Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[CH:11][C:12]([C:16](OCC)=[O:17])=[N:13][C:14]=1[I:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([I:15])=[N:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C)c(NC(=O)OC(C)(C)C)c(I)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1cc(CO)nc(I)c1NC(=O)OC(C)(C)C
Yield: 57.5 %

Procedure:
To a solution of ethyl 5-(tert-butoxycarbonylamino)-6-iodo-4-methylpyridine-2-carboxylate (1.94 g) in toluene (48 mL) was added diisobutylaluminium hydride (0.99 mol/L toluene solution, 25 mL) at −78° C., and the mixture was stirred under ice-cooling for 2 hours, and then stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−1/9) to give 3-(tert-butoxycarbonylamino)-6-hydroxymethyl-2-iodo-4-methylpyridine (1 g). This material was dissolved in N,N-dimethylformamide (5 mL). To the solution were added imidazole (0.24 g) and tert-butyldimethylchlorosilane (0.46 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=7/3) to give the title compound (1.3 g).
Reaction SMILES: [C:1]1([CH:7]=[N:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl>CC(C)=O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:9][N:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccccn1
Reactant: ON=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C(=NOCc1ccccn1)c1ccccc1

Procedure:
(E)-(5-mthyl-1, 2, 3-thiadiazol-4-yl) phenylmethanone oxime (0.30 g, 1.4 mmol) was dissolved in acetone (20 ml), potassium carbonate (0.32 g, 2.0 mmol) and hydrochloride of 2-picolylchloride (0.34 g, 2.0 mmol) were added and heated for 3 days with refluxing. After concentrating the thus reacted solution, the residue was extracted with ethylacetate, and after washing with water, the residue was dried with magnesium sulfate. The solvent was removed by distillation, the residue was refined in a column chromatography, and yielded (E)-(5-mthyl-1, 2, 3-thiadiazol-4-yl)phenyl-methanone O-(2-pyridyl) methyloxime.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@H](O)C2)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
(S)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 80 mg, 0.180 mmol), pyrimidin-5-ylboronic acid (66.8 mg, 0.539 mmol), Pd(PPh3)2Cl2 (7.57 mg, 10.78 μmol) and Na2CO3 (57.1 mg, 0.539 mmol) were added to a MW vial and was treated with a mixture of DME (762 μL), water (218 μL) and EtOH (109 μL). The vial was sealed, evacuated/purged with argon and the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL) and treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.7 mg, 0.090 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2) to yield the title compound as a yellow solid. UPLC-MS (condition 1) tR 2.36 min, m/z=445.0 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.82-1.94 (m, 1H) 2.68 (dd, 1H) 2.99-3.09 (m, 2H) 3.18-3.26 (m, 1H) 4.17-4.24 (m, 1H) 4.87 (d, J=3.67 Hz, 1H) 6.98 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.82-7.88 (m, 3H) 7.94 (dd, J=8.80, 2.45 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H).
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[C:13](=O)[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][CH:17]=1.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:13]1[C:12]([O:11][CH3:10])=[CH:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Solvent: CN(C)c1ccccc1
Product: COc1cnc(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Yield: 61 %

Procedure:
In ice bath, dimethyl-phenyl-amine (1.19 mL, 1.0 eq) was added dropwise to a slurry of 5-Methoxy-2-(4-nitro-phenyl)-3H-pyrimidin-4-one (2.3 g, 1.0 eq) in POCl3 (4.4 mL, 5.0 eq) and the mixture was refluxed overnight. Excess POCl3 was evaporated in vacuo and the residue was poured into ice-water. After formation of precipitates, the mixture was filtered and the residue was dried solid in vacuo. A product was obtained as a white solid (2.47 g, 61%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: c1ccc(Cc2cc3ccccc3s2)cc1

