Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Li]CCCC.[F:26][C:27]1[CH:38]=[CH:37][C:30]([C:31](N(OC)C)=[O:32])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[CH:38]=[CH:37][C:30]([C:31]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccc(F)cc3)cn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (50 g, 146.2 mmol) in anhydrous THF (700 mL) was dropwise added n-BuLi (2.5 M in hexane, 70 mL, 175 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 1 h, followed by the addition of a solution of 4-fluoro-N-methoxy-N-methylbenzamide (30 g, 163.9 mmol) in anhydrous THF (100 mL). After stirred at −78° C. for another 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl (250 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with propan-2-ol (150 mL) and stirred at RT for 30 mins. The solid was collected via filtration, washed with propan-2-ol (100 mL) and petroleum ether (300 mL), and dried under vacuum to give the title compound (26 g, yield 46%) as a yellow solid. MS (ES+) C20H23FN4O3 requires: 386. found 331 [M−56+H]+; purity: 100% (UV214).
Reaction SMILES: NC1C=C2C(=CC=1)N=CC=C2.[OH:12][N:13]=[CH:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:16].S(=O)(=O)(O)[OH:29]>>[OH:12][N:13]=[CH:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:16].[C:14]1(=[O:29])[C:19]2=[C:20]3[C:25](=[CH:26][CH:27]=[C:18]2[NH:17][C:15]1=[O:16])[N:24]=[CH:23][CH:22]=[CH:21]3
Reactant: O=S(=O)(O)O
Agent: Nc1ccc2ncccc2c1
Agent: O=C(C=NO)Nc1ccc2ncccc2c1
Product: O=C1Nc2ccc3ncccc3c2C1=O
Reaction time: 1 h
Yield: 31 %

Procedure:
2-Hydroxyimino-N-quinolin-6-yl-acetamide was prepared in 61% yield from 6-aminoquinoline according to Procedure A: 1H NMR (DMSO-d6): δ 12.4 (s, 1H), 10.8 (s, 1H), 9.0 (d, 1H), 8.8 (d, 1H), 8.7 (s, 1H), 8.2 (s, 2H), 7.81 (m, 1H), 7.78 (s, 1H); C11H9N3O2: APCI-MS m/z 216 (M+H)+. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 110 mL of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100° C. followed by slow addition of 2-hydroxyimino-N-quinolin-6-yl-acetamide (26.0 g, 0.121 mol). Heat to the reaction was maintained for approximately 1 h. The flask was removed from the heat source, and the reaction was poured slowly and carefully onto a mixture of 1 Kg of ice and 200 g of sodium carbonate. The residual reaction mixture in the reaction vessel was washed out with an additional 40 mL of cold water. The resulting aqueous slurry was stirred for about 1 h and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 7.31 g (31%) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione: 1H NMR (DMSO-d6): δ 11.1 (s, 1H), 8.8 (d, 1H), 8.7 (d, 1H), 8.2 (d, 1H), 7.6 (m, 1H), 7.4 (d, 1H); APCI-MS m/z 197 (M−H)−. The title compound was prepared in 77% yield from 3-H-pyrrolo[3,2-f]quinoline-1,2-dione and 4-hydrazinophenylmethane sulfonamide according to Procedure G: 1H NMR (DMSO-d6): δ 13.1 (s, 1H), 11.5 (s, 1H), 9.3 (d, 1H), 8.9 (d, 1H), 8.0 (d, 1H), 7.9 (m, 1H), 7.6 (d, 1H), 7.6(d, 2H), 7.4 (d, 2H), 6.9(d, 1H), 4.3 (s, 2H), 2.55 (d, 3H); APCI-MS m/z 396 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COc1ccc2ncc(C(=O)O)c(Br)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2ccc(OC)nc2c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
To a solution of 4-bromo-6-(methoxy)-[1,5]naphthyridine-3-carboxylic acid (for a synthesis see WO2004058144, Example 53(d)) (8.28 g, 29.3 mmol) in DMF (200 ml) was added K2CO3 (5.934 g, 43 mmol) and iodomethane (2.18 ml, 35 mmol) and the reaction was stirred at rt for 72 h. The reaction was partitioned between EtOAc and water. The organic phase was separated and washed twice more with water. The aqueous phases were re-extracted with EtOAc and this EtOAc phase separated and washed with water. The combined organic phases were dried and evaporated to give the desired product as a solid (7 g, 80%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:6].[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[ClH:1].[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[O:6])[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CCCCl)c1ccc(O)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CN(C)C=O
Product: Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 8 h
Yield: 16 %

