Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29]([S:35]([N:38](CC1C=CC(OC)=CC=1OC)[C:39]1[S:43][N:42]=[CH:41][N:40]=1)(=[O:37])=[O:36])=[CH:30]2>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29]([S:35]([NH:38][C:39]1[S:43][N:42]=[CH:41][N:40]=1)(=[O:37])=[O:36])=[CH:30]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: CC1(C)OB(c2ccc(Cl)cc2Br)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
Temperature: 100 °C

Procedure:
A pressure vessel was charged with 2-(2-bromo-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.732 g, 2.306 mmol), potassium carbonate (1.328 g, 9.61 mmol), 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (1 g, 1.922 mmol), tetrakis(triphenylphosphine)palladium(0) (0.222 g, 0.192 mmol) in dioxane (12.81 mL) and water (6.41 mL). The reaction was heated in an oil bath at 100° C. for 35 min. LC/MS indicated that the desired product (M+H=479.8) was generated. Water was added to the mixture and washed with EtOAc. The water layer was acidified with 5% HCl (15 mL) and washed with EtOAc again to afford a light yellow solid. The product was used in the next reaction without further purification. m/z (ESI) 480.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.FC1C=C(C(CCN2CCC(C3C=CC=CC=3[S@](C)=O)CC2)CN(C)C(C2C3C(=CC=CC=3)C=C([N+]([O-])=O)C=2)=O)C=CC=1F.[Br:66]Br>>[Br:66][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[OH:8].[Br:66][C:7]1[CH:6]=[CH:5][C:4]([OH:8])=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1cccc(Cl)c1
Reactant: BrBr
Agent: CN(CC(CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(F)c(F)c1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: Oc1cc(Cl)ccc1Br
Product: Oc1ccc(Br)c(Cl)c1

Procedure:
The requisite 4-(4-chloro-2-(R,S)-methylsulfinylphenyl)piperidine was prepared according to the procedures described in Example 2 except 3-chlorophenol was used in place of 3-methoxyphenol. The oxidation of the thiomethyl adduct was carried out according to the procedure described in Example 16, sub-part (e). 3-Chlorophenol (24.28 g) was reacted with bromine (29.78 g) to give 6.15 g of 2-bromo-5-chlorophenol (minor isomer) and 24.60 g 4-bromo-3-chlorophenol (major isomer) after purification by column chromatography (10:1 hexane:EtOAc); minor isomer-1H NMR (CDCl3) δ 7.37 (d, 1H), 7.04 (d, 1H), 6.82 (dd, 1H), 5.55 (s, 1H). Major isomer: 1H NMR (CDCl3) δ 7.36 (d, 1H), 6.91 (d, 1H), 6.57 (dd, 1H), 5.75 (s, 1H). Analytical data for all other intermediates follows. 2-Bromo-5-chloro-(N,N-dimethylthiocarbamoyl)phenol; 1H NMR (CDCl3) δ 7.52 (d, 1H), 7.18 (d, 1H), 7.13 (dd, 1H), 3.47 (s, 3H), 3.39 (s, 3H); MS m/z 296 (M+). 4-Chloro-2-N,N-dimethylthiocarbamoyl)bromobenzene; 1H NMR (CDCl3) δ 7.68-7.55 (m, 2H), 7.23 (dd, 1H), 3.12 (s, 3H), 3.05 (s, 3H); MS m/z 296 (M+). 4-Chloro-2-(thiomethyl)bromobenzene; 1H NMR (CDCl3) δ 7.43 (d, 1H), 7.06 (d, 1H), 6.97 (dd, 1H), 2.48 (s, 3H). 1-Benzyloxycarbonyl-4-hydroxy-4-(4-chloro-2-methylthiophenyl)piperidine; 1H NMR (CDCl3) δ 7.43-7.30 (m, 6H), 7.26 (d, 1H), 7.15 (dd, 1H) 5.15 (s, 2H), 4.25-4.00 (m, 2H), 3.84 (s, 1H), 3.50-3.25 (m, 2H), 2.52 (s, 3H), 2.15-1.90 (m, 4H); MS m/z 414 (M+Na). 1-Benzyloxycarbonyl-4-(4-chloro-2-methylthiophenyl)piperidine; 1H NMR (CDCl3) δ 7.43-7.30 (m, 5H), 7.18-7.10 (m, 3H), 5.16 (s, 2H), 4.42-4.20 (m, 2H), 3.07 (tt, 1H), 3.00-2.80 (m, 2H), 2.47 (s, 3H), 1.91-1.45 (m, 4H); MS m/z 398 (M+Na). 1-Benzyloxycarbonyl-4-(4-chloro-2-(R,S)-methylsulfinylphenyl)piperidine; 1H NMR (CDCl3) δ 7.98 (d, 1H), 7.42 (dd, 1H), 7.41-7.30 (m, 5H), 7.21 (d, 1H), 5.16 (s, 2H), 4.43-4.21 (m, 2H), 2.96-2.78 (m, 3H), 2.71 (s, 3H), 1.92-1.51 (m, 4H). 