Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([N:5]([C:9]([CH3:29])([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[CH3:27])=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:21]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:28])([CH3:29])[NH2:5])=[CH:14][CH:15]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cc2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
1,1-dimethylethyl[2-({4-[(2,3-dimethylphenyl)oxy]phenyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 75, 109 mg) was dissolved in 4.0 mL of dichloromethane and then TFA (1.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the removal of the volatiles, the residue was charged on a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M solution in MeOH). Evaporation afforded 68 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)OCCN2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(C(=O)N2CCOc3cnccc32)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
In a 10 ml flask, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (96.2 mg, 0.706 mmol) and 3-chloro-4-methoxy-5-nitro-benzoyl chloride (194 mg, 0.777 mmol) were dissolved in dichloromethane (3 ml). Triethylamine (0.15 ml, 1.059 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate:n-hexane=1:1. The fractions containing the product were collected and evaporated to obtain yellow solid (206 mg, 83.4%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[O:29](C(OC(C)(C)C)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=O.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:22])[CH3:23])=[N:10][CH:11]=[CH:12][CH:13]=2)[C:30](=[O:29])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:4][C:3]=1[C:25]([F:27])([F:26])[F:28]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(Br)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1nc(C(F)(F)F)c(Br)s1)c1cccnc1Oc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 323a, 135 mg, 0.29 mmol), BOC2O (75 mg, 0.34 mmol), DMAP (5 mg) and DIPEA (59 μl, 0.34 mmol) in THF (5 mL) was stirred at rt for 5 h. The solvent was removed and the residue was purified by flash chromatography (silica, 0-50% EtOAc/hexane gradient) provided Example A125a (149 mg) as a white foam. (M+H)+═574.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15](OCC)=[O:16])=[N:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccccc2OC)cc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1-n1cc(C)c(C=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution (5 mL) of ethyl 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate (1.6 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (10 mL) of lithium aluminum hydride (0.50 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr, ice-cooled again, and water (1.3 mL), 1N aqueous sodium hydroxide solution (6.5 mL) and water (1.3 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (0.79 g) of 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-methanol as a pale-yellow oil. This was dissolved in toluene (20 mL), manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (0.97 g, 70%) as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][CH2:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(C(CCC=C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(C(CCCC2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
17 g (40.7 mmol) of 1-benzyl-4-[4,4-bis(4-fluorophenyl)-butylidene]piperidine were hydrogenated in 850 ml of methanol with 5 g of palladium-on-charcoal (10%) at 45° C. in a shaking vessel for 2 hours. The catalyst was filtered off with suction and the solution was concentrated.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[ClH:10].O.[CH3:12]O>C1COCC1>[ClH:10].[NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([O:7][CH3:12])=[O:6])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCNCC1
Reaction time: 2.5 h

Procedure:
Isonipecotic acid (40 g, 310 mmol) was suspended, with stirring, in 250 mL of dry methanol and treated with HCl gas (lecture bottle) until solution was obtained. The solution was then cooled in an ice bath and treatment with HCl gas continued for an additional 20 min. After 2.5 h, the reacion mixture was stripped of solvent using a water aspirator (30° C.) and the resulting heavy, white cake suspended in 150 mL dry THF and filtered. The filter cake was washed with two portions of 50 mL THF, followed by washing with 3×50 ml Et2O, dried briefly in air (suction). The pale-yellow filtrate was discarded. Drying the slightly off-white solid was completed over-night in a desiccator (CaSO4) under high vacuum. The title compound (43.25 g) was obtaind analytically pure. Anal. (C7H14ClNO2) calcd: C, 46.80; H, 7.86; N, 7.80; Cl, 19.73. found C, 46.66; H, 7.78; N, 19.82. TLC Rf=0.63 (silica gel, 3:1 ethanol/conc. aq. ammonium hydroxide).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]1>CCO.[Pd]>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]1
Reactant: COC(=O)C=Cc1c[nH]cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(imidazol-4-yl)acrylate hydrochloride, as described above in Step A, (500 mg, 2.65 mmol) in EtOH (100 mL) was added 10% Pd on carbon (250 mg) and the reaction mixture was shaken under an atmosphere of hydrogen (45 psi) at ambient temperature for 18 hours on a Parr hydrogenation apparatus. The mixture was filtered through a pad of celite, washing with EtOH, and the filtrate was filtered through a pad of celite, washing with EtOH, and the filtrate was concentrated in vacuo to give the titled product.
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1/[CH:14]=[CH:15]/[C:16]([CH3:18])=[O:17]>C1COCC1>[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:12])([CH3:13])[C:7]=1/[CH:14]=[CH:15]/[C:16]([OH:17])([CH:2]=[CH2:3])[CH3:18]
Reactant: C=CBr
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(O)/C=C/C1=C(C)CCCC1(C)C
Temperature: 7.5 °C
Yield: 837.1 %

