Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:20]([S:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:21][CH2:22][S:23](=[O:26])(=[O:25])[NH2:24])=[O:7])(C)(C)C.C(N(CC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([CH:20]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:21][CH2:22][S:23](=[O:25])(=[O:26])[NH2:24])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:19]
Reactant: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Reactant: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: CO[C@@]1(NC(=O)[C@H](O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.95 g. (2 mmol.) of 7β-amino-7α-methoxy-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g. (2 mmol.) of N,N-diethylaniline in 100 ml of dry methylene chloride is stirred at 0-5° while 0.56 g. (2 mmol.) of D-O-dichloroacetylmandeloyl chloride in 10 ml. of methylene chloride is added dropwise over a 10 minute period. The mixture is stirred in the cold for 30 minutes then warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml. of cold dilute hydrochloric acid and 50ml. of cold 5% aqueous sodium bicarbonate, dried (MgSO4) and evaporated to dryness. The residue is dissolved in a mixture of 10 ml. of trifluoroacetic acid and 2 ml. of m-dimethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml. of ether and 50 ml. of water. The pH is adjusted to 9.3-9.5 with 5% aqueous sodium carbonate and the organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, extracted with 50 ml. of ethyl acetate which is discarded, layered with fresh ethyl acetate and adjusted to pH 1.5 with dilute hydrochloric acid. The aqueous layer is extracted with three 50 ml. portions of ethyl acetate and the combined extracts are dried and evaporated to a small volume. Petroleum ether is added dropwise to precipitate the title compound which is collected and dried.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33]OS(C3C=CC(C)=CC=3)(=O)=O)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.O>C(#N)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33][SH:10]3[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]3)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: C1CSCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc(-c2[nH]cc(CCC[SH]3CCNCC3)c2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
163 mg (1.18 mmol) of potassium carbonate and 122 μl (1.29 mmol) of thiomorpholine were added to a solution of 450 mg (1.07 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-[3-(p-toluenesulfonyloxy)propyl]-1H-pyrrole [prepared as described in step 23(iv) above] in 50 ml of acetonitrile. The resulting mixture was heated under reflux overnight. After cooling the reaction mixture to room temperature, water was added and then this was extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 95:5 by volume mixture of ethyl acetate and methanol as the eluant to give 340 mg (yield 83%) of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:24]([O:26][CH2:27][C:28](O)=[O:29])[CH3:25]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:28](=[O:29])[CH2:27][O:26][CH2:24][CH3:25])[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: CCOCC(=O)O
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: CCOCC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 1 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-ethoxyacetic acid, the title compound was obtained as a white solid (76%), mp 158.0°-9.0° C.; MS(CI): 391 (M+H); NMR (300 MHz,DMSO-d6): 1.12(t, 3H, J=7.0 Hz), 1.41-1.69(m, 4H), 2.27(m, 2H), 2.45(s, 2H), 2.95(m, 2H), 2.95(m, 2H), 3.45(q, 2H, J=7.0 Hz), 3.63(m, 1H), 3.78(s, 2H), 4.31(s, 1H), 6.92(m, 4H), 7.17-7.23(m, 4H), 7.47(d, 2H, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[NH2:10].[C:18](OCC)(OCC)(OCC)[CH:19]([CH3:21])[CH3:20]>C(#N)C.Cl.CCOCC>[ClH:17].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]2[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:18]([CH:19]([CH3:21])[CH3:20])[NH:10]2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1CN(N)c1ccc(Cl)cc1
Reactant: CCOC(OCC)(OCC)C(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)C1=Nc2ccccc2CN(c2ccc(Cl)cc2)N1
Yield: 122.8 %

Procedure:
