Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][O:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: Oc1ccc(Sc2ccccc2)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(Sc2ccccc2)cc1)OCC
Temperature: 25 °C

Procedure:
A mixture of 4-(phenylthio)phenol (4.7 g, 23 mmol), bromoacetaldehyde diethyl acetal (4.3 mL, 28 mmol) and K2CO3 (3.82 g, 28 mmol) in DMF (40 mL) was stirred at reflux for 6 h. The reaction mixture was allowed to cool down to room temperature and poured over ice and diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield a yellow oil that was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 2H), 7.27-7.06 (m, 5H), 6.92 (d, 2H), 4.84 (t, 1H), 4.02 (d, 2H), 3.84-3.68 (m, 4H), 1.13 (m, 6H).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:38]=[CH:37][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:38][CH:37]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccsc2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccsc2)CN1C(=O)Cn1cncn1
Yield: 35 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(thien-3-ylmethyl)pyrrolidine-2-carboxamide, gave Compound 72, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(thiophen-3-ylmethyl)pyrrolidine-2-carboxamide (172 mg, 35%). 1H-NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.42 (d, 2H), 7.32-7.30 (m, 1H), 7.03-6.90 (m, 8H), 5.05 (d, 1H), 4.97 (d, 1H), 4.81 (d, 1H), 3.87 (t, 1H), 3.24 (t, 1H), 3.05-2.97 (m, 1H), 2.96-2.89 (m, 1H), 2.77-2.64 (m, 2H), 1.73-1.65 (m, 1H). MS (EI) for C26H24FN5O3S found 505.9 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH:20]([F:22])[F:21])[CH:17]=2)[C:12]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[N:11][N:10]=1>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:30])[C:24]=1[CH2:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH:20]([F:21])[F:22])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:10][N:11]=1
Reactant: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A solution under N2 of 1,2,4-triazole (2.4 g, 34.8 mmoles) in DMF (100 ml) was added with NaH (1.05 g, 26.1 mmoles). The mixture was stirred at room temperature up to clarity, then added with 4-chloro-1(3,5-dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-phthalazine (6.8 g, 17.4 mmoles), prepared as described in example 99. The mixture was heated at 100° C. for 5 hours, extracted three times with CH2Cl2. The organic phase was anhydrified and dried to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 7:3 to 100% of ethyl acetate) to give 4.14 g of the title compound (yield: 28%). m.p.: 220-224° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28].[Br:29]Br.OS([O-])=O.[Na+]>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:17]3[O:16][C:15]([F:19])([F:18])[O:14][C:13]=3[C:12]([Br:29])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:3]=1[Cl:28]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Br)c3c2OC(F)(F)O3)c(F)c(N)c1Cl
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,2-difluoro-7-(trimethylsilyl)benzo[d][1,3]dioxol-4-yl)-5-fluoropicolinate (400 mg, 0.92 mmol) was stirred in 1,2-dichloroethane (5 mL), treated with bromine (1.0 g, 6.5 mmol) and stirred at 20-25° C. for 4 h. The solution was stirred with 10% NaHSO3 solution (30 mL) and extracted with ethyl acetate (35 mL). The organic phase was washed with saturated NaCl (5 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (370 mg, 92%): mp 168-170° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 1H), 5.02 (s, 1H), 3.99 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.23, −137.58; ESIMS m/z 439 ([M+H]+), 437 ([M−H]−).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1cccnc1Br
Product: COc1cccnc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (3.97 g) and 2-bromo-3-methoxypyridine (1.50 g) were heated with stirring at 100° C. for 48 hours. The cooled residue was partitioned between chloroform and water. The aqueous layer was further extracted with chloroform and the combined chloroform layers were washed with water, dried and evaporated to dryness. The brown residue was dissolved in aqueous acetic acid to pH 4 and extracted with ether to remove unreacted 2-bromo-3-methoxypyridine. The aqueous solution was basified with potassium carbonate to pH 9-10 and then extracted with chloroform. The combined chloroform extracts were washed, dried and evaporated to dryness. The residue was subjected to column chromatography on silica with chloroform as eluant to afford the title compound as an oil. This was treated with maleic acid in isopropanol to give as a white solid, 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-3-methoxypyridine dimaleate (0.82 g), m.p. 111°-112° C. (recrystallised from acetone - ethyl acetate).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([F:41])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][NH:37][C:36]4=[O:40])[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)C)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:31][C:30]1[C:25]([C:23]2[S:22][C:21]3[C:16]([C:15]4[C:10]([CH2:9][NH:7][CH3:6])=[CH:11][N:12]=[C:13]([F:41])[CH:14]=4)=[CH:17][CH:18]=[CH:19][C:20]=3[CH:24]=2)=[N:26][C:27]([NH:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])=[N:28][CH:29]=1
Reactant: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Dissolve [4-(2-{5-fluoro-2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophen-7-yl)-6-fluoro-pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl ester (0.19 g, 0.32 mmol) in dry CH2Cl2 (1.4 mL) and CF3COOH (1.4 mL). Stir at room temperature for 1 hour. Remove solvent completely. Dilute the trifluoro-acetic acid salt with CH2Cl2. Wash with saturated NaHCO3 solution, water and saturated aqueous sodium chloride. Dry with MgSO4. After filtration, remove solvent. Dry in vacuo overnight to afford the title compound (0.12 g, 78%). MS (ES) m/z 495 [M+1]+.
