Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:27]1[S:28][CH:29]=[CH:30][N:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1nccs1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(-c3nccs3)cc2C1

Procedure:
Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-Iodo-thiazole (CAS: 3034-54-6). Yellow oil. MS (m/e): 303.1 ([M+H]+, 100%)
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1>>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:4])=[N:29]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(OCc3c(-c4ccc(F)cc4)noc3CO)nn2C)n1
Yield: 68 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.28 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of 4-aminotetrahydropyran, to the title compound (80 mg, 68%) which was obtained as a white solid. MS: m/e=425.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[N+:7]=1[O-:30]
Reactant: CC1(C)CC(c2cccc(Cl)n2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(c2cccc(Cl)[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 20.6 %

Procedure:
152 mg of 4-(6-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 136 mg of m-chloroperbenzoic acid were heated at reflux in 15 ml of chloroform. After 10 hours and 20 hours 80 mg and 50 mg, respectively, of m-chloroperbenzoic acid were added. After 30 hours the mixture was allowed to cool to room temperature, washed in succession with sodium bisulphite solution and sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give, after trituration with n-hexane, a solid which was recrystallized from acetonitrile. There were obtained 33 mg of 2-chloro-6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 195°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][O:27]C4CCCCO4)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:12][CH2:13]2)=[O:7])=[CH:42][CH:43]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(COC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(CO)cc1
Yield: 100.1 %

Procedure:
N-{2-[4-(4-Fluorobenzoyl)piperidino]ethyl}-4-tetrahydropyranyloxymethyl-N-(2-methoxyphenyl)benzene sulfonamide (101 mg, 0.165 mmol) was dissolved in methanol (5 ml) to which was subsequently added p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) at room temperature. After 2 hour of stirring at the same temperature, methanol was removed by evaporation, and the resulting reaction solution was mixed with saturated sodium bicarbonate aqueous solution (5 ml), extracted with ethyl acetate, and washed with water and saturated brine. The water layer was extracted with ethyl acetate, and washed with water and saturated brine, and the organic layers were combined and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a silica gel column chromatography (ethyl acetate) to obtain 87 mg (100%) of the title compound in the form of colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-valine (10.86 g) and L-proline benzyl ester hydrochloride (12.09 g) in DMF (50 ml) were added HOBT (6.76 g) and WSCD (7.76 g) under ice-bath cooling. After being stirred at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 ml) and washed with 5% aqueous citric acid (200 ml) saturated aqueous sodium bicarbonate (200 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to give N-(tert-butoxycarbonyl)-L-valyl-L-proline benzyl ester (20.06 g) as an oil.
Reaction SMILES: CC1C=CC(S(N[C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=4)[N:23]=3)[CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.ClC1C=CC2N(C=C(NC(=O)C)N=2)N=1.[CH3:45][S:46]C1C=C(B(O)O)C=CC=1>>[CH3:45][S:46][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=3)[N:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CSc1cccc(B(O)O)c1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Agent: CC(=O)Nc1cn2nc(Cl)ccc2n1
Product: CSc1cccc(-c2ccc3nc(NC(C)=O)cn3n2)c1

Procedure:
Following the procedure described for compound N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.075 g, 0.36 mmol) was reacted with 3-(methylthio)phenylboronic acid (0.11 g, 0.64 mmol, Alfa Aesar, Ward Hill, Mass.) to afford the title compound as a yellow solid. MS (ESI positive ion) m/z: 299 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.91 (s, 1H), 8.30 (s, 1H), 8.06 (d, J=9.6 Hz, 1H), 7.90 (s, 1H), 7.80-7.82 (m, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.40-7.42 (m, 1H), 2.57 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [Na].[CH:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.Cl[C:8]1[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=1>O>[CH:2]1([CH2:5][O:6][C:8]2[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Nc1ccc(Cl)nn1
Reactant: OCC1CC1
Agent: [Na]
Solvent: O
Product: Nc1ccc(OCC2CC2)nn1
Reaction time: 23 h
Yield: 86.7 %

Procedure:
Sodium (127 mg) was added to a stirred cyclopropylmethanol (5 g). After the sodium had dissolved, 6-chloropyridazin-3-amine (0.648 g) was added and the mixture was heated to 170° in a glass pressure vessel with magnetic stirring for 23 h. The cooled reaction mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried (sodium sulfate) and evaporated to afford crude 6-cyclopropylmethoxypyridazin-3-amine (716 mg). 1H n.m.r. (CDCl3) δ 0.27-0.38, m, 2H; 0.52-0.66, m, 2H; 1.18-1.38, m, 1H; 4.18, d, 2H; 4.47 broad s, 2H; 7.78, AB q, 2H.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[C:13]1=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[C:13]1=[O:19]
Reactant: C[C@@H]1NCCN(CCCOCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1NCCN(CCCO)C1=O
Yield: 99 %