Procedure:
0.1 mols of magnesium turnings are suspended in 50 ml of THF and treated with some drops of a solution of 0.12 mols of vinyl bromide in 100 ml of THF with stirring and under nitrogen atmosphere. As soon as the Grignard starts to form, the mixture is is cooled to 5-10° C. and added with the remaining solution of vinyl bromide in 30 min. The mixture is then cooled to −60° C. and added with 0.09 mols of beta ionone in 100 ml of THF in 20 min. The mixture is left to warm to room temperature, then heated at 40° C. for 2 hours. After that, the reaction is quenched as above described and vinyl beta-ionol is recovered by double distillation under vacuum, to obtain 166 g of a product, corresponding to an about 84% yield, with purity higher than 90%, determined by NMR.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([OH:12])(=O)[CH:8]=[CH:9][CH3:10].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:13]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][C:16]([C:9]([CH3:10])=[CH:8][CH2:7][OH:12])=[CH:15][CH:14]=1
Reactant: CC=CC(=O)O
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=CCO)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To an ice cooled slurry of LiAlH4 (4.0 g) in dry ether (400 ml) was added ethyl 3-([1,1′-biphenyl]-but-2-enoate (3e, 11 g) in dry ether (200 ml) dropwise. The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with water (10 ml). A solution of 10% NaOH (5 ml) was added, stirred and then ether layer was decanted. The precipitate was washed with ether and combined ether extracts were concentrated. The crude product was purified by chromatography on silica gel to give 7.2 g (77.4% yield) of 3-([1,1′-biphenyl]-4yl)-2-butenol (4e formula 4, R=Ph), m.p. 112-114° C.
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11](/[CH:13]=[CH:14]/[CH:15]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]1[CH2:23][C:21](=[O:22])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:18]1=[S:19].[Cl-].[NH4+].N>C(O)C>[NH:1]([C:8]1[S:9][CH:10]=[C:11](/[CH:13]=[CH:14]/[CH:15]=[C:23]2[S:17][C:18](=[S:19])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:21]2=[O:22])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=C/C=C/c1csc(Nc2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=C/C=C/c2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 0.4 g of (2E)-3-(2-anilinothiazol-4-yl)acrylaldehyde, 0.29 g of rhodanine-3-acetic acid, 0.22 g of ammonium chloride, 0.2 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a reddish-brown powder having the following physical properties.
Reaction SMILES: [C:1]1([C:15]([O:17]C)=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=[O:12])=[CH:3][CH:2]=1.NC(N)=N>C(O)(C)C>[C:1]1([C:15]([OH:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c2ccccc12
Agent: N=C(N)N
Solvent: CC(C)O
Product: O=C(O)c1ccc(C(=O)O)c2ccccc12
Yield: 42.4 %

Procedure:
1.2 g of dimethyl naphthaline-1,4-dicarboxylate and 3 g of guanidine are dissolved in 10 ml of anhydrous isopropanol and the solution is boiled under reflux for 4 h. The solvent is removed in vacuo, the residue is slurried with water and the product is filtered off. 450 mg of naphthaline-1,4-dicarboxylic acid diguanidide are obtained; m.p.: 270° C. (Decomposition); Rf (acetone/water 10:1)=0.14; MS (FAB):299 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].O[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2N=[N:23]1.CN1CCOCC1.C1(NN)C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][C:5]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([NH:23][NH:22][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=3)=[O:17])[CH:13]=2)=[CH:4][N:3]=1
Reactant: On1nnc2ccccc21
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Solvent: CN1CCOCC1
Solvent: NNc1ccccc1
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(C(=O)NNc3ccccc3)c2)cnc1N
Reaction time: 18 h
Yield: 56 %

Procedure:
3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}benzoic acid (40 mg, 0.15 mmol) was dissolved in DMF (1 mL) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol), and 4-methylmorpholine (30 mg, 0.28 mol) were added sequentially. After one hour phenylhydrazine (30 mg, 0.27 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 hours. It was then diluted with ethyl acetate (10 mL), washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-N-methyl-6-{3-[(2-phenylhydrazino)carbonyl]phenyl}pyrazine-2-carboxamide (a tan color solid, 30 mg, 56% yield): 1H NMR (400 MHz, DMSO-d6): 10.42 (b, 1H), 8.92 (s, 1H), 8.84-8.82 (b, 1H), 8.57-8.57 (s,1H0, 8.41-8.39 (d, 1H), 7.94-7.89(m, 1H), 7.89-7.86 (d, 1H), 7.61-7.57 (t, 1H), 7.17-7.13 (t, 1H), 6.83-6.80 (d, 1H), 6.73-6.69(m, 1H), 2.85 (s, 3H); MS (EI) for C19H18N6O2: 440 (MH+).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:33])[CH:29]1[CH2:32][NH:31][CH2:30]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:31]3[CH2:32][CH:29]([N:28]([CH3:33])[CH3:27])[CH2:30]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Product: CN(C)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 38 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and N,N-dimethylazetidin-3-amine to afford a white solid. HPLC (Condition 7) tR=5.768 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=463.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.01 (s, 6H) 2.90-3.06 (m, 1H) 3.51-3.62 (m, 2H) 3.71-3.86 (m, 2H) 6.37-6.48 (m, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.53-7.93 (m, J=9.4 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.74 (d, J=1.95 Hz, 1H) 10.19-10.29 (m, 1H) 12.91-13.22 (m, 1H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:50][CH3:51])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38].[Cl:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[C:31]1[N:32]=[C:33]([CH2:50][CH3:51])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: Cc1ccc(B(O)O)c(Cl)c1
Reactant: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br
Agent: [Pd]
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(C)cc2Cl)c(CC)nc1NC1CCOc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine, ethylene glycol dimethyl ether, 2-chloro-4-methyl phenyl boronic acid and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.37–7.13, 6.99–6.90, 5.37, 4.64, 4.31, 2.69, 2.54, 2.40, 2.30, 1.29–1.17; HRMS (FAB) calcd for C24H26ClN3O+H 408.1842, found 408.1848.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[Cl-].[C:40]([O:44][C:45](=[O:48])[CH2:46][Zn+])([CH3:43])([CH3:42])[CH3:41].CCOCC.N#N>O1CCOCC1>[C:40]([O:44][C:45](=[O:48])[CH2:46][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: N#N
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
A solution of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (209 mg, 0.358 mmol), PdCl2(Amphos) (12.66 mg, 0.018 mmol), and (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in Et2O (1073 μL, 0.536 mmol) in dioxane (3576 μL) was heated to 80° C. under a purged stream of N2; the reaction was stirred for 16 h at 80° C. The crude was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 50% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(5-(2-tert-butoxy-2-oxo ethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (137 mg, 0.221 mmol, 61.8% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 620.3 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2cccs2)cc1
Reaction time: 2 h
Yield: 52.3 %

