Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (10 mg, 7%). MS (ISP) 547.0 [(M+H)+]; mp 308-310° C.
Reaction SMILES: O[CH:2]([C:4]1([O:13]C)[C:8]([O:9]C)=[CH:7][CH:6]([O:11]C)O1)[CH3:3]>OS(O)(=O)=O>[CH3:3][C:2]1[O:11][CH:6]=[CH:7][C:8](=[O:9])[C:4]=1[OH:13]
Reactant: COC1=CC(OC)OC1(OC)C(C)O
Agent: O=S(=O)(O)O
Product: Cc1occc(=O)c1O

Procedure:
2(1-hydroxy ethyl)-2,3,5-trimethoxy-2,5-dihydrofuran (2.30 g, 0.012 moles) was stirred at room temperature for 4 hours in 50 ml of 1N H2SO4. Isolation as described in Example 9 gave 67% assayed yield of pure maltol.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C(O)C>[C:1]1([CH:7]=[CH:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC=Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C(=Cc1ccccc1)COC1CCNCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Tert-butyl 4-(3-phenyl-2-propenyloxy)-piperidine-1-carboxylate (0.314 g, 0.989 mmol) prepared in Reference Example 110 was dissolved in ethanol (10 ml), to which 6N hydrochloric acid aqueous solution (3 ml, 18 mmol) was added, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was neutralized with sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dried in vacuo to afford 4-(3-phenyl-2-propenyloxy)piperidine (0.198 g, yield 92%) as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>C1(C)C=CC=CC=1.[NH4+].[Cl-].C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:8]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]1
Reactant: Fc1ccccn1
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC1(c2ccccn2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a dry flask under Ar, 2-fluoropyridine (3.18 ml, 37 mmol) and cyclobutanecarbonitrile (3.0 g, 37 mmol) were dissolved in toluene (55 mL). The solution was cooled to 0° C. A 1M solution of sodium bis(trimethylsilyl)amide in THF (40.7 mL, 40.7 mmol) was added slowly over 5 min. After 1 h, the solution was warmed to room temperature. After another 19 h, the reaction was diluted with NH4Cl (aq) and DCM. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield 4.68 g (80%) of 1-pyridin-2-yl-cyclobutanecarbonitrile as a pale yellow oil, m/z=159.7 [M+1]+.
Reaction SMILES: C(OC1C=C([C@@H](O)CNC(C)(C)CC2C=CC([O:30][CH2:31][CH2:32]CC)=CC=2)C2SC(OC(C)C)=NC=2C=1)(C)(C)C.Cl.[OH-].[Na+].[CH2:41]([O:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([NH:56][CH2:57][C@@H:58]([C:60]2[C:68]3[S:67][C:66](=[O:69])[NH:65][C:64]=3[CH:63]=[C:62]([OH:70])[CH:61]=2)[OH:59])([CH3:55])[CH3:54])=[CH:48][CH:47]=1)[CH2:42][CH2:43][CH3:44]>C(O)(C)C>[C:31]([OH:45])(=[O:30])[CH3:32].[CH2:41]([O:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([NH:56][CH2:57][C@@H:58]([C:60]2[C:68]3[S:67][C:66](=[O:69])[NH:65][C:64]=3[CH:63]=[C:62]([OH:70])[CH:61]=2)[OH:59])([CH3:54])[CH3:55])=[CH:48][CH:47]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(OC(C)(C)C)cc3nc(OC(C)C)sc23)cc1
Agent: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(O)cc3[nH]c(=O)sc23)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)O
Temperature: 20 °C