Procedure:
p-(4-Chlorobutyryl)phenol (130 g 4-benzamidopiperidine (134 g) triethylamine (70 g.) and dimethylformamide were stirred at 60° C for 2 days allowed to stand overnight then filtered. The filtrate was diluted with a large volume of diethyl ether whereupon an oil precipitatedwhich crystallised after being allowed to stand. This precipitate was filtered off, washed with diethyl ether then water, dried and converted tothe hydrochloride using hydrogen chloride gas dissolved in a mixture of isopropyl alcohol and ethanol to afford 4-benzamido-1-[4-(4-hydroxyphenyl)-4-oxobutyl]piperidine hydrochloride (43.5 g. 16%) m.p. 276° C. Analysis: Found: C, 65.60; H, 6.73; N, 6.75% C22H26N2O3HCl requires C, 65.80; H, 6.78; N,6.97%.
Reaction SMILES: F[C:2](F)(F)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:13][C:14]([F:20])([F:19])S(O)(=O)=O.[C:21]1([O:27]C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Br>C(O)(=O)C>[OH:27][C:21]1[CH:26]=[CH:25][C:2]([C:3]([C:24]2[CH:23]=[CH:22][C:21]([OH:27])=[CH:26][CH:25]=2)([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([F:20])([F:19])[F:13])=[CH:23][CH:22]=1
Reactant: COc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(C(c2ccccc2)(c2ccc(O)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 100 grams (0.57 mol) of trifluoroacetophenone, 100 grams (0.7 mol) trifluoromethane sulfonic acid, and 100 grams (10.9 mol) anisole is stirred at room temperature for 24 hours. The mixture is then transferred to a separatory funnel and the organic material is washed with water (3×11), saturated bicarbonate (3×500 ml) and water (2×500 ml). The organic phase is dried and the volatiles removed in vacuo. The resulting material is crystallized from aqueous methanol. 37.2 grams (0.1 mol) of this product is refluxed with glacial acetic acid saturated with anhydrous hydrobromic acid. The mixture is cooled and poured over crushed ice and the solid collected. The crude material is recrystallized from ethanol and petroleum ether to give 1,1-bis(4-hydroxyphenyl)-l-phenyl-2,2,2-trifluoroethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[C:21]1(=[O:36])[N:25]([CH2:26][C:27](=[O:30])[CH2:28][NH2:29])[C:24](=[O:31])[C:23]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:22]12>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:29][CH2:28][C:27]([CH2:26][N:25]3[C:21](=[O:36])[C:22]4=[CH:35][CH:34]=[CH:33][CH:32]=[C:23]4[C:24]3=[O:31])=[O:30])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: NCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Solvent: CCO
Product: O=C(CNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)CN1C(=O)c2ccccc2C1=O
Yield: 84 %

Procedure:
A suspension of 7-chloro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione (18g, 56 mmole) and (3-phthalimidoacetonyl)amine, ethylene ketal (28.88 g, 112mmole) in 800 ml. of absolute ethanol is heated on a steambath, under nitrogen for 24 hours. The above mixture is then evaporated to dryness in vacuo to give 27 g (84%) of 7-chloro-5-(o-chlorophenyl)-2-[(3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal as a buff-colored compound of melting point 180°-190° C. An analytical sample recrystallized from methanol ethyl acetate has a melting point of 200°-202° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH:3]=C.[BH4-].[Na+].C[OH:26]>C(Cl)Cl>[C:17]1([C:6]2[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:8][NH:9][C:5]=2[CH2:1][CH2:2][CH2:3][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO
Reactant: C=CCCc1[nH]nc(-c2ccc(C)cc2)c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2n[nH]c(CCCO)c2-c2ccccc2)cc1
Temperature: -78 °C

