Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:9][C:8](=[O:10])[N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[O:5])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8](=[O:10])[N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccc(OC)cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 6 h
Yield: 90.2 %

Procedure:
A mixture of 66.2 g (0.18 mole) of diethyl[1-(2,4-dimethoxy-benzyl)-4-oxo-2,2-azetidine-dicarboxylate] prepared according to the preceding paragraph, 70 ml of dimethyl sulfoxide, 12.7 g (0.22 mole) of sodium chloride and 6.5 ml (0.36 mole) of water is stirred on an oil bath (temperature 170°-180° C. for 6 hours. The reaction mixture is poured into 500 ml of a saturated aqueous sodium chloride solution, extracted five times with 100 ml ethyl acetate each, the organic phase is dried over anhydrous magnesium sulfate, filtered and from the filtrate the ethyl acetate is distilled off. Thus 47.6 g of ethyl-[1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidine-carboxylate] are obtained. B.p.: 170°-176° C./0.15 Hgmm.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH:9]=[CH:16][N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C(C)Oc1ccc(Cl)cc1
Solvent: CO
Product: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Temperature: 120 °C

Procedure:
A mixture of 3-(4-chlorophenoxy)-2-butanone (34.50 g) and N,N-dimethylformamide dimethylacetal (20.70 g) was heated under argon in an oil bath at 120° C. for 13 hours. The methanol produced in the reaction was removed under reduced pressure and the residual oil was triturated with n-hexane. The solid was collected by filtration and washed with cold diethyl ether to give 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one. Yield 32.50 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:12][C:13]([CH:15]=[CH:16][C:10]=2[CH:9]=[C:5]2[CH:6]=[CH:7][O:8][C:4]=12)=[O:14].[Br:17]Br>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]2[O:12][C:13]([CH:15]=[CH:16][C:10]=2[C:9]([Br:17])=[C:5]2[CH:6]=[CH:7][O:8][C:4]=12)=[O:14]
Reactant: BrBr
Reactant: COc1c2occc2cc2ccc(=O)oc12
Solvent: C1CCOC1
Product: COc1c2occc2c(Br)c2ccc(=O)oc12
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
8-methoxypsoralen (4.32 g, 20.0 mmol), obtained from Aldrich Chemical Company was dissolved in tetrahydrofuran (50 mL). To the mixture was added dropwise, with stirring, elemental bromine (4.0 g, 25 mmol) over 20 min at room temperature. The reaction mixture turned red when bromine was added. Precipitate appeared in 5 min. Extra bromine was consumed by solvent tetrahydrofuran in an extended 2 hr stirring or by the addition of 10% sodium thiosulfate solution. The crude product was collected by filtration and was purified with recrystallization from ethanol to give the product 5-bromo-8-methoxypsoralen (5.38 g, 91% yield) as a white solid. mp 178-80° C. 1H--NMR (DMSO(dimethylsulfoxide)--d6, ppm): 8.22(d, J=2.2 Hz, 1H), 8.11 (d, J=9.9 Hz, 1H),7.01(d,J=2.2 Hz, 1H),6.53(d, J=9.9 Hz, 1H),4.17(s,3H).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([O:19][CH3:20])=[O:18])[N:13]([CH3:21])[N:12]=2)=[CH:7][CH:6]=1>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([O:19][CH3:20])=[O:18])[N:13]([CH3:21])[N:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COC(=O)c1c(C)c(-c2ccc(OC)cc2)nn1C
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1c(C)c(-c2ccc(OC)c(I)c2)nn1C
Reaction time: 8 h