Procedure:
(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol, (1 equiv.) was suspended in isopropanol. At 50 to 60°, a 1M aqueous hydrochloric acid solution (3 equiv.) was added within about 30-60 min. After complete reaction (approx. 2.5 hours at 60° C.) the solution was cooled to 20° C. and sodium hydroxide 2M (3 equiv.) added gradually at this temperature. After complete addition the emulsified free base (R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one was extracted into ethylacetate and the organic layer washed with water. The organic layer was treated with activated carbon and filtered using microcrystalline cellulose as a filter aid. The filter cake was washed with ethyl acetate. The filtrate, containing the free base (R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one, was carefully concentrated to a defined residual volume by distillation at a jacket temperature of 55° C. under reduced pressure. Isopropylacetate was then added and partly removed by distillation to a defined residual volume at a jacket temperature of 55° C. under reduced pressure. Further isopropylacetate and a solution of acetic acid in isopropylacetate were added to the warm distillation residue at 50-55° C. During the acetic acid addition the batch was seeded with (R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one acetate salt to initiate the controlled crystallization of the acetate salt early at 50-55° C. After gradually cooling to 0° C. the product suspension was filtered and washed twice with cold isopropylactetate. The filter cake was dried at 50 to 90° C. under reduced pressure until constant weight to give crystalline (R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one acetate salt at a typical yield of approx. 80%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:30]=[C:31]1[CH2:36][S:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][CH2:41][C:39]3[CH:38]=[CH:37][C:34]4[S:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=4[N:40]=3)[CH2:14][CH2:13]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(N3CCN(CCN)CC3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(N3CCN(CCNCc4ccc5c(n4)NC(=O)CS5)CC3)c2n1
Reaction time: 12 h
Yield: 29.7 %

Procedure:
To a solution of (2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amine (155 mg, 0.508 mmol) in DCM-EtOH (5 mL, 1:1) were added Na2SO4 (144 mg, 1.02 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (99 mg, 0.508 mmol). After 12 h at 25° C., the imine was quenched by addition of NaBH4 (29 mg, 0.762 mmol) in one portion. After an additional 1 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (73 mg, 30%) as a light yellow solid: LCMS (ES) m/e 484 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.46 (d, J=4.8 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.13 (d, J=9.1 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 4.06 (s, 3H), 3.92 (s, 2H), 3.83 (bs, 4H), 3.54 (bs, 2H), 2.88 (s, 2H), 2.66-2.72 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:16](=[O:35])[NH:17][C:18]1[S:22][C:21]2[C:23]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:20]=2[CH:19]=1)C1C=CC=CC=1>>[CH3:28][O:27][C:26]1[C:20]2[CH:19]=[C:18]([NH:17][C:16]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:35])[S:22][C:21]=2[C:23]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:25]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCN(C)CC3)cc12

Procedure:
The title compound MS: m/e=380.2 (M−H) was obtained as a light yellow foam (46% yield) by the reaction of N-methyl-piperizine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21]C)=[O:20])[CH:14]=2)[C@H:10]([C:23](=[O:33])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:23](=[O:33])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)[C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)Nc2cccc(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)Nc2cccc(C#N)c2)[C@H](c2cccc(C(=O)O)c2)C1
Temperature: 50 °C
Yield: 88.7 %

Procedure:
Add to a solution of trans-3-(3-cyano-phenylcarbamoyl)-4-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.44 mmol) in MeOH (3 mL), sodium hydroxide as a 10% aqueous solution (0.40 mL, 1.00 mmol). Heat the mixture to 50° C. for 30 min then cool to room temperature and remove the MeOH under reduced pressure. Dilute the mixture with water and adjust the pH to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid causing a solid to precipitate from solution. Collect the formed solid by filtration, wash with water and dry on the filter pad to provide 0.17 g of trans-3-(3-carboxy-phenyl)-4-(3-cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a powder.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+]>Cl>[I:1][C:2]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(N)c(I)c1
Yield: 20.9 %