4-(4-Chloro-2-(R,S)-methylsulfinylphenyl)piperidine; 1H NMR (CDCl3) δ 7.97 (d, 1H), 7.43 (dd, 1H), 7.28 (d, 1H), 3.30-3.10 (m, 2H), 2.71 (s, 3H), 2.83-2.61 (m, 3H), 1.92-1.51 (m, 5H); MS m/z 258 (M+H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.FC(F)(F)C([NH:48][C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)=O>CS(C)=O.COC(C)(C)C>[NH2:48][C@H:49]1[CH2:53][CH2:52][N:51]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)([CH3:34])[CH3:33])=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[CH:22]=2)[CH2:50]1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CCNC1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 52 h
Yield: 60 %

Procedure:
A mixture of 975 mg (1.83 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 1.26 g (9.15 mmol) potassium carbonate and 800 mg (3.66 mmol) (S)-3-(trifluoro-acetamido)pyrrolidine hydrochloride in 10 ml dimethyl sulfoxide was stirred at 130° C. for 52 h. After cooling to room temperature the reaction mixture was diluted with 30 ml tert-butyl methyl ether and washed with 20 ml of water and 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in 25 ml of a 2 N solution of ammonia in ethanol. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography to give 640 mg (60%) of the title compound as a light brown foam.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCc1nccc2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 1-butylisoquinoline-7-carboxylic acid (79 mg, 0.26 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (1.8 mL) was added HBTU (100 mg, 0.264 mmol) and the reaction mixture stirred for 0.5 h. To this was added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (107 mg, 0.264 mmol) in methylene chloride (1.8 mL) containing N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 93:7 chloroform/methanol) gave 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide (103 mg): mp 109-110° C.; ESI MS m/z 546 [M+H]+.
Reaction SMILES: CN1[C@@H]2CC3C=CC(O)=C4O[C@H]5C(OC)=CC=C2[C@]5(C=34)CC1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:34][N:35]1[C@H:45]2[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([OH:53])=[C:49]4[O:54][C@H:39]5[C:40]([CH:42]=[CH:43][C@:44]2([OH:55])[C@:38]5([C:48]=34)[CH2:37][CH2:36]1)=[O:41].[H][H]>[Pd].C(O)(=O)C>[CH3:34][N:35]1[C@@H:45]2[CH2:46][C:47]3=[CH:52][CH:51]=[C:50]([OH:53])[C:49]4[O:54][C@H:39]5[C:40]([CH2:42][CH2:43][C@:44]2([OH:55])[C@:38]5([C:48]=43)[CH2:37][CH2:36]1)=[O:41]
Reactant: [H][H]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Agent: [Pd]
Agent: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of CPS-O (6.92 g contains 76% (5.26 g, 17.7 mmol) of oripavine), meta-chloroperoxybenzoic acid (MCPBA, 4.30 g) and glacial acetic acid (52 ml) is stirred at room temperature for 5 hours. The amount of oripavine is then expected to be not more than 1% by HPLC analysis. To the resulting 14-hydroxymorphinone mixture is added 5% Pd/C (0.55 g) and hydrogenation proceeds at room temperature at 48 psig of hydrogen for about 18 hours. The amount of unreacted 14-hydroxymorphinone is expected to be not more than 0.5% by HPLC analysis. The mixture is filtered to remove the catalyst and the filtrate is evaporated to almost dryness. The residue is dissolved in water and basified to pH 9 by ammonium hydroxide. The solids are collected by filtration and dried at 90° C. and under 25-inch Hg of vacuum for 3 hours to give crude oxymorphone (approximately 95% yield expected).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8]
