldimethylsilyloxy)-4-methylpentane-1,2-diol (40%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1.[OH-].[Na+]>Br.C(O)(=O)C.O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(Cc1cccc(NS(=O)(=O)C(F)(F)F)c1)CC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(O)ccc2CCC1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 439 mg (1.06 mmol) of the product of Example 30 in 8 mL 48% HBr and 8 mL acetic acid was heated to reflux for 75 minutes under N2. The reaction mixture was cooled to room temperature, diluted with 300 mL H2O, pH adjusted to 3-4 using 2N NaOH, and extracted with twice with 150 mL ethyl acetate. The ethyl acetate extracts were combined and washed once with brine and then dried over Na2SO4. Filtration, concentration and drying yielded 0.42 g of tan solid, which was purified by silica gel chromatography (4% methanol-CH2Cl2) to yield 357 mg of pure product, an off-white powder. (84% yield) m.p.: 191°-194° C.; MS (LSIMS): 400 M+H, Base; 1H NMR (AC 300, dimethylsulfoxide-d6): δ9.58 (br s, 1H, phenol OH); IR (cm31 1): 3330, 3280, 1670. Analysis calculated: C 54.13, H 4.04, N 3.51%; C 53.99, H 3.95, N 3.49%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:20](OC)=[O:21]>C1COCC1>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH2:20][OH:21]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Reaction time: 1 h
Yield: 102.8 %

Procedure:
Diisobutylaluminum hydride (159 mL, 159 mmol) was added dropwise at −60° C. to a solution of methyl 1H-indole-2-carboxylate (10.0 g, 52.9 mmol) in THF (100 mL). After being stirred for 1 hour, the reaction was quenched with saturated NH4Cl. The resulting mixture was extracted with ethyl acetate (2×100 mL) and washed with brine, dried, and concentrated to give (1H-indol-2-yl)methanol (8.0 g, 100% yield) as a solid. LCMS (ESI) m/z: 148.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]([O:41]C(C)(C)C)=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1>>[C:12]([C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:8]3[C:7]4[CH:9]=[C:10]([N:14]5[C:15](=[O:24])[C:16]6=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]6[C:18]5=[O:19])[CH:11]=[C:12]([CH3:13])[C:6]=4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])=[CH:32][CH:31]=2)[C:34]=1[C:39]([OH:41])=[O:40])([CH3:13])([CH3:6])[CH3:11]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2[nH]1
Product: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2cccc(C(C)(C)C)c2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1a from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:18])[C:5](I)=[C:6]([CH3:16])[NH:7]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.COCCOC>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:18])[C:5]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)=[C:6]([CH3:16])[NH:7]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCOc1ccc(F)c2c(=O)c(I)c(C)[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c(C)[nH]c12
Temperature: 170 °C
Yield: 60.7 %

Procedure:
5-Fluoro-3-iodo-2-methyl-8-propoxy-1H-quinolin-4-one (400 mg, 1.11 mmol), 4-methoxyphenyl boronic acid (504 mg, 3.3 mmol), 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium (II)-dichloro methane complex (PdCl2(DPPF)) (100 mg, 0.12 mmol) and a 2N sodium carbonate aqueous solution (1 ml) were added to 1,2-dimethoxyethane (3 ml), and the mixture was heated at 170° C. for 10 minutes (microwave reactor). The reaction mixture was cooled to room temperature, and filtration with Celite was carried out. The filtrate was extracted with dichloromethane, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=100:0→40:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 230 mg of powdery white 5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin -4-one (yield: 61%).