Procedure:
5-(But-3-enyl)-4-phenyl-3-p-tolyl-1H-pyrazole (360 mg, 1.248 mmol) was dissolved in MeOH (20 mL) and DCM (5 mL). The reaction was cooled to −78° C. and ozone was bubbled through the solution. After the starting material was consumed, the reaction was cooled in an ice bath. Sodium borohydride (70.8 mg, 1.872 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred for an hour. The solvent was removed under reduced pressure and the reaction was extracted (50 mL each of H2O and EtOAc). The aqueous layer was extracted again with EtOAc (50 mL). The combined organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (130 mg) as a white solid. LCMS m/z=293.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.74 (m, 2H), 2.25 (s, 3H), 2.54-2.62 (m, 2H), 3.33-3.44 (m, 2H), 4.44 (br. s., 1H), 7.16 (t, J=6.44 Hz, 6H), 7.24-7.30 (m, 1H), 7.32-7.38 (m, 2H), 12.71 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)(=O)=O)N=2)CC1.[NH:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]([OH:61])=[O:60])=[CH:58][C:53]=2[N:52]=[CH:51]1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4\[NH:19][C:18](=[O:20])[NH:17][C:16]\4=[O:21])=[C:9]3[N:8]=[C:7]([N:50]3[C:54]4[CH:55]=[CH:56][C:57]([C:59]([OH:61])=[O:60])=[CH:58][C:53]=4[N:52]=[CH:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CC(C)O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(-n4cnc5cc(C(=O)O)ccc54)nc23)N1
Temperature: 150 °C

Procedure:
A mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.028 mmol) was mixed with 1H-benzo[d]imidazole-5-carboxylic acid (20 mg, 0.140 mmol) in isopropanol (1 mL). The mixture was stirred under microwave heating at 150° C. for 20 minutes. The solvent was removed to provide (Z)-1-(4-(cyclopropylamino)-8-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid as a crude mixture which was taken on to the next step without further purification. LCMS (ES): >95% pure, m/z 446 [M+H]+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[OH:31])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[C:5]([C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:31])=[C:21]([CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:30]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cc2ccccc2)c(O)c2ccccc12
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of aluminum chloride (1.25 g, 9.4 mmole) in methylene chloride (25 mL) was stirred at 0° and treated dropwise with benzoyl chloride (1.1 mL, 9.4 mmole) and stirred for 5 minutes. A solution of 2-(phenylmethyl)-1-naphthol (2.0 g, 8.5 mmole) in methylene chloride (6 mL) was added dropwise over 15 minutes, and stirring was continued at 0° for 3 hours. The mixture was poured into 1.0N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. Recrystallization from toluene provided the title compound (1.15 g, 40%) as pale yelow crystals, mp 152°-155°.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl.C(=O)(O)[O-].[Na+]>FC(F)(F)S(O)(=O)=O.C1CCCCC1>[CH2:28]([O:23][C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCCCCCCCCCC[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCCCCCCCCCC[C@H](CCO[Si](C)(C)C(C)(C)C)OCc1ccccc1
Yield: 88.6 %

Procedure:
Trifluoromethanesulphonic acid (0.14 mL, 1.6 mmol) was added to a mixture of alcohol 10 (6.9 g, 20 mmol) and benzyl trichloroacetimidate (12.3 g, 49 mmol) in a 1:1 mixture of dichloromethane and cyclohexane (320 mL) at room temperature. After completion of the reaction (5 h) a saturated solution of sodium bicarbonate (50 mL) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The product was purified by flash chromatography to afford compound 45 as an oil (Rf 0.18, silica, 2% ethyl acetate in hexane, 7.7 g, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:10][C:11]1[C:12]([C:21]([F:22])([F:23])[F:24])=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:16]=1)[NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Product: N#Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1
Yield: 82.2 %