Reactant: CC(C)N
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Product: CC(C)NC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Yield: 23.9 %

Procedure:
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazol-5-carboxylic acid and isopropylamine as the raw materials, the same operation as the example 212(2) gave the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1)[CH3:8].O=S(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CC(C)(N)CO
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a 3-neck, 2 L round bottom flask was added 173.71 g (1.0 mol, 97%) of 2-amino-2-methyl-1-propanol in 300 mL of dry methylene chloride. The flask was equipped with a magnetic stir bar and thermometer and was placed into a dry ice/acetone bath and cooled to 0° C. From a separatory funnel, a solution of 4-ethylbenzoyl chloride (168.5 g, 1.0 mol), dissolved in about 300 mL of methylene chloride was slowly added, while maintaining the reaction temperature below 5° C. The mixture was allowed to stir at room temperature overnight. Solid propanol amine-HCl was filtered off and the filter cake was washed with methylene chloride. The combined methylene chloride extracts were concentrated partially on a rotary evaporator and used directly in the next step. The intermediate amide solution generated in the first step was cooled in an ice bath and DMF (0.5 mL) was added. 125 g (1.04 mol) of SOCl2 in 50 mL of methylene chloride from a separatory funnel was added drop-wise at a controlled rate, keeping the reaction temperature at 0.5° C. The reaction was stirred at room temperature for an additional 2-3 hours. The reaction mixture was cooled in an ice bath and 25% NaOH was added to make the aqueous layer basic (pH=11-12). The mixture was transferred to a large separatory funnel, the methylene chloride layer was separated, and the aqueous layer was extracted twice with chloroform. The combined organic phases were dried and evaporated to yield 201 g of 2-(4-ethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a yellow viscous oil. 1H NMR (CDCl3, 300 MHz), δ (ppm): 7.8 (d, 2H), 7.2 (d, 2H), 4.088 (s, 2H), 2.68 (q, 2H), 1.375 (s, 6H), 1.24 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:17].C(N(CC)CC)C.[OH-].[Na+].C(OCC)C>C1COCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C@@H:12]([OH:16])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(CC(=O)C(=O)O)cc([N+](=O)[O-])c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](O)C(=O)O)cc([N+](=O)[O-])c1N
Temperature: -35 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere a solution of 12.0 g (37.4 mmol) (1R)-B-chlorodiisopinocampheylborane in 40 mL THF was added dropwise within 15 min to a solution of 6.5 g (26.0 mmol) 3-(4-amino-3-methyl-5-nitro-phenyl)-2-oxo-propionic acid and 4.5 mL (32.4 mmol) triethylamine in 100 mL THF cooled to −35° C. and the reaction solution was stirred overnight at RT. Then the reaction solution was carefully combined with 60 mL 1 M NaOH and 150 mL diethyl ether at 5° C. and stirred for 15 min. The organic phase was separated off, extracted three times with 40 mL 1 M NaOH and once with 40 mL water. The combined aqueous phases were acidified with semiconc. HCl while cooling with an ice bath and extracted twice with 120 mL EtOAc in each case. The combined organic phases were dried over Na2SO4 and evaporated down i.vac. The crude product was obtained, which was further reacted without purification.
