Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:33]([F:36])([F:35])[F:34])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH2:23][C:22]([N:18]1[C:19]2[C:15](=[CH:14][C:13](/[CH:12]=[CH:11]/[CH:10]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=3)[C:33]([F:35])([F:36])[F:34])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)=[O:32]
Reactant: CC(C)(C)OC(=O)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](OCC)=[O:10])[CH:6]=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)c1ccnc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(CO)ccn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of ethyl 2-methoxy-pyridine-4-carboxylate (0.93 g, 5 mmol) in ether (5 ml) was added to lithium aluminium hydride (0.3 g, 8 mmol) in ether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Water was added, the mixture was filtered through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-hydroxymethyl-2-methoxypyridine (0.64 g, 89%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][CH:11]1[S:15](=[O:17])(=[O:16])[O:14][CH2:13][CH2:12]1>CC(=O)CC>[CH2:1]([NH:9][CH2:13][CH2:12][CH:11]([S:15]([OH:17])(=[O:16])=[O:14])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC1CCOS1(=O)=O
Reactant: CCCCCCCCN
Solvent: CCC(C)=O
Product: CCCCCCCCNCCC(C)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of octylamine (2.00 g, 15.5 mmol) in 2-butanone (17 mL) was added 2,4-butane sultone (2.21 g, 16.2 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. It was suspended in a solution of 25% EtOH/acetone (50 mL). The suspension was stirred for 5 minutes. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 8.45 (s (broad), 1H), 3.01 (m, 1H), 2.84 (m, 2H), 2.58 (m, 1H), 1.92 (m, 1H), 1.75 (m, 1H), 1.51 (m, 2H), 1.10 (d, 1H, J=6.8 Hz), 0.85 (t, 3H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 53.05, 47.27, 46.15, 31.83, 29.42, 29.13, 26.51, 26.27, 22.75, 17.19, 14.64. ES-MS 266 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:25])=[CH:27][CH:28]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CCNC(=O)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A mixture of 3-methoxyphenethylamine (16.557 g, 109.5 mmol), 4-benzyloxybenzoic acid (25.000 g, 109.5 mmol), 1-hydroxybenzotriazole hydrate (22.202 g, 164.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.047 g, 115.0 mmol) in anhydrous CH2Cl2 (300 ml) was stirred at 0° C. under N2 for 1 hr, then warmed to rt and stirred at rt for 19 hr. The reaction mixture was washed sequentially with 1M NaOH (150 ml), 1M HCl (150 ml), and H2O (150 ml), then dried over MgSO4 and concentrated in vacuo to give 39.00 g (99% yield) of yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH:6]([CH3:28])[CH2:5]1)[CH3:3].CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][C:4]1([N:2]([CH3:3])[CH3:1])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH:6]([CH3:28])[CH2:5]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(N(C)C)CC3C)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2ccc(N3CCC(F)(N(C)C)CC3C)c(F)c2)C(=O)O1
Yield: 62 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-(N,N-dimethylamino)-methyl-4-hydroxypiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.22 mmol) with DAST (1.53 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 62% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCN(C(C)C)C(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of 2.650 g (11.000 mmol) 2-bromo-4-trifluoromethyl-phenol and 1.47 mL 13.20 mmol) ethyl bromo-acetate in 20 mL Hünig base was stirred for 5 h at 120° C. The reaction mixture was diluted with EtOAc and the org. phase was washed with water, saturated aqueous sodium bicarbonate and saturated aqueous NaCl, dried over magnesium sulphate and evaporated down i. vac. Column chromatography (silica gel, gradient dichloromethane/MeOH 100:0→19:1) yielded the product.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N:5][CH:4]=[C:3]1[C:13]([O:15]CC)=O.O.[NH2:19][NH2:20]>>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]2=[N:5][CH:4]=[C:3]1[C:13]([NH:19][NH2:20])=[O:15]