Reaction SMILES: [C:1]([O:6]C)(=O)[C@@H:2]([CH3:4])[OH:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[OH:3][C@H:2]([CH3:4])[C:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:6]
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H](C)O
Product: C[C@@H](O)C(=O)N1CCOCC1
Temperature: 85 °C

Procedure:
A mixture of methyl (R)-lactate (104 g) and morpholine (260 ml) was heated for 60 hours at 85° C. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by means of a silica gel chromatography (silica gel 800 g, eluent: hexane-ethyl acetate=1:1→etyl acetate) to give N-[(2R)-2-hydroxypropionyl]morpholine (141 g) as a pale yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O.O>CCO>[Br:26][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])=[N:10][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(C)cc2C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(C)cc2C)n(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 128.9 %

Procedure:
Ethyl 1-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-1H-imidazole-4-carboxylate (1.23 g, 3.47 mmol) was dissolved in EtOH (15 mL) and treated with N-bromosuccinimide (1.25 g, 7.02 mmol). The solution was stirred at rt for 3 h. Water was added. Extraction with dichloromethane, which was then washed with NaCl solution, gave an orange solid (1.94 g). Purification by chromatography over silica gel (20% EtOAc in hexane) afforded a light tan solid (1.028 g, 68%): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, 2H), 7.03 (d, 2H), 7.00 (m, 1H), 6.86 (m, 2H), 4.44 (q, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, 3H); LC-MS m/z 433.1 (MH+), retention time 3.84 min (method 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14](=[O:17])[CH2:15]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[H-].[Na+].O>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:15][C:14]([C:13]2[CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[CH:11][C:12]=2[O:19][CH3:20])=[O:17])[CH:23]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)CBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OCc2ccccc2)cc1C(=O)COc1cccnc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To 5-benzyloxy-2-methoxyphenacyl bromide (4.0 g, 0.0119 mol) in 80 ml of dry dimethylformamide was added 3-hydroxypyridine (1.24 g, 0.013 mol, 1.1 equiv) followed by NaH (50% in oil, 0.604 g, 1.1 equiv). After stirring for 18 hours under N2, the mixture was poured into 500 ml of ice and water, and extracted 2×500 ml ethyl acetate. The organic layers were combined, washed 2×500 ml H2O and 1×300 ml brine, dried (Na2SO4), stripped to an oil, and chromatographed on silica gel using 1:1 hexane:ethyl acetate as eluant to yield 1.07 g of present title product as a solid; IR(KBr) 1670 cm-1;MS 349 (M+); 1H-NMR (300 MHz, CDCl3) delta (ppm) 3.95 (s, 3H), 5.1 (s, 2H), 5.35 (s, 2H), 2.0 (d, 1 H), 7.2-7.5 (m, 8H), 7.6 (d, 1H), 8.3 (d, 1H), 8.4 (d, 1H).