Procedure:
2-Benzylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles, 6.6 ml), benzyl bromide (10.2 mmoles, 1.3 ml) and THF (20 ml). Flash chromatography (hexanes) provided 0.66 g (39%) of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH:12]([C:14]([NH2:16])=[O:15])[NH2:13].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:13]/[NH:12][C:14]([NH2:16])=[O:15])/[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc(F)cc1
Yield: 108 %

Procedure:
To a solution of 1-(4-fluorophenyl)ethan-1-one (27.6 g, 199.80 mmol, 1.00 equiv) and hydrazinecarboxamide hydrochloride (22 g, 197.25 mmol, 0.99 equiv) in methanol (200 mL) was added a solution of sodium acetate (16.8 g, 204.79 mmol, 1.02 equiv) in water (80 mL) dropwise with stirring. The resulting solution was stirred at room temperature for 2 h. The solid was collected by filtration then air-dried to give 41.6 g of crude (E)-2-(1-(4-fluorophenyl)ethylidene)hydrazinecarboxamide as a white solid. LCMS (method A, ESI): RT=1.22 min, m/z=196.0 [M+H]+.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:13])[CH2:6][C:7]1[S:8][C:9](Br)=[CH:10][CH:11]=1.[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][O:4][C:5](=[O:13])[CH2:6][C:7]1[S:8][C:9]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(Br)s1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)Cc1ccc(-c2cccc([N+](=O)[O-])c2)s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
FR544 (The following reaction is carried out in an N2 atmosphere.) Dissolve Tetrakis-(triphenylphosphine)-palladium(0) (1.12 g, 0.97 mmol) and ester (43) (4.57 g, 19.44 mmol) in toluene (200 mL) and EtOH (20.0 mL), degas the reaction mixture carefully (5 times) and flush with N2. Add 3-nitrophenylboronic acid (3.57 g, 21.38 mmol) and a 3 M aqueous Na2CO3 solution (18.1 mL, 54.3 mmol), degas the reaction mixture again carefully (5 times) and flush with N2. Stir the mixture for 18 h at 100° C. Partition the reaction solution between EtOAc and water and extract the separated aqueous layer with EtOAc (3 times). Wash combined organic layer with brine and dry it with Na2SO4. Purify the obtained crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+5) to obtain [5-(3-nitro-phenyl)-thiophen-2-yl]acetic acid methyl ester (56) as a yellow solid (3.15 g, 58%). 1H NMR (400 MHz, CDCl3): 3.75 (s, 3H); 3.85 (s, 2H); 6.94 (br.d, 1H, J=3.8 Hz); 7.27 (d, 1H, J=3.8 Hz); 7.51 (t, 1H, J=8.0 Hz); 7.84 (ddd, 1H, J1=7.8 Hz, J2=1.5 Hz, J3=0.8 Hz); 8.08 (ddd, 1H, J1=8.3 Hz, J2=2.1 Hz, J3=1.0 Hz); 8.39 (t, 1H, J=1.9 Hz).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([B:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])(C)(C)C.Cl.[CH3:38][O:39][C:40]([NH:42][CH:43]([CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)C(O)=O)=[O:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:38][O:39][C:40](=[O:41])[NH:42][CH:43]([CH:47]1[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)[C:6](=[O:7])[N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([B:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:35])([CH3:36])[O:29]4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C1CCOCC1
Temperature: 25 °C

Procedure:
2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 0.717 mmol) was dissolved in DCM (8 mL) at room temperature. HCl (4N in dioxane, 8 mL) was added and stirring at room temperature was continued. After all starting material was consumed, the volatiles were removed in vacuo and the crude material was dissolved in DMF. Methoxy carbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (155 mg, 0.715 mmol), DIEA (276.6 mg, 2.1 mmol), and HATU (272 mg, 0.715 mmol) were added. After all starting material was consumed, the reaction was diluted with EtOAc and was washed with brine/aqueous bicarbonate. The organic layer was dried over sodium sulfate. Filtration and evaporation of solvents in vacuo gave the crude product, which was purified via flash chromatography on silica gel (eluent: EtOAc/hexanes) to yield 355 mg.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Yield: 53.9 %