Reactant: NN
Reactant: CCOC(=O)c1cnc2n(c1=O)CCCCC2
Solvent: O
Product: NNC(=O)c1cnc2n(c1=O)CCCCC2
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 2.36 g. of ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate in 10 ml. of 98% by W/V hydrazine hydrate is allowed to stand at room temperature for 2 hours. The precipitated crystals are filtered and washed with water and ethanol. 1.8 g. of (81%) 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carbohydrazide are obtained melting at 184°-186° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[N:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>C1COCC1>[Cl:16][C:17]1[N:18]=[N:19][C:20]([Cl:23])=[CH:21][C:22]=1[Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: C[Si](C)(C)Cl
Reactant: Clc1ccc(Cl)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(Cl)nnc1Cl
Temperature: -78 °C
Reaction time: 0.29 h
Yield: 91.6 %

Procedure:
A four-neck flask equipped with a mechanical stirrer, thermowell, and addition funnel was charged with 2,2,6,6-tetramethylpiperidine (25.1 mL, 147.7 mmol) and anhydrous THF (200 mL). The solution was cooled to −10° C.-0° C. and n-BuLi (2.5 M in hexanes, 59 mL, 147.7 mmol) was added over 10 min. The solution was stirred for 15-20 min then further cooled to −78° C. A mixture of freshly purified 3,6-dichloro-pyridazine (10 g, 67.1 mmol) and trimethylsilyl chloride (9.3 mL, 73.8 mmol) in THF (100 mL) was added dropwise via an addition funnel. The dark red solution was stirred at −78° C. for 1 hr, at which point the reaction was complete. The reaction was quenched cold with saturated ammonium chloride solution (100 mL) and immediately diluted with MTBE (200 mL). The layers were separated while still cold (additional water was added if necessary until all solids dissolved) and the aqueous phase was washed with MTBE (100 mL). The combined organic solution was washed with dilute citric acid solution (30 mL portions) until the aqueous washes were pH 6-7. The organic solution was then washed with brine, dried over Na2SO4, and concentrated to a residue. The crude material was purified by column chromatography on silica gel (100 g, 2:1 heptane:EtOAc) to provide 13.6 g of 20 as a reddish oil.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:48])([F:47])[C:10]1[CH:11]=[C:12]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:13][N:14]([C:34]1[N:35]=[N:36][N:37]([CH3:39])[N:38]=1)[C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[N:23]=2)[N:18]([C:29](Cl)=[O:30])[C@H:17]([CH2:32][CH3:33])[CH2:16]1.[CH2:49]([OH:51])[CH3:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:49]([O:51][C:29]([N:18]1[C:19]2[C:24](=[N:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=2)[C@@H:15]([N:14]([CH2:13][C:12]2[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:10]([C:9]([F:48])([F:47])[F:8])[CH:11]=2)[C:34]2[N:35]=[N:36][N:37]([CH3:39])[N:38]=2)[CH2:16][C@H:17]1[CH2:32][CH3:33])=[O:30])[CH3:50]
Reactant: CCO
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(C(F)(F)F)nc2[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Add triethylamine (25 μL) and 4-dimethylaminopyridine (10 mg, 80 μmol) to a solution of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carbonyl chloride (100 mg, 0.16 mmol) and ethanol (28 μL) in dichloromethane (0.9 mL). Stir the mixture at room temperature for 8 h. Evaporate the solvent and purify the crude material by silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (51 mg, 51%). MS (ES+): 626 (M+H).
