Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC=CC=1.[C:8]1([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]3[CH:22]=[CH:23][C:24]([C:26](OC)=[O:27])=[CH:25][C:16]=3[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O>[C:8]1([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]3[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:16]=3[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCn1c(-c2ccccc2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCn1c(-c2ccccc2)nc2cc(CO)ccc21
Reaction time: 1 h
Yield: 91 %

Procedure:
(a-4) To a stirred and cooled (ice-bath) solution of 103.9 parts of sodium dihydro-bis(2-methoxyethoxy)aluminate in 45 parts of methylbenzene was added dropwise a solution of 88.5 parts of methyl 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylate in 270 parts of methylbenzene. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was decomposed by the addition of a mixture of 200 parts of a sodium hydroxide solution 7.5 N and 200 parts of water. The methylbenzene-phase was separated, dried, filtered and evaporated. The residue was washed with 210 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 73 parts (91%) of 2-phenyl-1-propyl-1H-benzimidazole-5-methanol; mp. 112.9° C. (int. 60).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:11][S-:12].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:11][S:12][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:2]=1[Cl:1]
Reactant: C[S-]
Reactant: Clc1cc(I)ccc1CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A solution of 2-chloro-4-iodobenzyl bromide (4.82 g, 14.54 mmol) in N,N-dimethylformamide (30 mL) was treated with sodium thiomethoxide (2.04 g, 29.08 mmol). After the addition, the solution became cloudy and turned to a yellow color. The resulting reaction mixture was stirred for 3 h at 25° C. The reaction mixture was then diluted with ethyl acetate (100 mL). The organic layer was washed successively with water (2×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 2-chloro-4-iodobenzyl methyl sulfide (4.24 g, 97%) as a colorless oil which was used without further purification: EI-HRMS m/e calcd for C8H8CIIS (M+) 297.9080, found 297.9078.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20](F)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 54.4 %

Procedure:
Piperazine (0.06 g, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 24 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.13 g of the title compound as a solid, mp 166-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccccc1C(=O)Cn1cc(Cl)cnc1=O
Yield: 30 %

Procedure:
A solution of 5-chloropyrimidin-2-one (541 mg) and 2-bromo-2'-methoxyacetophenone (954 mg) in triethylamine (1 ml) and ethanol (25 ml) was stirred at ambient temperature for 31/2 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (150 ml) and this solution was washed with water (50 ml) and brine (25 ml), dried (MgSO4) and evaporated to give a foam. This was purified by preparative thin-layer chromatography on silica, developed in chloroform, then chloroform-ethanol (25:1) before crystallisation from ethyl acetate to give the title pyrimidinone (347 mg,); m.p. 123°-125°; λmax 248.5 nm ε 12200), 317.5 nm (ε 6700), λinf 229.5 nm (ε 12440), 349 nm (ε 2640).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([CH:30]1[CH2:35][C:34](=O)[O:33][C:31]1=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC=CC=1>O>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][N:21]2[C:34](=[O:33])[CH2:35][CH:30]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:31]2=[O:32])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
A mixture of 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (12.1 g, 41.1 mmol), 2-octylsuccinic anhydride (9.0 g, 41.1 mmol) and 20 ml of toluene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The solvent was removed under vacuum while heating the reaction mass. 18.7 g of a very viscous, clear yellow liquid was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([NH:13][N+]([O-])=O)[CH:10]=[C:9]([Br:17])[N:8]=1.NC1C([N+:25]([O-:27])=[O:26])=NC=CC=1>CCOC(C)=O>[Br:17][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([NH2:13])[CH:12]=[C:7]([Br:6])[N:8]=1
Reactant: Nc1cccnc1[N+](=O)[O-]
Reactant: O=[N+]([O-])Nc1cc(Br)nc(Br)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Temperature: 54 °C
Reaction time: 1 h

Procedure:
Concentrated sulphuric acid (250 ml) was heated in an oil bath until the temperature of the acid reached 47° C. 2,6-dibromo pyridin-4-yl-N-nitroamine (34.0 g, 114.5 mmol) was added in portions over 35 mins. The temperature of the mixture gradually rose throughout the addition period until it was 56° C. at the end. The mixture was stirred at 53-55° C. for 1 hour. Once the reaction was completed, the reaction mixture was cooled to in an ice-bath and poured on ˜2 L of crushed ice with stirring. The product precipitated and was filtered off. Combined with other batch 00110916-140-001 from an identical scale reaction. The crude, wet amino nitro pyridine was dissolved in 700 ml EtOAc and the water layer was separated. The organic layer was washed with water (2×150 ml), 1×150 ml aq. NaHCO3, brine (2×150 ml), dried (MgSO4) and concentrated under reduced pressure to give 28 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=4[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:37])[CH:3]=1.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=4[S:29]([NH2:32])(=[O:31])=[O:30])=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:37])[CH:3]=1
Reactant: CCCCc1cc(-c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cc(-c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2)c(S(N)(=O)=O)s1
Reaction time: 8 h

Procedure:
To a mixture of the product of step D (215 mg, 0.40 mmol) and anisole (3 drops) was added TFA (3 mL). After standing at room temperature overnight, the solvent was removed and the residue was dissolved in EtOAc and washed with 2N Na2CO3 and brine. The organic was dried over MgSO4 and concentrated in vacuo to provide the titled compound, Rf=0.31 (20:1 CH2Cl2 /MeOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=O)[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:13][CH3:14])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCc1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethylthiochroman (Compound 61) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate, water, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150 degrees C, 0.7 mm) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08 (2H, m), 7.13 (1H, d, J~8.6 Hz), 7.58 (1H, dd, J~8.6 Hz, 2 Hz), 7.99 (1H, d, J~2 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11]1(O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]=1.COC>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]2[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Cl)c1
Reactant: OC1=NCCCCC1
Agent: COC
Agent: Cl
Solvent: CO
Product: Clc1cccc(NN=C2CCCCCN2)c1
Yield: 96 %

Procedure:
300 G of hydrogen chloride gas were introduced into a solution of 1,000g(7 moles) of 3-chlorophenylhydrazine and 980 g (7.7 moles) of caprolactim-methyl-ether in 4,000 ml of methanol at 10° to 20°C while stirring and cooling with an ice bath, and the reaction mixture was kept for a further hour at 20°C, raised to the reflux temperature and kept at 65°C for 11/2 hours. After cooling, the crystals which had separated out were filtered off and further crystal fractions were isolated by concentrating the mother liquors under reduced pressure. After recrystallization from 2 parts of methanol, 1,845 g (96% of theory) of caprolactam-(3-chlorophenylhydrazone) hydrochloride were obtained as colorless crystals of melting point 280° to 282°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH2:15]([Li])CCC.IC.Cl>C1COCC1>[F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
25.0 g (120.1 mmol) of 3-fluoro-4-trifluoromethylbenzoic acid were dissolved in 250 ml of THF, and 100.9 ml (2.5M in hexane, 252.3 mmol) of n-butyllithium were added dropwise at −40° C. The mixture was stirred for 3.5 h, and a solution of 51.2 g (360.4 mmol) of iodomethane in 50 ml of dry THF was then added dropwise. The mixture was stirred for 16 h, and after half an hour the temperature slowly increased to room temperature (RT). For work-up, 150 ml of 1M HCl were added carefully. The mixture was extracted with diethyl ether, and the organic phase was then extracted with 1M NaOH. The aqueous phase was acidified and then extracted with diethyl ether. The organic phase was washed with water, dried and freed from the solvent. The residue was titrated with n-heptane and the solid was removed by filtration. What was isolated were 13.5 g of the pure product.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])[CH3:21].C(O[B:36]1[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]1)(C)C.Cl>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:22][C:23]1[CH:27]=[C:26]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)[S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])[CH3:21]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1sccc1OC(C)c1ccccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
2.5 M n-BuLi in hexanes (2.3 mL, 5.77 mmol, 1.5 Eq.) was added dropwise to a stirred solution of diisopropylamine (815 μL, 5.77 mmol, 1.5 Eq.) in anhydrous THF (20 mL) at −78° C. under nitrogen. The reaction was stirred at this temperature for 15 minutes then warmed to 0° C. for 30 minutes. The reaction was cooled to −78° C. and a solution of methyl 3-(1-(2-chlorophenyl)ethoxy)thiophene-2-carboxylate (1.14 g, 3.84 mmol, 1.0 Eq.) in anhydrous THF (10 mL) was added dropwise. After stirring at this temperature for 10 minutes, a solution of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]-dioxaborolane (1.78 mL, 5.77 mmol, 1.0 Eq.) in anhydrous THF (10 mL) was added dropwise and stirred at −78° C. for 15 minutes then warmed to ambient temperature for 45 minutes. 1M HCl (30 mL) was added and the mixture extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was recrystalised from cyclohexane to give the sub-title compound as a white solid (837 mg, 1.98 mmol, 51%); 1H NMR (400 MHz, CDCl3) δ 1.38 (12H, s), 1.67 (3H, d), 3.90 (3H, s), 5.80 (1H, quint), 7.18 (1H, s), 7.21-7.7.34 (2H, m), 7.38 (1H, dd), 7.77 (1H, dd).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:18]=2)[CH2:16][CH2:15][CH2:14]1.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>O1CCCC1>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH2:20][CH2:19][N:18]=[C:17]2[C:13]2([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)CBr
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(C1(CC(C)C)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.83 ml, 1.8M in hexanes) was added dropwise to a solution of diisopropylamine (0.71 ml) in dry tetrahydrofuran (5 ml) at ambient temperature. After 15 minutes the solution was cooled to -23° C. and treated slowly with a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (1 g) in tetrahydrofuran (11 ml). The dark green solution was stirred for 30 minutes, further cooled to -78° C. and treated with 1-bromo-2-methylpropane (5.1 ml). After 1 hour at -78° C. the mixture was allowed to warm to ambient temperature, then heated under reflux for 1 hour. The mixture was poured onto water, acidified, and washed with ether. The aqueous phase was then basified by addition of aqueous sodium hydroxide solution and extracted with ethyl acetate. The solvent was removed in vacuo to yield an orange gum which was purified by flash chromatography over silica gel using a 1:4 mixture of ethyl acetate and light petroleum ether as eluant to give 7-methoxy-1-[1-(2-methylpropyl)cyclobutyl]-3,4-dihydroisoquinoline as an oil (0.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH:13]=O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:18][N:17]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=Cc1c(Cl)c2ccc(Br)cc2[nH]c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Br)ccc2c2[nH]ncc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of 7-bromo-4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (8.0 g, 27.9 mmol) in 150 mL of DMF at 80° C. is added hydrazine hydrate (2 mL, 33.5 mmol) at 80° C. The reaction medium is stirred for 24 hours at 80° C. and then cooled to room temperature and filtered. The solid obtained is washed with diisopropyl ether and dried to give 5.3 g of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in the form of a pale yellow powder (yield: 72%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C@@:16]1([CH3:41])[N:21]=[C:20]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([CH3:38])([CH3:37])[S:18](=[O:40])(=[O:39])[CH2:17]1)(=O)=O.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)[C:45]1[CH:50]=CC=C[C:46]=1P(C1C=CC=CC=1)C1C=CC=CC=1.C([Sn](CCCC)(CCCC)CCCC)C=C>CC#N.CC#N.Cl[Pd]Cl.CN(C=O)C>[C:26]([O:25][C:23](=[O:24])[N:22]([C:20]1[C:19]([CH3:37])([CH3:38])[S:18](=[O:40])(=[O:39])[CH2:17][C@:16]([C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:50][CH:45]=[CH2:46])([CH3:41])[N:21]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])([CH3:29])([CH3:28])[CH3:27]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2OS(=O)(=O)C(F)(F)F)CS(=O)(=O)C1(C)C
Agent: Cl[Pd]Cl
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1ccc([N+](=O)[O-])cc1[C@]1(C)CS(=O)(=O)C(C)(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Reaction time: 0.03 h
Yield: 468.5 %