Procedure:
By using a similar procedure to that described in example 1 but with 1 g of ethyl 6-(3,5-diphenyl-phenoxy)hexanoate, 0.22 g of potassium hydroxide in pellets, 5 cc of water and 5 cc of ethanol as the starting material (2 hours; reflux), and after recrystallization in a mixture of 10 cc of n-hexane and 2 cc of ethyl acetate, 0.5 g (54%) of 6-(3,5-diphenyl-phenoxy)hexanoic acid was obtained as a white solid. (m.p.=104° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O>[C:35]([O:28][C:26]1[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=[C:17]([CH2:16][NH:15]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH:27]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(O)c2O1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc2c1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4Z)-6-bromo-4-({[(7-hydroxy-2,2-dimethyl-1,3-benzodioxol-5-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (30 mg, 67 μmol) in N,N-dimethylformamide (0.5 mL) is added pyridine (12 μL, 0.17 mmol) and acetyl chloride (10 μL). The reaction mixture is shaken overnight at room temperature and then purified by reverse-phase high performance liquid chromatography to give 6-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2,2-dimethyl-1,3-benzodioxol-4-yl acetate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14].Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[O:14]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of KHMDS (8.72 g, 44 mmol) in THF (300 mL) at −70° C. was slowly added over 10 min a solution of tert-butyl 4-methoxycarbonylpiperidine-1-carboxylate (7.1 g, 29 mmol) in THF (70 mL). After 1 h, 2-bromo-1-(tert-butyldimethylsilyloxy)ethane (10 g, 47 mmol) was added and the reaction was allowed to warm to room temperature for 1 h. The mixture was poured into aq. sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was used directly in the next step. TLC (50% ethyl acetate in hexanes) indicated a mixture of bromide starting material and title product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[B:24](OCCC)([O:29]CCC)[O:25]CCC>O1CCCC1>[CH2:17]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([B:24]([OH:29])[OH:25])=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)[CH3:18]
Reactant: CCCOB(OCCC)OCCC
Reactant: CCc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nn(-c2ccccc2)c2cc(B(O)O)ccc12
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-3-ethyl-1-phenyl-1H-indazole (2 g, 6.64 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). To the resulting mixture was then added a solution of n-BuLi (4 mL, 1.40 equiv) in tetrahydrofuran (5 mL) dropwise with stirring at −78° C. in 5 min. The resulting mixture was stirred for 30 min at the temperature. To the resulting mixture was then added a solution of tripropyl borate (1.49 g, 7.93 mmol, 1.20 equiv) in tetrahydrofuran (5 mL) dropwise with stirring at −78° C. in 5 min. The resulting solution was stirred for 1 h at −78° C. in a liquid nitrogen bath. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (2×50 mL), the organic layers combined and dried over anhydrous sodium sulfate, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield 3-ethyl-1-phenyl-1H-indazol-6-ylboronic acid as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[CH:16]1[C:25]2[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=2[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:27]([NH:26][C:17]1[CH:16]=[C:25]2[C:20](=[CH:19][CH:18]=1)[CH2:21][C:22](=[O:9])[CH2:23][CH2:24]2)(=[O:29])[CH3:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1ccc2c(c1)CCC=C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
m-Chloroperbenzoic acid (5.13 g, 20.8 mmol) was added to a chloroform solution (80 ml) of N-(7,8-dihydro-2-naphthalenyl)acetamide (3.00 g, 16.0 mmol) obtained in 1) under ice-cooling, which was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; hexane:ethyl acetate=1:1). 1N Sodium hydroxide solution (10.7 ml) was added to a methanol solution (100 ml) of the obtained oily substance (3.20 g, 8.89 mmol) under ice-cooling, which was stirred at room temperature for 30 minutes. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; ethyl acetate: methanol=10:1). p-Toluenesulfonic acid (50 mg, 0.262 mmol) and toluene (26 ml) were added to the obtained diol (596 mg, 2.62 mmol), which was stirred at 120° C. for 3 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:3), and powdered with diisopropyl ether, to give the titled compound (231 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH2:14][NH2:15].[Br:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25](O)=[O:26])=[CH:24][N:19]2[CH:18]=1>>[Br:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25]([NH:15][CH2:14][C:4]3[CH:5]=[C:6]([O:9][C:10]([F:12])([F:11])[F:13])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:26])=[CH:24][N:19]2[CH:18]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: COc1ccc(OC(F)(F)F)cc1CN
Product: COc1ccc(OC(F)(F)F)cc1CNC(=O)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2-methoxy-5-(trifluoromethoxy)phenyl)-methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:5][CH2:4]1)=[O:2].[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26])[CH3:24]>>[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:8][CH2:7]1)(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(C=O)CC1)CCCC2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C=O)CC1)CCCC3)C(=O)N2
Yield: 65.3 %