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH:9]=O)=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.C(N(CC)CC)C.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[BH4-].[Na+]>CO>[Br:11][C:6]1[CH:7]=[C:8]([CH2:9][NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:3]([NH2:2])=[N:4][CH:5]=1
Reactant: NCCCN1CCOCC1
Reactant: Nc1ncc(Br)cc1C=O
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ncc(Br)cc1CNCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To a solution of 2-amino-5-bromo-pyridine-3-carbaldehyde hydrobromide (4.30 g, 15.3 mmol) in MeOH (100 mL) was added triethylamine (4.3 mL, 31 mmol) and the mixture was stirred at room temperature for 10 min. The resulting suspension was treated with 4-(3-aminopropyl)morpholine (2.5 mL, 17 mmol) and the mixture was stirred for 7 h. TLC analysis indicated remaining starting material. Additional 4-(3-aminopropyl)morpholine (1.0 mL, 6.8 mmol) was added, and the mixture was allowed to stir overnight at room temperature. The mixture was cooled and then NaBH4 (0.87 g, 23.0 mmol) was added in two portions. The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH/Et3N, 97/2.5/0.5 to 85/14.5/0.5) gave the title compound (2.70 g, 54%) as a brown oil: MS (ESI) m/e 329 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:23][C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)[CH3:15]
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccco1
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccco1
Yield: 34 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and furan-2 carbaldehyde in 34% yield as a pale oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[C:10]([CH:16]=O)[CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20].Cl.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:14])[NH:19][N:20]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Temperature: 82 °C
Yield: 72.7 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-3-formylthiophene-2-carboxylic acid (3 g, 0.011 mol) in ethanol (30 ml) was added hydrazine hydrate (0.65 ml, 0.013 mol) in small drops. To this was added conc. HCl (1.8 ml, 0.058 mol) in a dropwise manner and heated to 82° C. for 2 days. The reaction mixture was allowed to cool down and 10% NaHCO3 (5 ml) was added slowly until pH=8. The solid was filtered, washed with water (200 ml) and dried to afford 2.1 g (71%) of the title compound. Rf=0.5 (CHCl3:MeOH, 8:2). 1H NMR (400 MHz, DMSO-d6) δ 12.98 (bs, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 7.88 (d, 2H, J=8.6 Hz), 7.59 (d, 2H, J=8.6 Hz).
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].CN([CH:20]=[O:21])C.O>C1COCC1>[Cl:14][C:9]1[C:8]([C:7]([F:6])([F:15])[F:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(C(F)(F)F)c1Cl
Temperature: -70 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
BuLi (1.6 M in hexane, 173 mL, 277 mmol) was added to a sol. of 2-trifluoromethyl-chlorobenzene (50.0 g, 277 mmol) in THF (500 mL) at −70° C. The sol. was stirred for 2 h at −70° C., and DMF (21.3 mL, 277 mmol) in THF (100 mL) was added. The mixture was allowed to warm to rt overnight. Water was added (200 mL), and the mixture was extracted with Et2O (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 20:1) yielded the title compound (37.4 g, 65%). LC-MS: tR=0.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Br.[CH3:12][N:13]([CH2:15][C:16]1[C:17]([S:23][CH2:24][CH3:25])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:13]([CH3:12])[CH3:14])[C:17]=2[S:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCSc1c(O)cccc1CN(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Reaction time: 1 h
Yield: 73.4 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.567 g, 3.6 mmol), 3-dimethylaminomethyl-2-ethylsulfanyl-phenol hydrobromide (0.77 g, 2.6 mmol) and cesium carbonate (1.19 g, 3.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. More cesium carbonate (1.19 g, 3.6 mmol) was added. After 1 h, the reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (662 mg, 52%) as a clear oil. Fumaric acid (30 mg, 0.26 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile fumarate (41.4 mg, 34%) was filtered off as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCc2cc(O)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reaction time: 0.33 h

Procedure:
Trifluoromethanesulfonic anhydride (2.51 mL) was added to a solution of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (2.00 g) and triethylamine (4.11 mL) in dichloromethane (20 mL) at −20° C., and the reaction solution was stirred at that temperature for 20 minutes. After confirming that the raw materials disappeared, the reaction solution was concentrated under reduced pressure, and water and chloroform were added to the residue and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain 3.30 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]([F:28])([F:27])[F:26])=[N:8]1.B1([O-])O[O:30]1.O.O.O.O.[Na+]>C1COCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:30])=[CH:13][CH:14]=2)[C:9]([C:25]([F:28])([F:27])[F:26])=[N:8]1
Reactant: [O-]B1OO1
Reactant: CC1(C)OB(c2ccc3c(c2)c(C(F)(F)F)nn3C2CCCCO2)OC1(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2c(c1)c(C(F)(F)F)nn2C1CCCCO1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-indazole (415 mg, 1.047 mmol) in THF (4 mL) and water (4.00 mL) was added sodium perborate tetrahydrate (483 mg, 3.14 mmol). The reaction mixture was heated at 50° C. for 2 h. The organic solvents were evaporated, extracted with EtOAc and washed with water and brine solution, then dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography on silica gel using 50% EtOAc/Petroleum Ether to give 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-ol (255 mg, 85%). 1HNMR 400 MHz, CDCl3: 6 ppm 1.68-1.75 (m, 4H), 2.05-2.17 (m, 2H), 2.46-2.52 (m, 1H), 3.71-3.77 (m, 1H), 3.98-4.01 (m, 1H), 4.89 (s, 1H), 5.74 (dd, J=2.40, 9.00 Hz, 1H), 7.08 (dd, J=2.40, 9.00 Hz, 1H), 7.13 (d, J=0.80 Hz, 1H), 7.59 (d, J=0.40 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li][CH2:12][CH2:13]CC.C(=O)C>C1COCC1.CCCCCC>[CH3:12][CH:13]1[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:6]1
Reactant: O=C(O)c1ccccc1Br
Reactant: [Li]CCCC
Agent: CC=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1OC(=O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 35 %

Procedure:
To a solution of 2-bromobenzoic acid (0.50 g, 2.49 mmol) in THF (12.0 ml) cooled at −78° C. was added 2.5M n-BuLi in hexane (2.0 ml). After stirring for 25 minutes, a solution of acetaldehyde (0.142 g, 3.23 mmol) in THF (0.3 ml) was added. The reaction was allowed to warm to room temperature after 8 minutes at −78° C., and then quenched into 10% HCl aqueous solution (30 ml). The acidic solution was rapidly stirred for 1.5 hours, and then extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 aqueous solution, brine, dried with anhydrous Na2SO4, and rotary evaporated to an oily residue. Gradient chromatography of the oil residue through a silica gel column with 20% to 30% EtOAc in hexane afforded 3-methyl-2-benzofuran-1(3 H)-one as a clear oil (130 mg, 35%).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:18][C:5]1[CH:6]=[C:7]([CH:9]=[O:10])[NH:8][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1ccc(C=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1[nH]c(C=O)cc1Br
Temperature: 50 °C
Yield: 58.9 %

Procedure:
15 g of 5-n-propyl-2-pyrrolaldehyde (0.11 moles) are dissolved in 600 mL of CCl4 under a nitrogen atmosphere. 23 g of NBS (0.13 moles) are added and the mixture is heated to 50° C. for 6 h. The succinimide is filtered out, the organic phase is washed with a saturated solution of NaHCO3, dried with Na2SO4 and evaporated. 14 g of product are obtained, which are used in the subsequent step. Formula: C8H10BrNO (m.w. 216.08). Yield 60%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][NH:25][CH3:26])=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(F)c(F)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of tert-butyl ({1-[(3,4-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (468 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 210 mg, 52%).
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:27][OH:28].[OH-].[Na+]>CO>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19](/[C:22](=[N:27]/[OH:28])/[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=N\O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Yield: 92.8 %

Procedure:
1-[3-(5,7-Difluoro-quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanone (78.4, 320 mg, 0.943 mmol) and hydroxylamine hydrochloride (131 mg, 1.886 mmol) in methanol (30 mL) was stirred at it overnight. LCMS showed the reaction was complete. The reaction solution was tuned with 1N NaOH aqueous solution until pH 8-9, solvent was evaporated, and the residue was purified by column chromatography to afford 310 mg (93% yield) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.29 (s, 1H), 8.99 (dd, 1H), 8.49 (d, 1H), 8.24 (d, 1H), 7.74 (d, 2H), 7.63 (dd, 1H), 4.76 (s, 2H), 2.15 (s, 3H). LCMS (method A): [MH]+=355, tR=5.32 min.