Reaction SMILES: CN(C)[CH:3]([CH2:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]#[CH:5]>CO.CCOCC>[CH:5]#[C:4][CH:3]=[CH:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CC(CC(=O)CCCCC)N(C)C
Solvent: CCOCC
Solvent: CO
Product: C#CC=CC(=O)CCCCC
Reaction time: 5 h

Procedure:
To a solution of 3-(dimethylamino)-1-decyn-5-one (2.2 g), described in Example 39, in methanol (20 ml) p-toluenesulfonic acid (1 g) is added. The solution is allowed to stay at room temperature for 5 hr. then diluted with ether. The organic layer is washed with water, dried (MgSO4) and evaporated to dryness. Chromatographic purification of the residue on 25 g silica gel with ether-hexane (1:4) affords 3-decen-1-yn-5-one.
Reaction SMILES: [N:1]1[N:5]2[C:6](=[O:14])[C:7]3[CH:13]=[CH:12][CH:11]=[N:10][C:8]=3[NH:9][C:4]2=[CH:3][CH:2]=1.[OH-].[K+].[CH3:17]O>>[CH3:17][N:9]1[C:8]2[N:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6](=[O:14])[N:5]2[N:1]=[CH:2][CH:3]=[C:4]12
Reactant: CO
Reactant: O=c1c2cccnc2[nH]c2ccnn12
Agent: [K+]
Agent: [OH-]
Product: Cn1c2ncccc2c(=O)n2nccc12
Reaction time: 0.5 h

Procedure:
1.8 g. of pyrazolo[1,5 -a]pyrido[2,3-d]pyrimidin-9(4H)-one are suspended in 10 ml. of methanol. 0.6 g. of potassium hydroxide are added and the mixture is stirred for 30 minutes. After this time, the potassium salt is filtered off and, after drying, suspended in 20 ml. of diethyleneglycol dimethyl ether. 2.5 g. of methyl iodide are added with stirring. After 20 minutes, 4-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off, washed with water and recrystallized from methanol, yield: 1.1 g. (55%); m.p. 249.2°.
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:19])=[O:18])[O:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[C:17]([C:16]1[CH:15]=[C:14]([C:10]2[O:11][C:12]([CH3:13])=[C:8]([CH:7]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])[NH2:19]
Reactant: Cc1oc(-c2cccc(C(N)=O)c2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2cccc(C(N)=O)c2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
A mixture of 3-{4-[cyclohexyl(hydroxy)methyl]-5-methylfuran-2-yl}benzamide (0.6 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.7 g), sodium carbonate (0.3 g) and sodium iodide (0.6 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (50% ethyl acetate/hexane to 100% ethyl acetate/hexane). To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (2.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (527 mg, 54%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)(C)(C)C.[CH2:16]([N:23]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:31]([O:33][CH3:34])=[O:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:35]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:31]([O:33][CH3:34])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)[C@@H]1CCCCC[C@H]1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Potassium bis(trimethylsilyl)amide (31.7 mL, 15.9 mmol) was added dropwise to a solution of t-butanol in anhydrous tetrahydrofuran under nitrogen at room temperature. After 30 min, a solution of cis-methyl 2-(dibenzylamino)cycloheptanecarboxylate (1.33 g, 3.78 mmol) in 50 mL anhydrous tetrahydrofuran was added dropwise via syringe. The reaction was stirred for 17 h and then was partitioned between 250 mL diethyl ether and 200 mL brine. The organic layer was concentrated and purified by flash chromatography on 120 g silica gel with 2 to 4% ethyl acetate in hexane to yield trans-methyl 2-(dibenzylamino)cycloheptanecarboxylate (895 mg, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 7.23-7.30 (8H, m), 7.16-7.22 (2H, m), 3.77 (2H, d, J=13.60 Hz), 3.51 (3H, s), 3.26 (2H, d, J=13.35 Hz), 3.02 (1H, ddd, J=11.08, 8.81, 2.77 Hz), 2.77 (1H, ddd, J=11.02, 6.99, 4.41 Hz), 1.88-1.99 (1H, m), 1.28-1.83 (9H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH3:12])[C:9]([OH:11])=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH3:12])[C:9]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: C[C@H](OC1CCCCO1)C(=O)O