Procedure:
3-[3-(4-Formyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (91 mg, 0.3 mmol), prepared as described in Example 8, Steps 1-4 above, was condensed with 5-ethylsulfonyloxindole (67 mg, 0.3 mmol, 50%pure) following the procedure used in Example 1 above. The reaction mixture was purified by flash chromatography using (dichloromethane: methanol 30/1, 20/1, 15/1) to give (100 mg, 64% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32](=[O:35])[NH:33][CH3:34])[C:22]([C:36]([F:39])([F:38])[F:37])=[CH:21][N:20]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8][CH2:9][CH3:10]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32](=[O:35])[NH:33][CH3:34])[C:22]([C:36]([F:38])([F:37])[F:39])=[CH:21][N:20]=1)[CH2:6][P:7](=[O:11])([OH:14])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1)OCC
Agent: Cl
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1

Procedure:
A solution of diethyl (3-methoxy-4-{[4-{[2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 53, 44.3 mg, 0.0781 mmol) in 37% HCl (1 mL) was heated at 80° C. for a total of 3.5 h. The reaction was concentrated in vacuo. The residue was dissolved in DMSO and submitted for mass-directed purification (under basic conditions; ammonium bicarbonate buffer, pH 9). The fractions containing product were combined and concentrated in vacuo, giving the title material as a white solid, 11.6 mg (27%). 1H NMR (400 MHz, MeOD) δ ppm: 8.33 (d, J=8.3 Hz, 1H), 8.29 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.62 (dd, J=7.8, 1.3 Hz, 1H), 7.49 (ddd, J=8.5, 7.4, 1.5 Hz, 1H), 7.18 (td, J=7.6, 1.0 Hz, 1H), 7.05 (t, J=1.8 Hz, 1H), 6.79 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 3.89 (s, 3H), 3.79-3.88 (m, 2H), 2.96 (d, J=20.2 Hz, 2H), 2.89 (s, 3H), 1.19 (t, J=6.9 Hz, 3H). MS (ES+): m/z 540.14 (100) [MH+]. HPLC: tR=2.63 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)[CH3:2].[H-].[Na+].[CH3:26][S:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1.CCOCC>CN(C=O)C>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([S:27][CH3:26])=[CH:29][CH:30]=2)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:19][CH:20]=1)[CH3:23]
Reactant: CCOC(OCC)c1ccc(CC(C(=O)OC)C(=O)OC)cc1
Reactant: CSc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(Cc2ccc(SC)cc2)(C(=O)OC)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of the product from Step 1 (1.42 g, 4.4 mmol) in DMF (14 mL) at 0° C. was added NaH (131 mg, 80% in mineral oil). After 1 h. 4-(methylthio)benzyl chloride (0.64 mL, 4.4 mmol) was added and the mixture was stirred a further 2 h at 0° C. Following a standard aqueous/Et2O work-up, the crude was purified by flash column (1:20 EtOAc/toluene) to give a colorless oil (1.92 g).