Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(C(C)=O)C(C)C>[C:1]1([CH:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)c1cccs1
Reactant: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(O)CC1
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(OC(c2ccccc2)c2cccs2)CC1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
Into 20 ml of methyl isobutyl ketone were dissolved 2.09 g of phenyl-2-thienylmethyl chloride, 3.50 g of 4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine and 1.94 g of N,N-diisopropylethylamine, and the resultant solution was heated under reflux with stirring for 2 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethanol-chloroform (1:50) by silica gel column chromatography to give 3.06 g of oily 4-(phenyl-2-thienylmethoxy)-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine.
Reaction SMILES: [OH:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1.C(Cl)Cl>[C:15]([O:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1)(=[O:17])[CH3:16]
Reactant: C=C1CC(C)(O)CCC2=C(C)CCC12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C1CC(C)(OC(C)=O)CCC2=C(C)CCC12
Reaction time: 8 h

Procedure:
A solution of 2.0 g of 6-hydroxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene in 5 ml of pyridine and 50 ml of methylene chloride was treated at -10° with 1.1 ml of acetyl chloride. The mixture was left to stand overnight at room temperature, then poured on to ice and worked up in a conventional manner. The crude product (3.1 g) which was obtained in the form of a brown oil, was chromatographed on 50 times the amount of silica gel. By elution with hexane/ether (19:1) there was obtained pure 6-acetoxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.01 ca 70°; IR(film): νmax = 3090, 1735, 1640, 1445, 1368, 1270/50/30, 1095, 1065, 1020, 905/900 cm-1. The compound has a flowery odour with a woody undertone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
A mixture of 5.02 g of 3,5-dichlorophenol, 5.57 g of tert-butyldimethylsilyl chloride, 5.24 g of imidazole and 50 ml of N,N-dimethylformamide was stirred at 20° C. for 3 hours and then was poured into a saturated solution of ammonium chloride and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain 9 g of residue is obtained which was chromatographed on silica, eluant: essence G with 1/00 of triethylamine to obtain 7.45 g of the expected product.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](Cl)(=[O:14])[C:11](Cl)=O.[NH2:16][C:17]1[S:18][C:19]([C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[C:20]([C:22]2[C:23]([F:44])=[C:24]([N:29]([CH2:41][O:42][CH3:43])[S:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=2[F:28])[N:21]=1>C(Cl)Cl>[CH:11]1([C:10]([N:16]([C:17]2[S:18][C:19]([C:45]3[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=3)=[C:20]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([N:29]([S:30]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=4[F:40])(=[O:32])=[O:31])[CH2:41][O:42][CH3:43])[C:23]=3[F:44])[N:21]=2)[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])=[O:14])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCCC1
Reactant: COCN(c1ccc(F)c(-c2nc(N)sc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: ClCCl
Product: COCN(c1ccc(F)c(-c2nc(N(C(=O)C3CCCCC3)C(=O)C3CCCCC3)sc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C

