Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:18]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:17][C@@H:9]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:51])C=1.CSC>C(Cl)Cl>[C:1]([O:7][C@H:8]1[C@@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:18]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:17][C@@H:9]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:51])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 75.4 %

Procedure:
To a solution of 36 (1.38 g, 2.27 mmol) in 65 mL of CH2Cl2 at -78° C. is added m-CPBA (612 mg, 64%, 2.27 mmol). The reaction mixture is allowed to warm to -15° C. and then quenched with dimethyl sulfide (1 mL, 13.6 mmol) and allowed to warm to room temperature. The reaction mixture is diluted with 50 mL of CH2Cl2, extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered, and concentrated to afford a white solid. The sulfoxide is purified using flash chromatography (30% EtOAc/hexane) to afford 1.07 g (76%) of the title compound 37 as a mixture of diastereomers: Rf 0.35 and 0.38 (30% EtOAc/hexane).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:24][C:23](=O)[N:22]=[CH:21]1)(=[O:19])[CH3:18]>>[C:17]([N:20]1[CH2:24][CH2:23][N:22]=[C:21]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Nc1ccnn1-c1cccc(C(F)(F)F)c1
Product: CC(=O)N1CCN=C1Nc1ccnn1-c1cccc(C(F)(F)F)c1

Procedure:
5-Amino-1-(3-trifluoromethylphenyl) pyrazole (19.0 g.) and 1-acetyl-2-imidazolinone (12.9 g.) were reacted as described in Example I to give 16.85 g. product, mp 194°-197°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17](OCC)=O.Br([O-])(=O)=[O:23].[Na+].S(=O)(O)[O-].[Na+]>C1CCCCC1.O>[CH3:17][C:3]1[S:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:6][C:2]=1[CH2:1][OH:23]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1CO
Reaction time: 2 h

Procedure:
Ethyl 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 35, 0.100 g) and sodium bromate (0.144 g) were suspended in a mixture of cyclohexane and water (1:1 v/v, 4 ml). To this was added a solution sodium bisulfite (0.99 g) in water (1 ml). The mixture was stirred for 2 hours, quenched with 1M sodium thiosulfate solution, then extracted with ethyl acetate. The organic layer was taken and washed with water, sodium thiosulfate and dried with brine and over MgSO4 and concentrated to give the title compound as a white crystalline solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH2:16][C:15]([C:21]([OH:23])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:15]3[CH2:16][O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([Cl:10])=[CH:20][CH:19]=4)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)C1=Cc2cc(Cl)ccc2OC1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
DIEA (45.5 μL, 0.26 mmol) was added to 6-chloro-2H-chromene-3-carboxylic acid (50.0 mg, 0.24 mmol) and HATU (99.3 mg, 0.26 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (49.7 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 66.6 mg of product in 69% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: [CH3:1]O.CO.C[O-].[Na+].[OH:8][C@H:9]([C@H:24]1[CH2:28][O:27]C(=O)[O:25]1)[C@H:10]1[C@H:15]2[N:16]=[C:17]([CH3:19])[O:18][C@@H:14]2[CH:13]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[O:11]1>C1(C)C=CC=CC=1>[OH:25][C@H:24]([CH2:28][OH:27])[C@H:9]([C@H:10]1[C@H:15]2[N:16]=[C:17]([CH3:19])[O:18][C@@H:14]2[CH:13]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[O:11]1)[O:8][CH3:1]
Reactant: COC(=O)C1=C[C@H]2OC(C)=N[C@@H]2[C@H]([C@H](O)[C@H]2COC(=O)O2)O1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1=C[C@H]2OC(C)=N[C@@H]2[C@H]([C@H](OC)[C@H](O)CO)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanol (460 ml) and a 25.4% sodium methoxide methanol solution (14.36 g) were added to a toluene solution (approximately 675 ml) of a compound, which was obtained by subjecting methyl (3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate (46.00 g) to Step A-5 of Example 1, at room temperature, and the mixture was stirred for 30 minutes at the same temperature. The solvent of the reaction solution was distilled off under reduced pressure until the amount of solution became approximately 138 ml, methanol (460 ml) was added, and the reaction solution was stirred for 30 minutes at room temperature. After acetic acid (4.41 g) was added to the reaction solution and the solvent was distilled off under reduced pressure until the amount of solution became approximately 138 ml, toluene (230 ml) was added to the reaction solution and then the solvent was distilled off again under reduced pressure until the amount of solution became 138 ml to give a toluene suspension of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:44][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])[CH:19]=2)[C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:16]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: OB(O)c1cccc2ncccc12
Product: Cn1cc(-c2cccc3ncccc23)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using quinolin-5-ylboronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-(quinolin-5-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 7.43-7.51 (m, 3 H) 7.64-7.68 (m, 1 H) 7.82-7.89 (m, 2 H) 8.01-8.05 (m, 2 H) 8.20 (s, 1 H) 8.33 (d, J=8.02 Hz, 1 H) 8.93 (dd, J=4.12, 1.60 Hz, 1 H). m/z (ESI) 421.1 (M+H)+.
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:39])[C:22]([O:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21)=O)C1C=CC=CC=1.[ClH:40].[H][H]>C(OCC)(=O)C.CO.[Pd]>[ClH:40].[NH2:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:39])[C:22]([O:30][C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:32])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N)CC1
Yield: 97.6 %