Procedure:
4-cyano aniline (130 mg, 1.1 mmol) and 2,4-dichloro-5-nitrobenzotrifluoride (260 mg, 1 mmol) were used as starting materials. A general synthetic method of intermediate I was employed to get 5-chloro-N-(4-cyanophenyl)-2-nitro-4-trifluoromethylaniline (I-1) (281 mg) with a yield of 82%, as a yellow solid, and with a melting point of 180-182° C.; MS m/z (%) 359.2 (M+NH4, 100). I-1 and 4″-formyl-2″,6″-dimethylphenol were coupled by Method A in Preparation Example 2. The product was dissolved in 15 mL of THF, and was reacted with (EtO)2P(O)CH2CN (1.5 mmol) and an equivalent mole of potassium t-butoxide in THF by Method C in Preparation Example 2 under stirring for about 3 h. The product obtained by conventional post-treatment was isolated and purified through medium pressure column (dichloromethane/methanol) to get Compound 1, with a melting point of 248-250° C. and a yield of 87%. 1H NMR δ ppm 2.15 (6H, s, 2×CH3), 5.85 (1H, d, J=16.4 Hz, ═CH), 6.27 (1H, s, ArH-6), 7.10 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.21 (2H, s, ArH-3″,5″), 7.32 (1H, d, J=16.4 Hz, CH═), 7.52 (2H, d, J=8.8 Hz, ArH-3′,5′), 8.67 (1H, s, ArH-3), 9.91 (1H, s, NH); MS m/z (%) 501.1 (M+Na, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1nc(-c2cccnc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzaldehyde (3.26 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.38 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, water was added, and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]phenyl}methanol as colorless crystals (3.00 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][OH:11].ClCCl>O1CCCC1.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Cc1cc(Cl)cc(CO)c1N
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C=O)c1N
Temperature: 40 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
The (2-amino-5-chloro-3-methylphenyl)methanol (10.8 g, 63.1 mmol) was dissolved in tetrahydrofuran (20 mL). Dichloromethane (50 mL) was added along with activated carbon (16.3 g). Activated manganese dioxide (16.8 g, 189 mmol) was added and the solution stirred at 40° C. for 16 h. The solution was cooled to room temperature and vacuum filtered through a celite. The solvent was removed at reduced pressure and the 2-amino-5-chloro-3-methylbenzaldehyde (7.90 g, 46.0 mmol) obtained by recrystallization from diethyl ether/hexanes (1:10, 100 mL). HRMS m/z 169.0280; calcd 169.0294.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>C(#N)C.C(OCC)C>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH:24][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: COC(CN)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)Cc1ccccc1NCC(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of methyl 2-phenyl-2-bromoacetate (53.8 g) in acetonitrile (450 ml) was treated with triethylamine (45.2 ml). The mixture was then cooled in an ice-bath and treated, dropwise during 15 minutes, with a solution of aminoacetaldehyde dimethylacetal (37.8 ml) in acetonitrile (80 ml), keeping the temperature below 45° C. The mixture was stirred at room temperature for 2 hours and then left to stand for 48 hours. The mixture was then diluted with diethyl ether (800 ml) and washed with water (3×250 ml). The ethereal was dried over magnesium sulphate and evaporated, to give methyl 2-(2,2-dimethoxyethylamino)phenylacetate (55.5 g), in the form of a colourless oil [N.M.R. (in CDCl3) 2.10 (1H, b), 2.57-2.79 (2H, m), 3.34 (3H, s), 3.37 (3H, s), 3.68 (3H, s), 4.50 (1H, t, J=6 Hz), 7.35 (5H, m)].
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[Si:16]([O:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:13])[CH:5]=[CH:4]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cccc2ccn(CCO[Si](C)(C)C(C)(C)C)c12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Add sodium hydride (2.75 g, 24 mmol, 35% in mineral oil) to 1-(tert-butyldimethylsilyloxy)eth-1-yl)indole (5.5 g, 20 mmol) in N,N-dimethylformamide (50 ml) and stir for 15 minutes at 20° C. Add (2-bromoethoxy)-tert-butyldimethylsilane and stir at 20° C. for 4 hours. Dilute with hexanes. Wash with 0.25 M aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexane containing 30% ethyl acetate to provide the desired compound (8.0 g, 89%) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]=[O:27]>O.O1CCCC1>[CH2:22]([Sn:17]([CH2:26][OH:27])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: C=O
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CO)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 197.2 %

Procedure:
To a mixture of diisopropylamine (62 mL, 0.44 mol) and tetrahydrofuran (1000 mL) were added dropwise n-butyl lithium (2.6 M n-hexane solution, 100 mL, 0.26 mol) and n-butyl lithium (1.6 M n-hexane solution, 95 mL, 0.15 mol) at −78° C., and then the reaction mixture was stirred for 30 minutes. To this mixture was added dropwise tributyltin hydride (100 mL, 0.37 mol) at −78° C., and then the reaction mixture was stirred for 60 minutes at 0° C. The reaction mixture was cooled to −78° C., after which paraformaldehyde (13 g, 0.15 mol) was added to the reaction mixture. The reaction mixture was slowly raised to room temperature, and then the reaction mixture was stirred overnight at room temperature. To the reaction mixture were water, an ammonium chloride aqueous solution, and diethyl ether, and the organic layer was separated. The organic layer was washed first with a saturated sodium hydrogencarbonate aqueous solution and then with saturated aqueous sodium chloride. The organic layer was separated, and was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:diethyl ether=4:1) to obtain the title compound (95 g, 80%).