Procedure:
50 mg (0.39 mmol) of cyclohexanecarboxylic acid were dissolved in 3 mL of dry DCM and 56 μL (0.39 mmol) of TEA were added to the mixture. A solution of 33 μL of oxalyl chloride in 2 mL of DCM was then added dropwise at r.t. After 3 h the solvent was removed under reduced pressure, toluene was added several times and re-evaporated again. The residue was dissolved in 2 mL of dry DCM and dropped into a solution of 50 mg (0.095 mmol) of N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in 3 mL of the same solvent containing 56 μL of TEA. The reaction was maintained at r.t. overnight under stirring. The solution was then diluted with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated, to give N-(cyclohexylcarbonyl)-N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]-(methoxymethyl)amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2-yl]cyclohexanecarboxamide as an oil. The latter was taken up with 5 mL of MeOH and 1 mL of TEA was added to the resulting solution. The reaction was maintained at r. t. overnight. The solvent was then evaporated, the residue re-dissolved with DCM and washed with brine. The organic phase was dried over Na2SO4 and evaporated again, to afford N-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)-amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2-yl]cyclohexanecarboxamide. The latter was finally dissolved with 9 mL of TFA and 1 mL of water and heated at 75° C. for 6 h. The solvent was removed under reduced pressure, the residue re-dissolved with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The crude was finally purified by flash chromatography on a silica gel precoated column, eluted with DCM-MeOH 98/2, yielding 35 mg (63% overall) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][C:17](=[O:20])[CH:18]=[CH:19][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To compound of Step A (161.0 g, 561.8 mmol) in DMF (800 mL) was added methyl acrylate (58.0 g, 674.2 mmol), TEA (170.5 g, 1685.4 mmol) and dichlorobis(triphenylphosphine) palladium(II) (7.9 g, 11.2 mmol). The mixture was heated at 80° C. for about 32 hours. The mixture was cooled, diluted with 1000 mL of EtOAc and washed with 10% aqueous sodium bisulfate. The aqueous portion was extracted three times with EtOAc and the combined organics were dried (Na2SO4) and concentrated to dryness. The residue was dissolved in a small amount of DCM and filtered through 7 inches of silica gel in a 2 L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent was concentrated to dryness and recrystallized from EtOAc/hexanes to afford about 116.9 g (71%) of Step B compound.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.COC(N1C2C(=C(NC(NC3C4C(=CC(C(C)(C)C)=CC=4)OCC3)=O)C=CC=2)C=N1)=O>>[NH:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4ccc(C)cc43)cccc21
Agent: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Product: Cc1ccc2c(c1)C(NC(=O)Nc1cccc3[nH]ncc13)CCO2

Procedure:
The title compound was prepared using the procedure as described in Example 1E, substituting the product of Example 7C for the product of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.20 (m, 1H), 7.12-6.94 (m, 3H), 6.86 (d, J=7.5 Hz, 1H), 6.70 (d, J=7.5 Hz, 1H), 4.92 (m, 1H), 4.33-4.00 (m, 2H), 2.22 (s, 3H), 2.20-1.93 (m, 2H). MS (ESI) m/e (M+H)+. Calcd. For C18H18N4O2.0.9H2O0.25NaCl: C, 61.21; H, 5.65; N, 15.86. Found: C, 61.02; H, 5.74; N, 15.84.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:3])=[O:4]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (3.0 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.38 g) at room temperature. After stirring the reaction mixture at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. (2.62 g, yield 87%). melting point: 140-141° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH2:10][C:11]2([C:24]([O:26]CC)=O)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7]([Br:29])=[CH:6][N:5]=1.O>C1COCC1>[Br:29][C:7]1[CH:8]=[C:9]2[C:4](=[N:5][CH:6]=1)[NH:3][C:24](=[O:26])[C:11]1([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]1)[CH2:10]2
Reactant: CCOC(=O)C1(Cc2cc(Br)cnc2N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Reaction time: 1 h

Procedure:
Sodium hydride (201 mg, 5.3 mmol) was added to a solution of 1-tert-butyl 4-ethyl 4-((2-amino-5-bromopyridin-3-yl)methyl)piperidine-1,4-dicarboxylate (1.71 g, 3.87 mmol) suspended in THF (17 mL) at room temperature. The reaction mixture was stirred for 1 hour and then diluted by addition of water (50 mL). The resulting precipitate was filtered and washed with pentane. The title compound was obtained as a beige solid (1.2 g, 78%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].BrC1C=C(C=CC=1)C=O.C(N(CC)CC)C>C1COCC1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:9]1[CH:2]=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCO
Agent: O=Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(C#CCCO)c1