To a mixture of 3 g (0.012 m) of 1-[(2-aminophenyl)methyl]-1-(4-chlorophenyl)hydrazine of Example 12b and 3.56 g (0.024 m) of triethyl orthoisobutyrate in 50 ml of acetonitrile, sufficient ethereal HCl was added to make the mixture acidic. The mixture was refluxed overnight (about 16 hours), cooled and the product filtered off as the hydrochloride salt. Recrystallization by suspending the product in ethanol, adding sufficient methanol to afford a solution and diluting with anhydrous ether gave 2.5 g (62%) of 4,5-dihydro-4-(4-chlorophenyl)-2-(isopropyl)-3H-1,3,4-benzotriazepine hydrochloride, m.p. 255°-258° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@:10]1([C:26]#[C:27][Si](CC)(CC)CC)[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[C:22]([F:25])[N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[C:26]([C@:10]1([CH2:9][OH:8])[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[C:22]([F:25])[N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[CH2:12][CH2:11]1)#[CH:27]
Reactant: CC[Si](C#C[C@@]1(CO[Si](C)(C)C(C)(C)C)CC[C@H](n2cnc3c(N)nc(F)nc32)O1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#C[C@@]1(CO)CC[C@H](n2cnc3c(N)nc(F)nc32)O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound 22 (101 mg, 0.200 mmol) was dissolved in tetrahydrofuran (10 ml), and a solution of 1-M tetrabutylammonium fluoride in tetrahydrofuran (0.42 ml, 0.42 mmol) was added to the resultant solution, followed by stirring at room temperature for five minutes. After acetic acid (24 μl) was added to the resultant reaction mixture, the resultant mixture was concentrated under reduced pressure. The thus-obtained residue was purified by means of silica gel column chromatography (silica gel 15 ml, chloroform:methanol=40:1 to 20:1), to thereby yield compound 23 (53.0 mg, 0.191 mmol, 95.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].C(=O)([O-])[O-].[Ca+2].[C:15](Cl)(Cl)=[S:16].C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([N:7]=[C:15]=[S:16])[CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(F)cc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(F)cc1N=C=S
Temperature: 0 °C
Yield: 88.1 %

Procedure:
Under stirring at 0° C., a solution of 5-fluoro-2-methylaniline (1.23 g, 9.84 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of calcium carbonate (2.46 g, 24.6 mmol) and thiophosgene (750 μl, 9.84 mmol) in a methylene chloride/water (1/1, 40 ml) mixture. After completion of the dropwise addition, the reaction mixture was stirred further at 0° C. for 35 minutes. The reaction mixture was poured in ice-1N HCR, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give 5-fluoro-2-methylphenyl isothiocyanate (1.45 g, 88%) as a brown oil.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:13](Cl)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1sccc1Oc1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2Oc2ccccc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfonamide was prepared from 3-phenoxythiophene-2-sulfonyl chloride and 5-amino-4-bromo-3-methylisoxazole using the method described in Example 1. The product was recrystallized from acetonitrile/H2O to give a solid m.p. 121°-123° C., 61% yield.
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[F:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:28]4[CH:29]=[N:30][C:25]([F:24])=[CH:26][CH:27]=4)[C:3]=3[CH3:23])=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2ccc(F)nc2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide with commercially available 6-fluoropyridin-3-ylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 199). HPLC Ret time=2.98 min. LCMS [M+H]+ 410.25.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:39])[CH2:10][N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][CH2:13][O:14][C:15]2[CH:23]=[C:22]3[C:18]([C:19]([Cl:31])=[N:20][N:21]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CN=C1.Cl[Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48].C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]([O:39][Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:10][N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][CH2:13][O:14][C:15]2[CH:23]=[C:22]3[C:18]([C:19]([Cl:31])=[N:20][N:21]3[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc2c(Cl)nn(C(=O)OC(C)(C)C)c2c1)C[C@H](O)c1ccc(F)c(N)c1