Procedure:
A solution of (S)-1-(3-benzyloxy-propyl)-3-methyl-piperazin-2-one (9.07 g, 34.6 mmol) in methanol only heated for 14 h at 70° C. under a hydrogen atmosphere (7 bar) in the presence of palladium (10% on activated charcoal, 7.36 g). After cooling, insoluble material was removed by filtration and the filtrate evaporated to produce the title compound (5.90 g, 99%). Colorless oil, MS (ISP)=173.1 (M+H)+.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH3:11])[CH:4]=1>C(O)(=O)C.O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:1])=[C:5]([CH3:11])[CH:4]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)ccc1CBr
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Hydrobromic acid (conc., 2 eq.) was added to a stirred solution of the alcohol from step 1 (1 eq.) in acetic acid (0.22M). The mixture was stirred at 50° C. for 12 h, cooled down to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water, aqueous sodium hydrogen carbonate (3×), brine, dried over MgSO4, filtered and concentrated to afford the desired benzyl bromide as a light yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(OC3CCCCC3)cc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2ccc(OC3CCCCC3)cc2c1O
Yield: 78.7 %

Procedure:
To a mixture of 1-bromo-6-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (1.0 g) in ethyl acetate (20 ml) was added 10% Pd/C (50% wet) (460 mg) and then ammonium formate (1.5 g). Resulting mixture was refluxed for 4 h. After cooling, reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (5%-10% ethyl acetate in methylene chloride) to give the title compound (640 mg). MS-(+)-ion M+1=344.22.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)[CH3:3].C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([N:7]1[CH:8]=[CH:9][N:10]=[C:6]1[N:5]=[CH:4][N:2]([CH3:3])[CH3:1])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)C=Nc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the crude 2-[dimethylamino)methylene]aminoimidazole (2) was added methylene chloride (750 mL), triethylamine (98 mL, 700 mmol) and trityl chloride (62.98 g, 226 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 3 hrs. Solvent was removed in vacuo and the crude 3 was crystallized from methanol.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([C:29]1[N:34]=[CH:33][C:32]([C:35]2[CH:36]=[N:37][N:38](C3CCCCO3)[CH:39]=2)=[CH:31][N:30]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1.Cl.CO.C([O-])(O)=O.[Na+]>ClCCl>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:52])[F:51])[CH:48]=1)[CH2:6][N:7]([C:29]1[N:30]=[CH:31][C:32]([C:35]2[CH:39]=[N:38][NH:37][CH:36]=2)=[CH:33][N:34]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C4CCCCO4)c3)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cn[nH]c3)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Temperature: 25 °C
Yield: 10 %

Procedure:
A 25 ml round-bottom flask is charged with 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidin-4-ol (0.15 mmol), 1N HCl (0.8 ml, 0.8 mmol) and MeOH (2 ml). The mixture is then heated to 60 degree for 30 minutes. After cooling down to rt, sat. NaHCO3 and dichloromethane are added, then organic layer is collected. Removal of solvent and purification with reverse phase column chromatography give 1-[4-((2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidin-4-ol (11.3 mg, 0.015 mmol, 10% for 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N:17]=[C:18]=[O:19].FC1C=CC=C(N=C=O)C=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([NH:17][C:11]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=2[F:9])=[O:19])=[N:3][CH:4]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: Nc1ccc(Br)cn1
Agent: O=C=Nc1cccc(F)c1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Br)cn2)c1

Procedure:
The desired product was prepared by substituting 2-amino5-bromopyridine and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+)) m/e 324.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[Br:12]N1C(=O)CCC1=O.CCOCC>ClC(Cl)C>[Br:12][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]=2[CH:10]=1
Reactant: CC1(C)Cc2ccccc2O1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: CC1(C)Cc2cc(Br)ccc2O1
Temperature: 25 °C
Yield: 79 %

Procedure:
2,2-Dimethyl-2,3-dihydrobenzo[b]furan (prepared according to the method of Baker and Shulgin, J. Org. Chem., 28, 1963, 2468) (500 mg, 3.38 mmol) was taken up in dichloroethane (5.5 ml) and stirred at room temperature under nitrogen, and N-bromosuccinimide (661 mg, 3.72 mmol) added in one portion. The reaction was then refluxed for 2 h, ether was added (10 ml) and a white precipitate of succinimide filtered off. The filtrate was evaporated to dryness, and then purified by column chromatography using 5% ether in pentane as eluant to give the title product (604 mg, 79%); 1HNMR (400 MHz, CDCl3) δ: 1.43 (s, 6H), 2.92 (s, 2H), 6.54 (d, 1H), 7.16 (d, 1H), 7.19 (s, 1H); LRMS: M+H, 227. (TS+).
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:5][CH:4]=1.CN(C)[CH:21]=[O:22]>O1CCCC1.II>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH:21]=[O:22])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: Brc1ccc2c(c1)C(OC1CCCCO1)CC2
Reactant: CN(C)C=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)C(OC1CCCCO1)CC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
A mixture of magnesium (228 mg) and iodine (3 mg) in tetrahydrofuran (3 ml) is heated at 60° C. under argon atmosphere, and thereto is added dropwise with stirring a solution of 6-bromo-1-tetrahydropyranyloxyindane (2.60 g) in tetrahydrofuran (5 ml). After addition, the mixture is stirred at 70° C. for one hour. To the mixture is added dropwise a solution of dimethylformamide (959 mg) in tetrahydrofuran (2 ml) under ice-cooling, and the mixture is stirred under ice-cooling for one hour. The reaction solution is poured into a mixture of ice-acetic acid, and extracted with ethyl acetate. The extract is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate) to give 1-tetrahydropyranyloxyindane-6-carbaldehyde (1081 mg).
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:21]=2[O:29][CH3:30])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-])=O)[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].Cl.O>C(O)C.[Fe]>[NH2:16][C:7]1[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:19])[C:2]([OH:1])([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][C:21]=1[O:29][CH3:30])[C:10]2=[O:11]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc([N+](=O)[O-])c(NC(C)=O)c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc(N)c(NC(C)=O)c2C1=O
Yield: 98.1 %