Procedure:
To a mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (16 g, 30.1 mmol) in ethyl acetate (300 mL) and methanol (150 mL) was added 1N HCl (31.6 mL, 31.6 mmol) followed by Pd/C (3.20 g, 3.01 mmol) and the mixture was stirred under balloon hydrogen atmosphere for 2 h. The mixture was then filtered through a pad of CELITE® and the pad was thoroughly washed with ethyl acetate. The filtrate was concentrated under reduced pressure and dried under high vacuum overnight to afford the title compound (12.75 g, 98% yield),as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.11-8.16 (2 H, m), 7.62 (1 H, t, J=7.40 Hz), 7.48 (2 H, t, J=7.78 Hz), 4.19 (2 H, q, J=7.11 Hz), 4.13 (2 H, d, J=3.51 Hz), 2.71-2.83 (2 H, m), 2.53 (1 H, brs), 2.32-2.46 (2 H, m), 2.01-2.13 (2 H, m), 1.74-1.85 (2 H, m), 1.03 (3 H, t, J=7.03 Hz). LCMS (M+H)=398.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:34]=4)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2oc(N3CCNCC3)nc2COCC(F)(F)F)cc1
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CCN2CCN(c3nc(COCC(F)(F)F)c(-c4ccc(F)cc4)o3)CC2)cc1S(N)(=O)=O
Reaction time: 16 h
Yield: 58.2 %

Procedure:
A solution of 1-[5-(4-fluoro-phenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperazine (0.15 g; 0.42 mmol) in dry dioxane (5 ml) is treated with 5-(2-chloroethyl)-2-methoxy-benzenesulfonamide (0.25 g; 1.0 mmol), sodium iodide (0.15 g; 1.0 mmol) and diisopropylethylamine (0.36 ml; 2.09 mmol) and heated to 100 C. for 16 hours. The reaction mixture is partitioned between ethyl acetate (40 ml) and dilute sodium bicarbonate (20 ml). The aqueous phase is extracted with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol-ethyl acetate gradient (1%-20%) is followed by a second chromatography using a methanol-dichloromethane gradient (1%-5%). Crystallization from ethyl acetate/hexane affords the product as a white solid (0.14 g; 56%). HNMR (CDCL3): 7.81 (d, 1H, J=2.4 Hz), 7.54 (m, 2H), 7.42 (dd, 1H, J=8.7, 2.0 Hz), 7.14 (t, 2H, J=8.8 Hz), 7.02 (d, 1H, J=8.7 Hz), 5.16 (s, 2H), 4.04 (s, 3H), 4.01 (qt, 2H, J=8.8 Hz), 3.62 (m, 4H), 2.85 (m, 2H), 2.66 (m, 6H).
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][N:7]=1>C(O)C>[I:12][C:9]1[CH:10]=[CH:11][C:6]2[N:7]([CH:2]=[CH:3][N:5]=2)[CH:8]=1
Reactant: O=CCCl
Reactant: Nc1ccc(I)cn1
Solvent: CCO
Product: Ic1ccc2nccn2c1