Reactant: CC[Si](Cl)(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CN(CCOc1ccc2c(Cl)nn(C(=O)OC(C)(C)C)c2c1)C(=O)OC(C)(C)C)c1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-Tert-butyl 6-(2-((2-(3-amino-4-fluorophenyl)-2-hydroxyethyl)(tert-butoxycarbonyl)amino)ethoxy)-3-chloroindazole-1-carboxylate (601.2 mg) which can be prepared according to the method described in Reference example 69, etc. and imidazole (290.3 mg; Tokyo Chemical Industry Co., Ltd) were dissolved in dehydrated DMF (5 mL), added with chlorotriethylsilane (705 μL; manufactured by Shin-Etsu Chemical Co., Ltd.), and then the mixture was stirred for three hours at room temperature. The reaction solution was added to saturated solution of sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=84:16→64:36) to obtain the title compound (480 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([C@H:40]([C:41]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=34)[CH2:13][CH2:14]2)=[O:42])[CH2:39][N:38]([CH:51]([CH3:52])[CH3:53])[C:36](=[O:37])[O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:45][CH:46]=1
Reactant: OCCOc1n[nH]c2nccc(N3CCNCC3)c12
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ccnc3[nH]nc(OCCO)c23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0815 mL, 0.468 mmol) was added to 2-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol dihydrochloride (0.0472 g, 0.140 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.234 mL, 0.117 mmol, see Example B) and TBTU (0.0451 g, 0.140 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1). A LiOH solution (1 mL, 2M) was added and stirred for 10 minutes. Ether (20 mL) was added. The organic layer was separated, washed with brine (5 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (ethyl acetate) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The solvent was removed, and the resulting solid was dissolved in MeOH (2 mL). A LiOH solution (2 mL, 2M) was added and stirred for 10 minutes. DCM (20 mL) and water (10 mL) were added. The organic layer was separated, dried over sodium sulfate and concentrated to give (S)-2-(4-chlorophenyl)-1-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.018 g, 32%) as a solid. MS APCI (+) m/z 487.3 detected.
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[OH:21])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][CH3:6].[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:37]([O:36][C:35]([N:18]1[CH2:19][CH2:20][C@H:15]([CH2:14][O:13][C:10]2[N:11]=[N:12][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:9]=2)[C@H:16]([OH:21])[CH2:17]1)=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCCCc1nnc(OC[C@H]2CCNC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-3-ol dihydrochloride (1.14 mmol, 0.50 g) in DCM and saturated NaHCO3 (1 M, 1:1, v/v), was added di-t-butyl carbonate (3.42 mmol, 0.75 g). The reaction was stirred for 1 hour at room temperature. The reaction was allowed to settle and the layers were separated. The organic layer was dried and the crude product was purified by flash chromatography to give (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.50 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH2:17]([O:19][CH:20]([O:22][C@@H:23]1[C@@:53]2([CH3:54])[C:27](=[CH:28][CH2:29][C@@H:30]3[C@@H:52]2[CH2:51][CH2:50][C@@:49]2([CH3:55])[C@H:31]3[CH2:32][CH2:33][C@@H:34]2[C@H:35]([CH3:48])[CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][C@@H:25]([O:56][CH:57]([O:59][CH2:60][CH3:61])[CH3:58])[CH2:24]1)[CH3:21])[CH3:18]>O1CCOCC1.CCCCCC>[CH2:17]([O:19][CH:20]([O:22][C@@H:23]1[C@@:53]2([CH3:54])[C:27](=[CH:28][CH2:29][C@@H:30]3[C@@H:52]2[CH2:51][CH2:50][C@@:49]2([CH3:55])[C@H:31]3[CH2:32][CH2:33][C@@H:34]2[C@H:35]([CH3:36])[CH2:48][C:9]#[C:8][C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])([CH3:11])[CH3:10])[CH2:26][C@@H:25]([O:56][CH:57]([O:59][CH2:60][CH3:61])[CH3:58])[CH2:24]1)[CH3:21])[CH3:18]
Reactant: CCOC(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)OCC)C1
Reactant: C#CC(C)(C)OC(C)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CCOC(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC#CC(C)(C)OC(C)OCC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)OCC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.6 %

Procedure:
A stirred solution, cooled to 9° C., of 46.8 g (0.3 mol) of 3-(1-ethoxyethoxy)-3-methyl-but-1-yne in 1.0 liters of dioxane was treated dropwise under argon with 150 ml (0.3 mol) of 2M n-butyl lithium in hexane. The solution was stirred at 7°-9° C. for 2 hours and at room temperature for 2 hours. Thereafter, there was added to the mixture a solution of 67.0 g of (20S)-1α,3β-bis(1-ethoxyethoxy)-20-methyl-21-(p-toluenesulphonyloxy)-pregn-5-ene in 0.4 liters of dioxane and, while stirring, solvent was distilled off until the internal temperature was 93° C. The mixture was then stirred at 100° C. under argon for 64 hours. After cooling, carbon dioxide was conducted into the mixture. The mixture was poured into ice water, and the emulsion was extracted with ether. The extracts were washed with saturated sodium chloride solution, dried and evaporated. There were obtained 73.6 g of crude 1α,3β,25-tris(1-ethoxyethoxy)-cholest-5-en-23-yne.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][N:15]4[CH2:16][CH2:17][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20]4)=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN1CCC(c2ccccc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CCC(c5ccccc5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-4-phenyl-piperidine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:36])[CH3:35])[CH:20]=3)=[O:17])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:35])[CH3:36])[CH:20]=3)=[O:17])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(N)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)C)nn3-c3ccc4ncccc4c3)c(F)c2)ccn1
Reaction time: 60 h
Yield: 76 %

Procedure:
A solution of the above 1-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (44 mg, 0.061 mmol theory) and pyridine (0.30 mL, 3.7 mmol) in CH2Cl2 (1 mL) was treated with acetic anhydride (0.040 mL, 0.39 mmol). The reaction was stirred for 60 h and then partitioned between EtOAc and 2 M aq Na2CO3. The organic layer was washed with water and brine. The aqueous phases were back extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated in vacuo and purified by reverse-phase chromatography to provide 1-(4-(2-acetamidopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (25 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.01 (s, 1H), 8.96-8.94 (m, 2H), 8.49 (m, 1H), 8.18-8.11 (m, 4H), 7.95 (dd, J=8.8, 2.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.21 (dd, J=11.8, 2.7 Hz, 1H), 6.98 (m, 1H), 6.65 (dd, J=5.8, 2.4 Hz, 1H), 6.43 (s, 1H), 2.93 (m, 1H), 2.03 (s, 3H), 1.26 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 540.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:10]/[OH:11])/[CH3:9].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][CH2:21][OH:22]>C(#N)C>[OH:22][CH2:21][CH2:20][CH2:19][O:11]/[N:10]=[C:8](/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])\[CH3:9]
Reactant: OCCCCl
Reactant: C/C(=N\O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C/C(=N\OCCCO)c1ccccc1N
Yield: 81 %

Procedure:
(E)-1-(2-aminophenyl)ethanone oxime (0.2 mmol) was added into anhydrous acetonitrile (MeCN) (10 mL), followed by adding K2CO3 (1.1 equivalent weights) and 3-chloropropan-1-ol (5 equivalent weights) therein to obtain a mixture. The mixture was heated under reflux for 36 hours and was purified using a silica gel column (n-hexane/acetone=2:1), thereby obtaining (E)-1-(2-aminophenyl)ethanone O-3-hydroxypropyl oxime (168 mg, yield 81%).
Reaction SMILES: [CH3:1][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][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:24].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1>[CH3:1][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][CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:24])[CH2:15][CH2:14]1
Reactant: Cc1c(OC2CCNCC2)ccc2ccccc12
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(OC2CCN(CCCC(=O)c3ccc(F)cc3)CC2)ccc2ccccc12

Procedure:
A solution of 3.47 g of (12.5 mmole) of 4-(1-methyl-2-naphthalenyloxy)piperidine, 2.63 g (13.1 mmole) of 4-chloro-1-(4-fluorophenyl)-1-butanone, 5.2 g (52 mmole) of potassium bicarbonate and a pinch of potassium iodide in 60 ml of toluene is heated at reflux for 80 hours. The mixture is partitioned between toluene and water and the organic phase washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 4-[4-(1-methyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone.