Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[OH:11][CH:12]1[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>[Cu](I)I.ClCCl.O.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[NH:14]1[CH2:15][CH:12]([O:11][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Ic1ccc2nccn2c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: c1cn2cc(OC3CNC3)ccc2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
6-Iodoimidazo[1,2-a]pyridine (400 mg), tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg), and toluene (2 ml) were mixed, and copper iodide (I) (40 mg), 1,10-phenanthroline (60 mg), and cesium carbonate (1 g) were added thereto, followed by stirring at 100° C. overnight. CHCl3 and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with dichloromethane (5 ml), and TFA (1.5 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 6-(azetidin-3-yloxy)imidazo[1,2-a]pyridine (189 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[S:20][C:21]([CH2:25][CH2:26][O:27]CC4C=CC=CC=4)=[C:22]([CH3:24])[N:23]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:35]>C(O)C.[H][H].[OH-].[Pd+2].[OH-]>[ClH:35].[ClH:35].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[S:20][C:21]([CH2:25][CH2:26][OH:27])=[C:22]([CH3:24])[N:23]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3nc(C)c(CCOCc4ccccc4)s3)cc3ccccc23)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCN1CCN(c2nc(-c3nc(C)c(CCO)s3)cc3ccccc23)CC1
Yield: 27 %

Procedure:
1-(1-Ethylpiperazin-4-yl)-3-[4-methyl-5-(2-benzyloxyethyl)thiazol-2-yl]isoquinoline (512 mg) was converted into a hydrochloride, which was then dissolved in ethanol (7 ml), followed by the addition of palladium hydroxide (222 mg), and the mixture was stirred in hydrogen atmosphere at room temperature for 3 days. After palladium hydroxide was filtered off, the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system). The resulting product was converted into a hydrochloride in a conventional manner, and then recrystallized from ethanol/isopropyl ether, to give the hydrochloride of the title compound as pale yellow crystals (129 mg, yield; 27%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1.[ClH:17]>C(O)(=O)C>[ClH:17].[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(C2=NCCN2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C2=NCCN2)cc1

Procedure:
1 g (4.58 mmol) of ethyl 4-(2-imidazoline-2-yl)benzoate was heated under reflux in 4 ml of hydrochloric acid and 8 ml of acetic acid. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][CH3:36]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:12]([CH2:33][CH2:34][CH2:35][CH3:36])[C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)c2cc(/C=C/C(=O)OC)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 4 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (Intermediate 5 STEP B, 500 mg, 1.24 mmol) was dissolved in dry DMF (4.5 ml) and added dropwise to a stirred suspension of NaH (60% oil dispersion, 59.6 mg, 1.49 mmol) in dry DMF (4.5 ml) cooled at 4° C. The mixture was stirred for 10 min at 0° C. and then 1-bromobutane (0.205 ml, 1.86 mmol) was added dropwise. The resulting yellow solution was stirred overnight at RT and then partitioned between EtOAc and saturated solution of NH4Cl. The organic layer was rinsed twice with water, dried over Na2SO4 and concentrated to dryness. The crude mixture was purified by column chromatography (eluent:petroleum ether:AcOEt 75:25) to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester as white foam (225 mg).
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH:4]C(=O)OCCCC.S(=O)(=O)(O)O.[C:29](=O)(O)[O-].[Na+]>CO>[CH3:29][O:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH2:4]
Reactant: O=C([O-])O
Reactant: CCCCOC(=O)NCC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(CN)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of tent-butyl 2-hydroxy-2,2-diphenylethylcarbamate (0.42 g, 1.39 mmol) in methanol (10 mL) was treated with concentrated sulfuric acid (2 mL). The reaction was stirred at 23° C. for a week and then at 40° C. for 2 hours. Solid sodium bicarbonate was added to the reaction until the pH reached ˜6-7 and the methanol was evaporated. The residue was then taken into ethyl acetate/water and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on preparative HPLC (ammonium acetate/acetonitrile/water) to give the title material (0.140 g, 46%). 1H NMR (400 MHz, CDCl3) δ: 3.11 (3H, s), 3.54 (2H, br s), 3.98 (2H, br s), 7.24-7.30 (2H, m), 7.31-7.36 (8H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[C:6]2[C:7]=1[CH:13]=[CH:14][NH:8]2
Reactant: C=C[Mg]Br
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Solvent: C1CCOC1
Product: COc1ccc2[nH]ccc2c1Br
Reaction time: 0.5 h
Yield: 3 %

Procedure:
To a −40° C. solution of 2-bromo-4-nitro-anisole (1.16 g, 5 mmol) in THF (10 ml) was added vinylmagnesium bromide (1M in THF, 15 ml). The reaction mixture was stirred for 30 min while allowing the temperature to rise to −20° C. The reaction was quenched by addition of a saturated solution of NH4Cl, diluted with Et2O, and the aqueous layer was extracted twice with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 4-bromo-5-methoxyindole XLVI (38 mg, 3% yield) as an oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClC1C=C2C(=CC=1)C(=O)NCC2>>[C:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[N:39]([CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]4[O:24][N:23]=[C:22]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:21]=4)[CH2:17][CH2:18]3)[CH2:38]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1NCC(c2ccccc2)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc1
Agent: O=C1NCCc2cc(Cl)ccc21
Product: O=C1c2ccccc2C(c2ccccc2)CN1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1

Procedure:
According to the same procedure described in Example 61, using the compound prepared in Example 65 instead of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate and 4-phenyl-3,4-dihydroisoquinolin-1(2H)-one (prepared according to the reported preparation in Davies, R. V.; et al. J. Chem. Soc. Perkin Trans. 1 1978, 180) instead of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one, the title compound having the following physical data was obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11][C@@:10]1([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=2)[CH:42]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:56]([C:53]1[CH:52]=[CH:51][C:50]([CH2:49][C:43]2[CH:42]=[C:41]([C@@H:10]3[CH2:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@@H:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:14]([O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@H:9]3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:46]=[CH:45][C:44]=2[O:47][CH3:48])=[CH:55][CH:54]=1)[CH3:57]
Reactant: CCc1ccc(Cc2cc([C@@]3(O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2OC)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@@H]3C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2OC)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
A solution of the (1S,2R,3S,4R,5R)-2,3,4-trisbenzyloxy-5-(benzyloxymethyl)-1-[3-(4-ethylbenzyl)-4-methoxyphenyl]cyclohexanol (124 mg, 0.16 mmol) as obtained in Example 65 in methylene chloride (2 mL) was cooled to −5° C., and triethylsilane (0.39 mL, 2.44 mmol) was added thereto. To the mixture, triofluoroacetic acid (0.12 mL, 1.6 mmol) was added and the reaction mixture was stirred at −5° C. for one hour, and then a saturated sodium hydrogen-carbonate was added thereto. The resulting mixture was extracted with methylene chloride and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:9)] to obtain the title compound (10 mg, 8%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][C:11]1C=CC(S(O)(=O)=O)=C[CH:12]=1>CC(C)=O>[CH3:10][C:11]1([CH3:12])[O:6][C@H:3]([C:2]([CH3:9])([CH3:1])[CH2:7][OH:8])[CH2:4][O:5]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(CO)[C@@H](O)CO
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](C(C)(C)CO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9756.8 %

Procedure:
(R)-3,3-dimethylbutane-1,2,4-triol (2.7 g, 20 mmol) and 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) were added to 25 mL of acetone and catalytic 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) and stirred overnight at ambient temperature. The solution was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with aqueous Na2CO3, dried over MgSO4 and filtered. The filtrate was concentrated to provide 1.7 g of the desired product as a clear oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([CH:10]([OH:12])[CH3:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1>O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([C:10]([CH3:11])=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C(C)=O)n1Cc1ccccc1Cl
Reaction time: 17 h
Yield: 59.2 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazole (1.07 g, 3.65 mmol), activated maganese dioxide (6 g) and toluene (75 mL) was heated at 90° to 100° C. under a slight vacuum with a Dean-Stark water separator for 17 hours. The inorganics were filtered, the concentrated filtrate was applied to a flash silica gel column, and the product was eluted with 3:7 hexane/ethyl acetate to give 0.628 g (59%) of [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[N:16]=[N:15][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)=[O:18])=[CH:13][CH:12]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[Cl:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:21][CH2:20][NH:19][C:17]([C:14]1[N:15]=[N:16][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cl)nn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2)nn1
Yield: 6.8 %

Procedure:
A mixture of phenylboronic acid (0.022 g; 0.179 mmol), 6-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyridazine-3-carboxamide (0.050 g; 0.149 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.012 g; 0.015 mmol), sodium iodide (0.044 g; 0.298 mmol) and sodium carbonate (0.032 g; 0.298 mmol) in dimethoxyethane (3 mL) and water (1 mL) was irradiated in the microwave oven at 130° C. for 15 minutes. The resulting solution was reported between water and ethyl acetate and the organic layer was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 20 to 80% ethyl acetate in heptane) to afford 0.0038 g (7%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-phenylpyridazine-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14]Br)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].[S-:22][C:23]#[N:24].[K+]>CC(C)=O>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][S:22][C:23]#[N:24])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCCBr)ccc(C(C)=O)c1O
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCSCCSC#N)ccc(C(C)=O)c1O

Procedure:
(2.8 mMole) S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-mercaptoethyl bromide and 5.0 g. potassium thiocyanate are heated to reflux for 2 hours in 25 ml. acetone. Subsequently, the precipitate is filtered off with suction, the solution is evaporated and the residue is stirred with diethyl ether. After evaporating the diethyl ether, there is obtained 0.7 g. (71% of theory) of the title compound in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7](=S)[NH:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[S:5][CH:6]=1.O.[NH2:17][NH2:18]>>[Br:1][C:2]1[N:3]=[C:4]([C:7](=[N:17][NH2:18])[NH:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[S:5][CH:6]=1
Reactant: C[C@H](NC(=S)c1nc(Br)cs1)C(F)(F)F
Reactant: NN
Solvent: O
Product: C[C@H](NC(=NN)c1nc(Br)cs1)C(F)(F)F

Procedure:
To a solution of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbothioamide (46 g, 1.0 eq.) was added hydrazine hydrate (15 g, 2.0 eq.). It was refluxed overnight. TLC and LCMS showed the reaction was complete. It was concentrated and the residue was purified by a flash column to obtain (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbohydrazonamide.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>C1C=CC=CC=1>[O:11]=[C:7]([CH3:6])[CH2:8][C:9]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:10]
Reactant: C=C1CC(=O)O1
Reactant: CCNCC
Solvent: c1ccccc1
Product: CCN(CC)C(=O)CC(C)=O
Reaction time: 1 h

Procedure:
To a solution of diethylamine (35 g, 0.48 mol) in benzene (75 ml), diketene (40.2 g, 0.48 mol) in benzene (100 ml) was added dropwise at 20°~30° C., stirring was continued for 1 hr. under reflux, and evaporated. The residue (75 g) was chromatographed on silica gel (wako Gel C-200) with dichloromethane/ethyl acetate (10:1) as eluent to give the title compound as a yellow viscous oil; yield: 48.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 13 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-chlorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid, gave (S)-2-amino-N-(4-(4-chlorophenoxy)phenyl)-3-phenylpropanamide (45 mg, 13%).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1
Yield: 50.2 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.37 mmol), 4-bromobenzaldehyde (62 mg, 0.34 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system gave the title compound (52 mg, 46% yield): >95% purity by LCMS, ESI-MS: 305.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.00 (d, 2H), 7.95 (d, 2H), 7.46 (d, 2H), 7.19 (d, 1H), 7.16 (s, 1H), 2.63-2.58 (m, 1H), 1.94-1.76 (m, 4H), 1.53-1.42 (m, 4H), 1.38-1.25 (m, 2H). MS (ESI) m/z: Calculated: 304.38; Observed: 305.2 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][NH2:13]>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:13][CH3:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 154a from 2,6-dichloro-3-nitro-pyridine and methylamine (40% in water) in ethanol.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9](C(O)=O)=[CH:10][C:5]=2[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.C1(P([N:47]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[K+]>O1CCOCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:47])=[CH:10][C:5]=2[N:4]([C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1
Reactant: O=C(O)c1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine-6-carboxylic acid (1.95 g, 4.03 mmol) and diphenylphosphoryl azide (1.047 mL, 4.83 mmol) in 1,4-dioxane (19.50 mL) was added a mixture of TEA (0.842 mL, 6.04 mmol) in 1,4-dioxane (10 mL) drop-wise over 5 min. The reaction mixture was heated to 80° C. for 2 h. A solution of KOH (1 N, 20.13 mL, 20.13 mmol) was added at 80° C. The reaction mixture was stirred overnight. Room temperature was obtained and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc/hexanes) to give 3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine MS ESI calc'd. for C25H20BrN4 [M+H]+ 455. found 455.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.C([Mg]Br)CC.[C:11]([C:15]1[CH2:19][CH2:18][C:17](=O)[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl>C(OCC)C>[CH2:2]([C:18]1[CH2:17][CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:19]=1)[CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)C1=CC(=O)CC1
Agent: CCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCCC1=CC(C(C)(C)C)=CC1
Temperature: 0 °C
Yield: 57 %

Procedure:
To a 300 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 120 ml of dehydrated diethyl ether and 89 ml (178 mmol) of tetrahydrofuran solution of 2.0M n-propyl magnesium bromide were charged under a nitrogen atmosphere. In the ice bath, 20.6 g (149 mmol) of 3-tert-butylcyclopentenone was added dropwise over 1 hour. The resultant solution was stirred at room temperature for 20 hours, and then the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The obtained organic layers were combined, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, twice with water and twice with saturated brine, and dried over magnesium sulfate and the solvent was distilled off. Thereafter, the resulting product was purified by column chromatography to obtain 16.8 g (GC purity 82%) of a pale yellowy transparent liquid. The yield was 57%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1c(-c2ccnn2C)csc1C(=O)NC(Cc1ccccc1)CN(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(-c2ccnn2C)csc1C(=O)NC(CN)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[3-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part b) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.[OH-].[K+].[Cl:14][CH2:15][CH2:16][CH2:17]Br>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:15]([Cl:14])[CH2:16][CH3:17])[C:8]([CH3:11])=[CH:7]2
Reactant: ClCCCBr
Reactant: Cc1cc2cccc(Cl)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(Cl)n1c(C)cc2cccc(Cl)c21
Yield: 52.3 %

Procedure:
40 g of 7-chloro-2-methyl-1H-indole are placed in 60 ml of toluene with 2.8 g of KOH under nitrogen. After stirring for 30 minutes at AT, 7.7 g of 3-chloro-1-bromopropane are added and then the mixture is heated to reflux for 3 hours. The medium is extracted with ether. The organic phase is washed with water, with a 10% HCl solution, with water and with a saturated NaCl solution. It is dried and evaporated and 6.19 g of the expected compound are obtained.