Procedure:
Silver sulfate (261 mg, 0.837 mmol) and iodine (212 mg, 0.837 mmol) were added successively to a solution of methyl 3-(4-methoxyphenyl)-1,4-dimethyl-1H-pyrazole-5-carboxylate (217.8 mg, 0.837 mmol) in EtOH (8.4 mL) at 25° C. and the reaction was stirred vigorously overnight. The reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (80 mL) and washed with satd Na2SO3 (30 mL). The organic layer was washed with brine (2×30 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 1125 mL) to afford methyl 3-(3-iodo-4-methoxyphenyl)-1,4-dimethyl-1H-pyrazole-5-carboxylate, as a colorless solid. Rf=0.31 (20% EtOAc/hexanes). LCMS calc.=387.02. found=386.91 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 7.99 (d, J=2.1 Hz, 1H); 7.48 (dd, J=8.5, 2.2 Hz, 1H); 6.82 (d, J=8.5 Hz, 1H); 4.12 (s, 3H); 3.89 (s, 3H); 3.86 (s, 3H); 2.31 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=1.[CH:18](OC)(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.C1COCC1>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[N:1]=[CH:18][N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)c(F)cc2N)n1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nccc(-n2cnc3cc(F)c(Br)cc32)n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
To a solution of 4-N-(2-amino-5-bromo-4-fluorophenyl)pyrimidine-2,4-diamine (500 mg, 1.68 mmol) in methanol (6 mL) and THF (20 mL) was added trimethyl orthoformate (5.59 ml, 50.32 mmol) and TsOH (0.03 ml, 0.17 mmol). The reaction mixture was stirred at 70° C. for 1.5 hr. Reaction had only progressed 6% by LC-MS. Extra trimethyl orthoformate (6 mL, 54.23 mmol) was added and stirred at 70° C. for 1 hr. Reaction mixture was cooled and sat NaHCO3 (10 mL) was added. The product was extracted with DCM (3×10 mL) and the organics were washed with brine and then dried (Na2SO4), filtered and concentrated in vacuo to obtain title compound as a beige solid (500 mg, 63.8% yield); 1H NMR (500 MHz, DMSO) delta 9.17 (s, 1H), 8.97 (d, J=6.7 Hz, 1H), 8.37 (d, J=5.5 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.20 (s, 2H), 7.14 (d, J=5.6 Hz, 1H); LC-MS: m/z=+309.75 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@H:21]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31]([CH2:37][O:38][CH3:39])[N:32]=4)[CH:28]=3)[C:22](OC)=[O:23])=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[BH4-].[Li+]>O1CCCC1>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@H:21]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31]([CH2:37][O:38][CH3:39])[N:32]=4)[CH:28]=3)[CH2:22][OH:23])=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COCn1cc2cc(C[C@@H](OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)C(=O)OC)cc(C)c2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCn1cc2cc(C[C@H](CO)OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)cc(C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-1-Methoxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)-1-oxopropan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (0.70 g, 1.32 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0° C. To this solution was added lithium borohydride (0.12 g, 4.0 equiv). After 30 min, the ice bath was removed and the mixture stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and carefully quenched with 10% citric acid. The organic layer was separated and washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated to afford 0.68 g (99%) which was used without purification. Mass spec.: 505.3 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:16]([C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:22]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 21 h
Yield: 71.5 %

Procedure:
A solution of 5.0 g (21.7 mmol) of 3,5-dinitrobenzoyl chloride in 75 ml of methylene chloride was added dropwise with stirring to an ice bath cooled mixture of 4.7 ml (27 mmol) of diethyl iminodiacetate and 6.0 ml (43 mmol) of triethylamine in 25 ml of methylene chloride. The reaction mixture was stirred in the cooling bath for 30 minutes and then was left at room temperature for 21 hours. After washing with NaHCO3 solution, the organic layer was dried and concentrated to an oil which was chromatographed on 150 g of silica gel using 20-30% ethyl acetate-hexane. The combined pure fractions were recrystallized from methanol to give 5.95 g (72% yield, 79°-80°) of N-(3,5-dinitrobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH2:14]>C1(C)C=CC=CC=1>[CH3:13][NH:14][C:11]([NH:10][C:8]1[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)=[O:12]
Reactant: CN
Reactant: CC(C)(C)c1cc(N=C=O)on1
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1cc(C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Into a solution of 3-t-butyl-5-isoxazolyl isocyanate (2.84 g) in toluene (51 ml) is introduced methylamine (1.58 g) at room temperature. The mixture is stirred at room temperature for 2 hours and then at 50° C. for 4 hours. The reaction mixture is evaporated to remove the solvent, and the residue is recrystallized from ethyl acetate to give 1-methyl-3-(3-t-butyl-5-isoxazolyl)urea (2.80 g) as crystals melting at 195.0° to 196.0° C. (decomp.). The yield is 83.6%.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1)C>C1COCC1.CO>[C:9]1([CH2:8][CH2:7][C:6]([OH:15])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: CCOC(=O)CCC1=CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC1=CCCCC1
Reaction time: 2 h