Procedure:
100 ml RBF was charged with (R)-2-(5-((bis-(tert-butoxycarbonyl))amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-nitrophenyl trifluoromethanesulfonate (794 mg, 1.204 mmol), bis(acetonitrile)palladium(II)dichloride (31.2 mg, 0.120 mmol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (130 mg, 0.241 mmol) and DMF (6 ml). The mixture was stirred for 2 min until all solids dissolved. Allyltri-n-butylstannane (0.746 ml, 2.407 mmol) was added, the vial was sealed and stirred at 75° C. (heating block) for 30 min. The mixture was concentrated in vacuo and purified by FC on 40 g RediSep Gold column using 5-70% EtOAc in heptane to afford (R)-tert-butyl-N-(5-(2-allyl-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (623 mg, 1.129 mmol, 94% yield). LC/MS (ESI+) m/z=574 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[C:43](Cl)[N:44]=1)[C:38]([O:40][CH3:41])=[O:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:43]2[CH:42]=[C:37]([CH:36]=[C:35]([Cl:34])[N:44]=2)[C:38]([O:40][CH3:41])=[O:39])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cc(Cl)nc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A mixture of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 56 mg of methyl 2,6-dichloroisonicotinate, 95 mg of potassium phosphate, 6 mg of bis(tri-tert-butylphosphine)palladium(0), and 2.0 mL of dimethylacetamide was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 66 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinate as a pale yellow oily compound. ESI+: 614
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:23]=[C:22](F)[C:21]([F:25])=[CH:20][C:9]=1[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:11].[Cl:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[N:31][C:32]=1[F:33]>CS(C)=O.CCOC(C)=O>[Cl:26][C:27]1[CH:28]=[C:29]([O:34][C:22]2[C:21]([F:25])=[CH:20][C:9]([C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[O:11])=[C:8]([F:7])[CH:23]=2)[CH:30]=[N:31][C:32]=1[F:33]
Reactant: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Reactant: Oc1cnc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(Oc3cnc(F)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
Potassium carbonate (1.40 g, 10.14 mmol) was added to a solution of 4-Methylphenyl 2,4,5-trifluorobenzoate (Preparation 12, 1.80 g, 6.76 mmol), 5-chloro-6-fluoropyridin-3-ol (1.05 g, 7.10 mmol) in DMSO and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in EtOAc (50 mL), washed with water (2×25 mL) and the organic layer dried over sodium sulfate, filtered, and concentrated in vacuo. The remaining crude was then purified by silica gel chromatography eluting with 10 to 50% EtOAc in heptane to afford the title compound (1.48 g, 56%):
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][NH:7]1)=[O:5].[C:22]([O:26][C:27]([NH:29][CH:30]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][N:7]1[C:31](=[O:32])[CH:30]([NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:5]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CCOCC1
Reactant: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a solution of 4-(4-bromo-benzenesulfonyloxy)-pyrrolidine-2-carboxylic acid methyl ester HCl salt (4 g, 10 mmol) in DCM (50 mL) was added tert-butoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (2.86 g, 11 mmol), HATU (5.7 g, 15 mmol) and DIPEA (7 mL, 40 mmol). The solution was stirred at room temperature for 16 h. The solution was diluted with DCM and washed twice with aq NH4Cl and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The desired product was purified by silica gel column chromotography from hexane/EtOAc to provide 4-(4-bromo-benzenesulfonyloxy)-1-[2-tert-butoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidine-2-carboxylic acid methyl ester (4.25 g 70% yield). LCMS found 606 ([M+H]+.