Procedure:
This is an example of a coupling reaction to form compounds such as the title compound by coupling compounds such as bromo benzaldehyde and 3-butyn-1-ol. A 1-L, 3-necked round-bottom flask was equipped with a magnetic stirring bar, a condenser with a nitrogen inlet, and two stoppers. The vessel was charged with 3-bromobenzaldehyde (18.5 g, 0.1 mol), 3-butyn-1-ol (10.5 g, 0.15 mol), triethylamine (100 mL), and THF (100 mL). To this mixture was then added PdCl2 (PPh3)2 (1.4 g, 2 mmol) and CuBrMe2S (0.405 g, 4 mmol). In other examples, the title compound was also obtained by using CuI together with a palladium-containing entity. The reaction mixture was heated to reflux using a heating mantle. After 4 h when TLC (thin layer chromatography) showed complete consumption of the bromide, the mixture was allowed to cool to room temperature, transferred to a 1-L round-bottom flask and concentrated under reduced pressure. The residue was dissolved in 250 mL of ethyl acetate. The solution was washed with water and brine, dried over MgSO4, and filtered. After filtration, the solvents were removed from the filtrate by evaporation under reduced pressure to obtain the title compound as pale yellow oil (16.8 g, yield 97%). Purity of the compound so obtained was determined by HPLC to be greater than 95%. TLC (Rf=0.32, SiO2, ethyl acetate/hexanes, 1:1). MS (electro spray, positive mode), M+ 174. 1H NMR (400 MHz, CDCl3) δ: 2.72 (t, 2H, J=6.3), 3.84 (t, 2H, J=6.2), 7.47 (t, 1H, J=7.7), 7.66 (dt, 1H, J=7.7, 1.4), 7.81 (dt, 1H, J=7.7, 1.4), 7.91 (t, 1H, J=1.4), 9.98 (s, 1H). It was found in the context of this invention, as illustrated by the embodiment given in this example, that the amount of palladium catalyst can be reduced down to catalyst amounts in the order of 0.1% (mol/mol). In contrast, conventional methodologies rely on Pd catalyst amounts in the range 1%-5%, with the percentages referred to the same units. This reduction in the amount of palladium catalyst leads to a significant cost reduction. Furthermore, this reduction in the amount of palladium catalyst leads to a reduction in the palladium contamination of the final product.
Reaction SMILES: [CH3:1][CH:2]1[CH:9]([CH3:10])[N:8]2[C:4](=[C:5]([CH:23]([CH:25]3C(=O)O[C:28](C)([CH3:32])[O:27][C:26]3=[O:34])[CH3:24])[C:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH2:28]([O:27][C:26](=[O:34])[CH2:25][CH:23]([C:5]1[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]2[C:4]=1[CH2:3][CH:2]([CH3:1])[CH:9]2[CH3:10])[CH3:24])[CH3:32]
Reactant: CC1Cc2c(C(C)C3C(=O)OC(C)(C)OC3=O)c(-c3ccccc3)c(-c3ccccc3)n2C1C
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(C)c1c(-c2ccccc2)c(-c2ccccc2)n2c1CC(C)C2C

Procedure:
2.5 mmoles of 59b are dissolved in a mixture of 20 ml absolute pyridine and 2 ml of absolute ethanol and upon addition of some copper powder the batch is reacted as described for 60a. Purification is by column chromatography (silica gel, n-hexane/CH2Cl2 2+1) in isolation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](=[S:8])[NH2:7].Br[CH2:17][C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:8][CH:17]=[C:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[N:7]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Reactant: COC(=O)CC(=O)CBr
Product: COC(=O)Cc1csc(-c2cc(OC)c(OC)c(OC)c2)n1

Procedure:
3,4,5-Trimethoxybenzothioamide (1.0 g) and methyl 4-bromoacetoacetate (858 mg)) were reacted in the same manner in Preparation Example 2 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1([C:12]2[NH:13][C:14](C3C=CC(Br)=CC=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[B:25]1(B2OC(C)(C)C(C)(C)O2)[O:29]C(C)(C)C(C)(C)[O:26]1.CC([O-])=O.[K+]>O1CCOCC1.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>[BH:25]([OH:29])[OH:26].[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1([C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ncc(-c3ccc(Br)cc3)[nH]2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ncc[nH]2)CCC1
Product: OBO
Temperature: 80 °C
Reaction time: 18 h