Procedure:
2N LiOH (3.5 mL) was added to a solution of 3-Cyclohex-1-enyl-propionic acid ethyl ester (0.6 g, 3.4 mmol, from Step 1 dissolved in THF (12 mL) and MeOH (3 mL). The mixture was stirred for 2 h under N2 and then partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a clear oil. 1H NMR (CDCl3): δ 1.54 (m, 2H), 1.62 (m, 2H), 1.92 (m, 2H), 1.97 (m, 2H), 2.26 (m, 2H), 2.46 (t, 2H, J=8.3 Hz), 5.44 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20].[C:23](Cl)(=[O:25])[CH3:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:23](=[O:25])[CH3:24])[CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCc1ccccc1OCCCCCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOC(C)=O
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A solution of 4.3 g (13.96 mmol) of 2-[[5-(acetyloxy)pentyl]oxy]benzenepropanoic acid methyl ester and 2.18 g (27.8 mmol) of freshly distilled acetyl chloride in 250 mL of dry dichloromethane was stirred with ice-bath cooling while 7.5 g (56.7 mmol) of anhydrous aluminum chloride was added in one portion. The resulting mixture was stirred at 0°-5° C. for 2 hr before being treated with ice. Work-up with dichloromethane in the usual manner gave an oil which was chromatographed on 100 g of silica gel. Elution with 1:1 hexane-ether afforded 4.22 g (86.4%) of 2-[[5-(acetyloxy)pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester as an almost colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[CH3:11][O:12][C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15](O)=O>C(Cl)Cl.CO>[CH3:11][O:12][C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15]1[S:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1ccc(N)c(S)c1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3OC)sc2c1
Temperature: 150 °C
Yield: 84.2 %

Procedure:
A thoroughly mixed paste of 2-amino-5-methoxybenzenethiol (2.0 g, 12.88 mmol) and 2-methoxy-4-nitrobenzoic acid (2.54 g, 12.88 mmol) in trimethylsilylpolyphosphate (10 ml) was stirred and heated at 150° C. under an atmosphere of argon for 30 min. On cooling to room temperature, the reaction mixture was suspended in DCM/MeOH and an orange solid was collected by filtration. The filtrate was washed with 1 M HCl (2×50 ml), sat. NaHCO3 (2×50 ml), brine (70 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a solid which was combined with that collected and recrystallised from AcOH to give the title compound (3.43 g, 83%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([S:21][C:22]2[NH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl.O>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([S:21][C:22]2[NH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Sc1ncc(-c2ccccc2)[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1ccc(OCc2ccccc2)cc1)Sc1ncc(-c2ccccc2)[nH]1
Yield: 42 %

Procedure:
The crude product from Step A was dissolved in a MeOH/H2O mixture (2:1, 4 ml). 0.7 g KOH was then added to the solution and the mixture was refluxed for 2 h. Subsequently, the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2; ethyl acetate). The yield was 42%.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][C@@:17]([CH3:24])([O:22][CH3:23])[C:18]([F:21])([F:20])[F:19])[C:13]([NH2:25])=[C:12]([F:26])[CH:11]=2)[CH2:5][S@@:4](=[O:27])[CH2:3]1.[C:28]([C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH:35]=O)([CH3:31])([CH3:30])[CH3:29]>>[NH2:25][C:13]1[C:14]([O:16][C@@:17]([CH3:24])([O:22][CH3:23])[C:18]([F:21])([F:19])[F:20])=[CH:15][C:10]([CH2:9][C@H:6]2[C@H:7]([OH:8])[C@@H:2]([NH:1][CH2:35][C:34]3[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:33]=3)[CH2:3][S@:4](=[O:27])[CH2:5]2)=[CH:11][C:12]=1[F:26]
Reactant: COc1cc(C=O)cc(C(C)(C)C)c1
Reactant: CO[C@](C)(Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1N)C(F)(F)F
Product: COc1cc(CN[C@H]2C[S@](=O)C[C@@H](Cc3cc(F)c(N)c(O[C@@](C)(OC)C(F)(F)F)c3)[C@@H]2O)cc(C(C)(C)C)c1