Procedure:
To a solution of 50% aq. chloroacetaldehyde (1.5 eq, 125 mmol, 16 ml) in ethanol (625 ml) is added 2-amino-5-iodo-pyridine (1 eq, 113 mmol, 25 g) at room temperature. The reaction mixture is heated at reflux for 18 hours. The solvent is removed in vacuo and the crude product is dissolved in water (400 ml). The aqueous solution is treated with sodium bicarbonate to pH=8 and extracted with DCM (3×250 ml). The organic portion is dried (MgSO4) and evaporated to give a beige solid of the title compound. 1H nmr (CDCl3) 8.44 (1H, s), 7.60 (1H, s), 7.53 (1H, s), 7.42 (1H, d, J=9.4 Hz), and 7.33 (1H, d, J=9.58 Hz).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH:34][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Product: Clc1cccc(CNc2nccc(-c3cnc4c(NCCN5CCOCC5)nccn34)n2)c1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of [3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 50 supra) (200 mg, 0.50 mmol) and 3-chlorobenzylamine (281 mg, 1.99 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1˜20:1) to afford the crude product (125 mg). Then the crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford {3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 60 mg, 26.0%). 1H NMR (300 MHz, CD3OD): δ 8.71 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.59 (d, 1H, J=6.6 Hz), 7.49-7.28 (m, 5H), 4.87 (brs, 2H), 4.16 (brs, 2H), 3.93 (brs, 4H), 3.58-3.28 (m, 5H). LC-MS: [M+H]+ 466.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:23][C:24]1[C:25]([Zn+])=[N:26][CH:27]=[CH:28][CH:29]=1>O1CCCC1.[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>[CH3:23][C:24]1[C:25]([C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH:12]=2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccnc1[Zn+]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 82 %

Procedure:
A solution of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.10 g, 24.8 mmol; Bursavich, M. G.; et al. Org. Lett. 2001, 3, 2317) in tetrahydrofuran (50 mL) was treated with 3-methyl-2-pyridylzinc bromide (0.5 M in tetrahydrofuran, 65.0 mL, Aldrich), tetrakis(triphenylphosphine)-palladium(0) (280 mg, 0.24 mmol) and the mixture heated to 70° C. for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, the residue taken up in dichloromethane and washed with 1N sodium hydroxide. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 50% ethyl acetate: hexanes) to provide 5.50 g (82% yield) of the title compound as a light yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 1.44 (s, 9H), 2.32 (s, 3H), 2.44 (m, 2H), 3.54 (m, 2H), 3.99 (m, 2H), 5.88 (br s, 1H), 7.17 (dd, 1H, J=7.8, 4.8 Hz), 7.62 (br d, 1H, J=7.5 Hz), 8.36 (dd, 1H, J=4.8, 1.7 Hz); MS (DCI/NH3) m/e 275 (M+H)+; 292 (M+NH4)+.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH3:42][S:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=O>CO>[CH3:42][S:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1/[CH:46]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1
Reactant: CSc1ccccc1C=O
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A solution of (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.10 g, 0.21 mmol) in methanol (0.60 mL) was added with DBU (0.047 mL, 0.32 mmol) and 2-methylsulfanylbenzaldehyde (0.035 g, 0.23 mmol) obtained in Step 2 was further added, followed by stirring at room temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained compound was washed with hydrogen chloride-ethyl acetate solution and the precipitated solid was filtered. Then the solid was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate to separate the mixture into organic layer and aqueous layer. The organic layer was concentrated under reduced pressure and the residue was washed with ethyl acetate/hexane (2/1, 1.0 mL) to obtain Compound 146 (0.016 g, 28%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([O:16][C@H:17]3[CH2:21][CH2:20][O:19][CH2:18]3)[CH:13]=[C:12]([O:22]CC3C=CC=CC=3)[CH:11]=2)=[N:6][CH:7]=1>[Pd].C(O)C.C1COCC1>[OH:22][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[CH:13]=1)[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:30]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
10% Palladium on charcoal (500 mg) was added to a solution of N-(5-methylpyrazin-2-yl)-3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (5.0 g, 12.34 mmol) in ethanol (50 mL) and THF (100 mL) and the mixture stirred under an atmosphere of hydrogen at RT for 16 hours. The mixture was filtered through Celite®, the solvents evaporated in vacuo to a residue which was crystallised from ethyl acetate to give the desired material (3.6 g). 1H NMR δ (d6-DMSO): 2.0 (m, 1H), 2.25 (m, 1H), 2.5 (s, 3H), 3.75-3.95 (m, 4H), 5.1 (m, 1H), 6.5 (d, 1H), 7.0 (d, 1H), 7.05 (d, 1H), 8.35 (s, 1H), 9.25 (s, 1H), 9.75 (s, 1H), 10.8 (s, 1H); m/z 316 (M+H)+.
Reaction SMILES: [Na].[O:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]#[N:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:18](OCCC(C)C)=[O:19].Cl>C(O)C>[OH:19][N:18]=[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:16]#[N:17]
Reactant: CC(C)CCON=O
Reactant: N#CCc1ccccc1Oc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
To anhydrous ethanol (15 ml) was dissolved sodium (0.55 g, 0.024 mole) and a mixture of 2-phenoxyphenylacetonitrile (4.18 g, 0.02 mole) and anhydrous ethanol (3 ml) was added dropwise to the mixture below 0° C. over 7 minutes. Isoamyl nitrite (3.51 g, 0.03 mole) was further added dropwise to the mixture below 0° C. over 10 minutes, followed by stirring at room temperature for 24 hours. After completion of the reaction, 5% hydrochloric acid was added to the reaction mixture, which was extracted with ether and dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-hydroxyimino-2-phenoxyphenylacetonitrile (4.53 g, yield: 95.1%) as crystals having a low melting temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH2:31]([N:33]([CH2:45][CH3:46])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH2:43][CH3:44])[CH3:32]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)=[CH:3][C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH2:45][CH3:46])[CH2:31][CH3:32])=[C:35]([CH2:43][CH3:44])[CH:36]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Reactant: CCc1cc(B(O)O)ccc1N(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)c(CC)c3)c2)cc1
Yield: 39.4 %