Procedure:
N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3 ml). This solution was added with iron (0.098 g), conc. HCl (0.05 ml) and water (0.3 ml). The reaction mixture was heated for 2 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography (ethylacetate 100%) to afford the title compound (90 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[OH:17][CH:18]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[Br:1][C:2]1[C:3]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][CH2:19][CH:18]([OH:17])[CH2:28][N:29]([CH3:30])[CH3:31])=[CH:22][CH:23]=2)=[N:6][CH:7]=1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Sc2ccccc2)n1
Agent: Cl
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Br)c(Sc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 5-bromo-2-chloro-4-(phenylthio)pyrimidine (Method 6) and 4-[2-hydroxy-3-(N,N-dimethylamino) propoxy]aniline hydrochloride (Method 8), the product was obtained. NMR: 2.2 (s, 6H), 2.3 (m, 2H), 3.7 (m, 1H), 3.9 (m, 2H), 4.7 (d, 1H), 6.5 (d, 2H), 7.0 (d, 2H), 7.6 (5H), 8.3 (s, 1H), 9.5 (s, 1H); MS (MH+): 475, 477.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:61][C:62]([F:71])([F:70])[C:63]1[CH:64]=[CH:65][C:66](=O)[NH:67][CH:68]=1>C(Cl)Cl>[CH3:19][C:5]1[N:4]([CH2:3][CH2:2][O:1][C:66]2[CH:65]=[CH:64][C:63]([C:62]([F:71])([F:70])[F:61])=[CH:68][N:67]=2)[C:12]2[C:7]([CH:6]=1)=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCO
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
A solution of 1-(2-hydroxyethyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.130 g, 0.49 mmol) in CH2Cl2 (3 mL) at 0° C. was treated with DBAD (0.302 g, 1.31 mmol), PPh3 (0.343 g, 1.31 mmol) and 5-(trifluoromethyl)-2(1H)-pyridinone (0.87 g, 0.53 mmol). The mixture was allowed to slowly warm to rt and then stirred for 14 h. Concentration was followed by column chromatography (SiO2, hexanes/EtOAc) to afford the title compound (0.160 g): 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.75 (dd, J=8.8 and 2.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.57 (s, 1H), 4.67 (t, J=5.6 Hz, 2H), 4.54 (t, J=5.6 Hz, 2H), 2.54 (s, 3H); MS (ES) m/z 414 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:73]1[CH2:77][CH2:76][C@@H:75]([OH:78])[CH2:74]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([N:73]4[CH2:77][CH2:76][CH:75]([OH:78])[CH2:74]4)=[O:37])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)N5CCC(O)C5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid (60 mg, 0.11 mmol), HATU (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (43 mg, 0.33 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of (R)-3-pyrrolidinol (14 mg, 0.16 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3-hydroxypyrrolidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide as white solid. Yield: 40 mg, 59%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2cc[nH]n2)cc1
Yield: 95.7 %

Procedure:
To a refluxing suspension of 3-(4-nitrophenyl)-pyrazole (18 g) and Raney nickel (3.3 g) in methanol (190 ml) was added dropwise a solution of 85% hydrazine hydrate (22 g) in methanol (50 ml). The solution was refluxed for 30 minutes more, filtered and evaporated to dryness. The oily residue, after crystallization from water, furnished 14.5 g of 3-(4-aminophenyl)-pyrazole; M.p. 104° C. 3-(3-Aminophenyl)-pyrazole, M.p. 144°-145° C., was prepared in a similar manner starting from 3-nitroacetophenone.
Reaction SMILES: [C:1]1([C:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])=[CH:8][S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.O.[Pd]>[C:1]1([CH:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])[CH2:8][S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)C=C(CS(=O)(=O)O)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(O)CC(CS(=O)(=O)O)c1ccccc1

Procedure:
To 2-phenyl-propene-1,3-disulfonic acid (J. Amer. Chem. Soc., 66, 1105-9 (1944)) in THF-water (1:1) is added 10 wt % of 5% palladium on carbon and the mixture hydrogenated on a Parr shaker under 15 lb hydrogen pressure until the reaction is complete by thin layer chromatography (TLC). The mixture is filtered (Celite) and concentrated in vacuo to afford the title compound.