Procedure:
The title compound was prepared in an analogous manner as described for example 48g starting from (1R,3R,4S,5S)-3-amino-5-[4-amino-3-fluoro-5-((R)-2,2,2-trifluoro-1-methoxy-methyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol (example 48f) and 3-tert-butyl-5-methoxy-benzaldehyde and was obtained after purification by column chromatography on silica gel with (EtOAc/5% MeOH) 70-0% hexane as a colorless foam: TLC (AcOEt-MeOH 19:1) Rf=0.43; HPLC RtH1=2.55 min; ESIMS [M+H]+=591; 1H NMR (600 MHz, DMSO-d6): δ 6.92 (s, 1H), 6.75 (s, 2H), 6.72 (s, 1H), 6.67 (d, 3H), 5.01 (br s, 1H), 4.60 (br s, 2H), 3.77-3.68 (m, 3H), 3.73 (s, 3H), 3.61 (d, 1H), 3.30 (s 3H), 3.15 (m, 1H), 3.10 (m, 2H), 2.96 (m, 1H), 2.70 (m, 1H), 2.50-2.25 (m, 5H), 1.24 (s, 9H).
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)(=[O:4])[CH3:3].Br[CH:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[C:27]([CH:29]2[CH2:30][CH2:31]2)=[O:28])[CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)SC1CCNC/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}piperidine hydrochloride (1.15 g) and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (0.88 g) in N,N-dimethylformamide (20 ml) was added potassium carbonate (0.24 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:1) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (0.48 g, yield: 27%) as a colourless amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[OH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:36][C:35]6[CH:38]=[CH:39][CH:40]=[C:33]([OH:32])[CH:34]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=Cc1cccc(O)c1
Product: Oc1cccc(CN2CCc3[nH]c(-c4n[nH]c5cc(-c6cc(F)c(O)cc6CC(F)(F)F)ccc45)nc3C2)c1

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3-hydroxybenzaldehyde (56.6 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 26.1% yield, 30 mg.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([CH2:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: O=S(=O)(CCCO)c1cccc(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccc(S(=O)(=O)CCCO)c1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-(3-bromo-benzenesulfonyl)-propan-1-ol (Intermediate 6), the title compound was obtained as a brown solid after purification by preparative HPLC.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[OH:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.[C:24]1([CH2:30][O:31][C:32]([C:34]2([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:24]1([CH2:30][O:31][C:32]([C:34]2([NH:40][C:19]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][OH:13])=[CH:23][CH:22]=3)=[O:21])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)=[O:33])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(O)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
Under ice-cooling, 6.94 g (36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g (35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 6.83 g (56%) of the title compound.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[CH2:17]([OH:19])[CH3:18]>>[C:17]([NH:14][C:11]1[CH:12]=[CH:13][C:5]([Br:4])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:19])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Sn]Cl
Product: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
Tin(II) chloride (46.67 g, 206.84 mmol) was added portionwise to a solution of 2-bromo-5-nitro benzoic acid (12.71 g, 49.9 mmol) in dry ethanol (200 mL). The mixture was heated at 70° C. for 45 min, then ethanol was evaporated. The residue was cooled to 0° C., and acetic anhydride (43 mL) and pyridine (26 mL) were added. The solution was stirred at room temperature for 14 h and evaporated. The residue was partitioned between aq. 2M HCl and ethyl acetate (400 mL). The organic phase was washed with brine and dried over MgSO4. The residue from evaporation was crystallized from water to give 5-acetylamino-2-bromobenzoic acid (12.4 g, 96%).
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:24][CH:25]=1
Reactant: CN(CCc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCc1ccc(O)cc1)C(=O)OC(C)(C)C
Reaction time: 6 h

Procedure:
To a solution of 1.13 g (3.32 mmol) of tert-butyl 4-(benzyloxy)phenethyl(methyl)carbamate in 15 mL of methanol was added 35 mg of 10% palladium on carbon. The reaction was stirred under a hydrogen balloon atmosphere for 6 h, filtered through celite and evaporated to give tert-butyl 4-hydroxyphenethyl(methyl)carbamate as a colorless oil which was subsequently used without purification.