Procedure:
In a manner similar to that of Example 1d, by reacting 1.4 g (2.9 mmol) of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate (obtained in Example 5b) with 900 mg of 4-diethylamino-3-ethylphenylboronic acid (4 mmol) in the presence of tetrakis(triphenylphosphine)palladium, 674 mg of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-ethyl[1,1′;3′,1″]terphenyl-4-carboxylate (yield=39%) are obtained in the form of a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[ClH:20].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:20].[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=2)[NH2:8])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: NCCN1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cccc(NCCN2CCOCC2)c1

Procedure:
3-Fluoronitrobenzene and 2-morpholin-4-yl ethylamine were added, and the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 and then treated with 4 M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain 3-[N-(2-morpholin-4-ylethyl)amino]aniline hydrochloride. F: 222.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Na].[Cl:13][O-].[Na+].Cl>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH3:11])[C:2]=1[OH:1]
Reactant: [O-]Cl
Reactant: Cc1c(O)cccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: Cc1c(C(=O)O)ccc(Cl)c1O
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 22.8 g of 3-hydroxy-2-methylbenzoic acid in 300 ml of water, cooled to 2° C., were added 55 ml of 3N sodium hydroxyde to adjust the pH to 10. To the clear solution were added within 20 minutes, at 2° to 6° C., 125 ml of 1.2N sodium hypochlorite solution, the pH being raised to 12.5. Then, 90 ml of 3N hydrochloric acid were added at once, a precipitate being formed immediately. The mixture was stirred at 0° C. for 30 minutes, and subsequently the precipitate was isolated by filtration and crystallized from diethylether/hexane to give 15.0 g of 4-chloro-3-hydroxy-2-methylbenzoic acid as white crystals of m.p. 191° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH:5]([CH3:7])[CH3:6].F[B-](F)(F)F.[NH:14]=[C:15](SC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:6][CH:5]([C:4]1[NH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:2][CH:3]=1)[CH3:7]
Reactant: CCOC(=O)C(=N)SC
Reactant: CC(C)C(=O)CN
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCOC(=O)c1ncc(C(C)C)[nH]1
Yield: 57 %

Procedure:
The same operation as in Example (lb) was performed using 1-amino-3-methylbutan-2-one hydrochloride obtained in Example (35c) (about 17.6 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate obtained according to a method known in the literature (J. Med. Chem., 38, 1995, 2196-2201) (about 22 mmol), to obtain 1.83 g of the title compound as a yellow solid (57%).