Procedure:
2-Thiophenylacetyl chloride (12.38 g, 77.1 mmol) in CH2Cl2 (40 ml) was added to a solution of anisole (8.33 g, 77.1 mmol) and AlCl3 (10.3 g, 77.1 mmol) in CH2Cl2 (200 ml) at room temperature. The reaction was completed after 2 hours, and the mixture was poured over a 10% HCl/ice slurry. The organic layer was washed with H2O and brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude solid was chromatographed on SiO2 (1 kg) eluting with CH2Cl2 /Hexane, 3/1, to afford 23 (9.37 g, 52.4%), m.p. 44.0°-45.5° C. and the ortho isomer (2.14 g, 12%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[O:7][CH2:8][C:9]1[N:10]=[CH:11][N:12]([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)[CH:13]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[C:14]([N:12]1[CH:13]=[C:9]([CH2:8][O:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:35]=[CH:34][CH:33]=2)[N:10]=[CH:11]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Yield: 42.8 %

Procedure:
A mixture of 4-(3-nitro-phenoxymethyl)-1-trityl-1H-imidazole (1.5 g, from above) and 10% Pd/C (0.18 g) in ethyl acetate (60 mL) and ethanol(30 mL) was hydrogenated at 1 atmosphere overnight. The reaction mixture was filtered through a celite pad and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (40:60) to afford 3-(1-trityl-1H-imidazol-4-ylmethoxy)phenylamine (0.6 g).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.CN(C)C=O.[OH-].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4](=[O:6])[CH2:5][S:1][CH2:2]1
Reactant: O=C1CSCN1
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSCN1CCCCBr
Reaction time: 44 h

Procedure:
A mixture of 4-thiazolidinone (25 g), dimethylformamide (DMF hereafter, 500 ml) and KOH (27.16 g) was stirred under N2 at room temperature for 1.5 h. To the resulting mixture was added 1,4-dibromobutane (101 ml), which rapidly caused the reaction mixture to turn milkyl white. Stirring was continued at room temperature for 44 h. The reaction mixture was poured into H2O (1000 ml) and the aqueous mixture was extracted with ethyl acetate (EtOAc hereafter, 3×300 ml). The combined extracts were washed successively with H2O (300 ml) and brine (300 ml), dried over Na2SO4, and concentrated in vacuo to an amber oil. HPLC (high performance liquid chromatography) of a 44.95 g aliquot yielded 7.15 g of an oil which upon distillation yielded a clear liquid, b.p. 134°-137° C./0.12 mm Hg.
Reaction SMILES: [Br-:1].[Li+].[C:3]([O:11][CH2:12][C@@H:13](OS(C1C=C(Cl)C(Cl)=CC=1Cl)(=O)=O)[C@@H:14]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH:16]=[N:17][O:18][CH3:19])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O1CCCC1.CN1CCN(C)C1=O>[C:3]([O:11][CH2:12][C@@H:13]([Br:1])[C@@H:14]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH:16]=[N:17][O:18][CH3:19])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Br-]
Reactant: CON=CC[C@H](OC(=O)c1ccccc1)[C@@H](COC(=O)c1ccccc1)OS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CON=CC[C@H](OC(=O)c1ccccc1)[C@H](Br)COC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
1.52 g of lithium bromide was added to a solution of 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate in 17.9 mL of tetrahydrofuran and 16.1 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 50° C. for 3 hours. Thereafter, ethyl acetate and a 25% lithium bromide aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a 13% lithium bromide aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 4.84 g of (2R,3S)-2-bromo-5-(methoxyimino)pentane-1,3-diyl dibenzoate in the form of a colorless oily product.