Procedure:
A mixture of concentrated hydrochloric acid (150 ml) and 2-iodo-4-nitroaniline (30.0 g) is stirred and warmed to 45°-50° C. A solution of stannous chloride dihydrate (90.0 g) in concentrated hydrochloric acid (110 ml) is added while maintaining the reaction temperature at 65°-70° C. After the addition is completed, the mixture is cooled in an ice bath and 50% sodium hydroxide (250 ml) is added slowly. The mixture is filtered and the isolated damp solid is stirred in 600 ml water at reflux. The solution is decolorized with charcoal, filtered and cooled to afford 5.55 g of title compound, m.p. 95°-99° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.NC1C=CC=C2C=1C=C(C)N=C2C>>[NH2:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2
Reactant: Cc1cc2c([N+](=O)[O-])cccc2cn1
Agent: Cc1cc2c(N)cccc2c(C)n1
Product: Cc1cc2c(N)cccc2cn1

Procedure:
The title compound was prepared from D3 using the procedure outlined in D2.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([C:7]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)=[C:10]3[NH:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2c(-c3ccccc3)nn3cccnc23)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2c(-c3ccccc3)nn3c2NCCC3)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a mixture of 4-(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-amine (60 mg, 0.2 mmol, 1 eq) in 3 mL of ethanol is added sodium borohydride (17 mg, 0.45 mmol, 2.2 eq). The mixture is stirred at room temperature for 2 h. The mixture is then poured into water, extracted with dichloromethane (3×50 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. 29 mg (47%) of 4-(2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-amine are obtained as a white solid which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[C:8]1([C:4]2[CH:3]=[C:2]([B:29]([OH:34])[OH:30])[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Brc1cccc(-c2cccc3ccccc23)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2cccc3ccccc23)c1
Temperature: -60 °C
Yield: 71.9 %

Procedure:
Under an argon gas atmosphere, a mixture of 200.0 g (706.3 mmol) of 1(3-bromophenyl)naphthalene and 2.1 L of dehydrated THF was cooled down to −60 degrees C., and added with 543 ml (847 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degree C. 398.5 g (2.119 mol) of triisopropyl borate was dropped into the reaction solution at −60 degrees C. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for 17 hours. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by toluene, 126 g of 3-(1-naphthyl)phenylboronic acid was obtained at an yield of 67%.
Reaction SMILES: C(OC(=O)CC([C:9]1([CH2:22][CH:23]=[CH2:24])[CH2:21][CH2:20][C:12]2([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]2)[CH2:11][CH2:10]1)C#N)C>[OH-].[K+].C(O)CO.O.C(O)(=O)C>[CH2:22]([C:9]1([CH2:11][C:12]([OH:17])=[O:13])[CH2:21][CH2:20][C:12]2([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]2)[CH2:11][CH2:10]1)[CH:23]=[CH2:24]
Reactant: C=CCC1(C(C#N)CC(=O)OCC)CCC2(CC1)OCC(C)(C)CO2
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CC(=O)O
Solvent: O
Product: C=CCC1(CC(=O)O)CCC2(CC1)OCC(C)(C)CO2
Temperature: 190 °C
Reaction time: 3 h

Procedure:
3-(9-Allyl-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-3-cyano-propionic acid ethyl ester (4.21 g) is dissolved in a solution of KOH (16.5 g) in ethylene glycol (110 mL) and the resulting mixture is heated to 190° C. and stirred at this temperature for 3 h. After cooling to room temperature, the solution is diluted with water and neutralized with acetic acid. The resulting solution is extracted several times with ethyl acetate. The extracts are combined and the solvent is evaporated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:0→1:1) to give the title compound. Yield: 3.54 g (quantitative); Mass spectrum (ESI+): m/z=283 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH2:7][CH2:6][C:5](=[O:14])[N:4]2[CH2:15][CH2:16][CH2:17][C@@H:18]([C:19]3[NH:20][C:21]([C:24]4[CH:29]=[CH:28][C:27](B5OC(C)(C)C(C)(C)O5)=[CH:26][CH:25]=4)=[CH:22][N:23]=3)[N:3]12.[Br:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[C:45](Cl)[CH:44]=[N:43]2.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[C:45]([C:27]1[CH:26]=[CH:25][C:24]([C:21]3[NH:20][C:19]([C@H:18]4[N:3]5[C:2](=[O:1])[C@@H:8]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH2:7][CH2:6][C:5](=[O:14])[N:4]5[CH2:15][CH2:16][CH2:17]4)=[N:23][CH:22]=3)=[CH:29][CH:28]=1)[CH:44]=[N:43]2
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)[nH]3)N2C1=O
Reactant: Clc1cnc2cc(Br)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(-c5cnc6cc(Br)ccc6n5)cc4)[nH]3)N2C1=O
Temperature: 80 °C
Yield: 86.5 %