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To (2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (29.5 g) was added anhydrous tetrahydrofuran (250 ml). To the mixture was added, with stirring at room temperature, 1,1-carbonyldiimidazole (33.1 g), taking 10 minutes. The mixture was stirred for 30 minutes at room temperature and cooled with ice, to which was added dropwise morpholine (34.8 g) during 15 minutes. The resultant mixture was stirred for 15 minutes on an ice bath, then the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (300 ml), which was washed with a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent:hexane:ethyl acetate=1:4) to afford N-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (17.5 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=C)=[CH:23][CH:22]=5)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[O:35])=[CH:23][CH:22]=5)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a clear solution of 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 89A, 0.15 g, 0.368 mmol) in THF (1.5 mL) were added NMO (50% in water, 0.092 mL, 0.442 mmol) and osmium tetroxide (4% in water, 0.068 mL, 0.011 mmol) at room temperature. The solution was vigorously stirred at room temperature overnight. Sodium periodate (0.102 g, 0.479 mmol) in water (0.5 mL) was added. The mixture was stirred vigorously at room temperature under nitrogen for 30 min. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×2 mL). The combined ethyl acetate extracts were dried (sodium sulfate), filtered through a pad of silica gel which was then rinsed with ethyl acetate and concentrated to give 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.15 g, 0.366 mmol, 100% yield) as a green solid. The compound had an HPLC retention time=3.64 min. (condition C); LC/MS M+1=409.9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[H-].[Na+].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccn2)c2cccc(Br)c21
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of 4-bromoisatin (8.94 g, 39.5 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added sodium hydride (3.34 g, 86.9 mmol, 60% dispersion in mineral oil) in portions at 0° C. The brown reaction mixture was stirred for 30 min followed by the addition of a solution of 2-(bromomethyl)pyridine hydrobromide (10.0 g, 39.5 mmol) neutralized with sodium hydride (1.52 g, 39.5 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide at 0° C. The reaction mixture was stirred for 16 h and quenched with water (100 mL). The reaction mixture was extracted with diethyl ether (3×100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with water (5×200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with ether to afford the title compound (10.6 g, 85%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, 1H), 7.67 (t, 1H), 7.30 (t, 2H), 7.25-7.19 (m, 2H), 6.94 (d, 1H), 5.04 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 180.5, 157.3, 154.2, 152.3, 149.5, 138.4, 137.5, 128.6, 123.3, 122.3, 121.5, 116.4, 110.3, 45.8.
Reaction SMILES: [C:1]([O:5][P:6]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:31][CH2:32]I>>[P:6]([O:13][CH2:32][Cl:31])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tetrabutylammonium di-tert-butyl phosphate (57 g, 0.126 mol, Digital Specialty Chemicals) and chloroiodomethane (221 g, 1.26 mol) was stirred at room temperature for four hours before the volatiles were removed under vacuum. 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate in vacuo and removal of remaining volatiles using a vacuum pump provided di-tert-butyl chloromethyl phosphate as a light brown or yellow oil, which was utilized in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[I:9]I.OO>C1CCCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1
Reactant: II
Reactant: Nc1ccc(Br)cc1
Agent: OO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Nc1ccc(Br)cc1I
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 150.5 %

Procedure:
To a solution of 4-bromo-aniline (500 g, 2.90 mol, 2.0 equiv, Saibain Chem) in cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol, 1.0 equiv, Qualigens) and the mixture was heated at 50° C. After 30 min, the reaction mixture became homogenous. 30% aqueous hydrogen peroxide solution (250 mL, Spectrochem) was added to the reaction mixture. The reaction was heated for 4 h at 50° C. The reaction was cooled to room temperature, diluted with ethyl acetate (5.0 L) and washed with aqueous sodium-sulphite (2.5 Kg in 4.0 L) solution. The organic layer was washed with water (3.0 L) and brine (3.0 L) dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate and hexanes) to get 4-bromo-2-iodoaniline (650 g, 75.0%), as off white solid. TLC solvent system: 100% hexanes. Product's Rf: 0.6. MS (ESI, positive ion) m/z: 297.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=2.5 Hz, 1H), 7.23 (dd, J=8.4, 2.1 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 4.09 (s, 2H).