Procedure:
{1-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester (110 mg, 0.28) in 1,4-dioxane (2.5 mL) was treated with bis(pinacolato)diboron (150 mg, 0.59 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), and KOAc (71 mg, 0.73 mmol). The mixture was stirred in a sealed tube at 80° C. for 18 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford {1-[1H-imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester boronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[C:4]([F:18])[CH:3]=1.[H-].[Na+].I[CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([CH3:22])[CH2:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: CI
Reactant: O=C(NCc1ncccn1)c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ncccn1)C(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask was charged with 4-bromo-2-fluoro-N-(pyrimidin-2-ylmethyl)benzamide (74.5 mg, 0.24 mmol), NaH (60% dispersion in mineral oil, 11.5 mg, 0.288 mmol) in DMF (2 mL), to the slurry was added iodomethane (20 μl, 0.312 mmol) and to the resulting mixture was stirred at room temperature for 10 min, then was quenched by water (20 μl), concentrated and the crude residue was dissolved in EtOAc, washed with water, and brine, dried (Na2SO4), concentrated and 4-bromo-2-fluoro-N-methyl-N-(pyrimidin-2-ylmethyl)benzamide was obtained as oil (55.3 mg, 71%). LCMS (m/z): 324.1/326.1 (MH+), 0.66 min.
Reaction SMILES: [CH3:1][C@@:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=O.[OH-].[Li+].Cl.CN1CCOCC1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:41][NH2:42]>C1COCC1.O.O>[CH3:1][C@@:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[N:11]1)[C:3]([NH:42][O:41][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][O:35]1)=[O:5]
Reactant: NOC1CCCCO1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2cnccn2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@](CCn1cc(-c2cnccn2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]butanoate (0.32 g, 0.908 mmol) in THF-H2O (20 mL:10 mL) was added lithium hydroxide (0.217 g, 9.08 mmol, 10 eq). The mixture was allowed to stir at room temperature overnight. The mixture was then acidified with 1M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The solid was taken up in 2-methyltetrahydrofuran (20 mL). N-methyl morpholine (0.185 g, 1.81 mmol, 1.4 eq) was added, followed by CDMT (0.273 g, 1.55 mmol, 1.2 eq). The reaction mixture was allowed to stir for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.182 g, 1.55 mmol, 1.2 eq) was added, and the reaction mixture was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude was purified by flash chromatography, eluting with 0-10% MeOH/EtOAC to give (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (182 mg, 33% yield). LC-MS M−H 424.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]([CH3:59])([CH3:58])[CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][C:20]=3[N:19]=[C:18]([NH:34][C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[N:16]=[C:15]1[CH2:54][O:55][CH2:56][CH3:57])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]([CH3:58])([CH3:59])[CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][C:22]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][C:20]=3[N:19]=[C:18]([NH:34][C:35]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[N:16]=[C:15]1[CH2:54][O:55][CH2:56][CH3:57])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(/C=C/C(=O)OCC)ccc3c2n1CC(C)(C)OCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OCCNC(=O)OC(C)(C)C
Yield: 58 %

Procedure:
Palladium on carbon 10% (100 mg, 940 μmol) in ethanol (10 mL) was added to a suspension of (E)-ethyl 3-(1-(2-(2-(tert-butoxycarbonylamino)ethoxy)-2-methylpropyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl)acrylate (280 mg, 351 μmol) in ethyl acetate (30 mL). The mixture was stirred for 6 h in a hydrogen atmosphere at room temperature, filtered and solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 100% ethyl acetate in heptane) to give the title compound (0.163 g, 58%) as white solid; LC-MS (UV peak area, ESI) 74%, 800.5 (MH+).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[N+]=[N-]>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]12[CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(Br)cc21
Reactant: C=CCCCC
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCCC1CC12C(=O)Nc1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution containing 1-hexene (10 equiv.) and 1 mol % of rhodium (II) acetate in dry dichloromethane (10 mL) was degasified under an argon atmosphere. To this reaction mixture, a solution of 5-bromo-3-diazo-oxindole (1 equiv.) (J. Am. Chem. Soc. 1958, 80, 2257–2263) was added dropwise slowly over 1 h under an argon atmosphere at room temperature. The reaction mixture was stirred for 16 hours at room temperature, and concentrated to dryness in vacuo. The solid residue was chromatographed using hexane and ethyl acetate (v/v 1:1) as eluent. The chromatographed material gave the title compound in 70% yield. MS: m/z 294.3 [M+1]+. 1H NMR (CCl3D): δ 8.32 (br, 1H), 7.25 (d, 1H), 6.89 (d, 1H), 6.78 (d, 1H), 1.89 (m, 2H), 1.65 (m, 1H), 1.51 (m, 2H), 1.18–1.31 (m, 4H), 0.79 (t, 3H).