Procedure:
In a 10 ml seal tube, methyl (4S,7S)-6,10-dioxo-4-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)octahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (240 mg, 459 μmol) (Intermediate 3), 6-bromo-2-chloroquinoxaline (112 mg, 459 μmol) and Cs2CO3 (299 mg, 917 μmol) were combined with 1,4-dioxane (3.00 ml) and water (0.5 ml) to give a light brown solution. It was degassed for 10 min and tetrakis(triphenylphosphine)palladium (0) (53.0 mg, 45.9 μmol) was added. The reaction mixture was heated at 80° C. for 16 h. It was diluted with EtOAc (6 ml) and concentrated in vacuo. The residue was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% and 10% MeOH/CH2Cl2) to afford methyl (4S,7S)-4-(5-(4-(6-bromoquinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate as a red solid (240 mg, 86.6%). ESI-LRMS m/e calcd for C28H26BrN7O4 [M+] 604. found 605 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]>>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:15]2[CH2:16][CH2:17][N:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]4[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=4)[N:11]=3)[CH2:13][CH2:14]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: Clc1cccc(Oc2cccc(N3CCNCC3)n2)c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Oc4cccc(Cl)c4)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-[6-(3-chloro-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-methoxybenzene-1-sulfonyl chloride. 1H NMR (DMSO-d6) δ: 3.81 (s, 3H), 7.10 (d, 2H), 7.59 (m, 2H), 7.73 (m, 5H), 7.92 (d, 1H), 8.10 (d, 1H), 9.05 (s, 1H), 10.14 (s, 1H); MS (ES): 442.08 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].[NH2:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][N:14]([C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:13]1>C(O)CCC>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:11][C@H:12]2[C@H:16]([OH:17])[CH2:15][N:14]([C:18](=[O:31])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=3)[CH2:13]2)[CH:7]=1
Reactant: Cc1cc(Cl)cc(Cl)[n+]1[O-]
Reactant: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Solvent: CCCCO
Product: Cc1cc(Cl)cc(N[C@@H]2CN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C[C@H]2O)n1
Temperature: 130 °C
Reaction time: 10 h
Yield: 15.6 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine 1-oxide (200 mg), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (340 mg), and n-butanol (0.6 mL) was stirred at 130° C. for 10 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=20:1), and then the resulting solids were washed with hexane and diethyl ether to obtain 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (75 mg). (2) A mixture of 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (68 mg), morpholine (0.02 mL), sodium t-butoxide (42 mg), Pd(OAc)2 (1 mg), 2-(di-t-butylphosphino)biphenyl (3 mg), and toluene (1 mL) was heated at 100° C. for 10 h. The mixture was cooled to room temperature, then the reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (NH silica gel, ethyl acetate, and silica gel, hexane/acetone=1:1) to obtain the title compound (8 mg).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:28][N:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:30][Si](C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH2:30][N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(F)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Temperature: -12 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4S)-4-benzyl-3-[(2E)-3-(2,4-difluorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one, from preparation 28 (46.83 g, 140 mmol) in dichloromethane (300 mL) was added N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine (50.2 mL, 210 mmol) at room temperature. The solution was cooled to −12° C. and a solution of trifluoroacetic acid (1.05 mL) in dichloromethane (10 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 24 hours and saturated sodium hydrogen carbonate solution (180 mL) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (180 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude residue. Purification of the residue by column chromatography using toluene:methyl tert-butyl ether (12:1) followed by dichloromethane:methyl tert-butyl ether (19:1) as the eluent afforded the title compound (which is the second eluting diastereomer), 63.0 g (49%).