Reaction SMILES: Br[C:2]1C=CC2N(C(C3SC(SC)=CC=3)=CN=2)C=1.CC1(C)C(C)(C)OB(C2C(C3C=CC(C(OC)=O)=CC=3)=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2)O1.[CH3:61][S:62][C:63]1[S:67][C:66]([C:68]2[N:72]3[CH:73]=[C:74]([C:77]4[C:78]([C:101]5[CH:110]=[CH:109][C:104]([C:105]([O:107][CH3:108])=[O:106])=[CH:103][CH:102]=5)=[N:79][N:80]([C:82]([C:95]5[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=5)([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)[C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)[CH:81]=4)[CH:75]=[CH:76][C:71]3=[N:70][CH:69]=2)=[CH:65][CH:64]=1>>[CH3:61][S:62][C:63]1[S:67][C:66]([C:68]2[N:72]3[CH:73]=[C:74]([C:77]4[C:78]([C:101]5[CH:102]=[CH:103][C:104]([C:105]([O:107][CH2:108][CH3:2])=[O:106])=[CH:109][CH:110]=5)=[N:79][N:80]([C:82]([C:83]5[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=5)([C:95]5[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=5)[C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)[CH:81]=4)[CH:75]=[CH:76][C:71]3=[N:70][CH:69]=2)=[CH:65][CH:64]=1
Reactant: CSc1ccc(-c2cnc3ccc(Br)cn23)s1
Reactant: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(SC)s4)n3c2)cc1
Agent: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(SC)s4)n3c2)cc1

Procedure:
260 mg 6-bromo-3-[5-(methylsulfanyl)-2-thienyl]imidazo[1,2-a]pyridine (compound in Production Example 58) and 1 g mixture of methyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate and methyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate were reacted in the same manner as in Example 10, whereby 515 mg mixture of methyl 4-{4-[3-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]-pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}benzoate and ethyl 4-{4-[3-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]-pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}benzoate was obtained as a pale yellow amorphous. A mixture of 300 mg of this ester derivative, 1.3 mL of 1 N aqueous sodium hydroxide and 7 mL ethanol was stirred at 50° C. for 5 hours. An aqueous saturated ammonium chloride solution, ethylacetate, tetrahydrofuran and water were added to the reaction solution, and the organic layer was separated. To dissolve insolubles, dichloromethane and methanol were added to this organic layer which was then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was subjected to azeotropic distillation with toluene to give 416 mg crude product of 4-{4-[3-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}-benzoic acid as white crystals. From 414 mg of this carboxylic acid, 62 mg of the title compound was obtained as a pale yellow amorphous by the same reaction as in Example 361.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)([O:10][CH2:11][CH2:12]O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15]2)([O:10][CH2:11][CH2:12][N:31]2[C:27](=[O:37])[C:28]3[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30]2=[O:32])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCO)c2cccc(Cl)c2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN2C(=O)c3ccccc3C2=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 50.9 %

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)ethyl)piperidine-1-carboxylate (1.000 g, 2.6 mmol), phthalimide (1.490 g, 10.1 mmol), triphenylphosphine (4.130 g, 15.7 mmol), and DIAD (3.430 g, 17.0 mmol) in THF was stirred at rt for 40 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.6792 g (51%) of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 537 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:26][C:25]1[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)CNC(=O)OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
N-(Benzyloxycarbonyl)glycine (2.72 g, 13.13 mmol) was dissolved in CH2Cl2 and an excess of thionyl chloride at room temperature. After 2 h, the reaction was evaporated under vacuum and the residue was stripped with toluene twice and dried under vacuum. The white solid was taken into CH2Cl2 and 4-methoxy-2-nitroaniline (2.1819 g, 12.98 mmol) was added as a solid, followed by triethylamine (2.0 mL, 1.455 g, 14.38 mmol). The reaction was stirred at RT for 24 h, then was evaporated under vacuum. The residue was dissolved in EtOAc and washed with aqueous 1N NaHCO3. The EtOAc layer was dried (MgSO4) and concentrated under vacuum. Thin layer chromatography analysis (1:1:1 hexanes/Et2O/CH2Cl2) showed good conversion to the acylated material. The crude material was dissolved in 2:1:1 hexanes/Et2O/CH2Cl2 initially, with the addition of enough Et2O/CH2Cl2 and sonication/heating to dissolve all the solid material. Silica gel chromatography (2:1:1 hexanes/Et2O/CH2Cl2 (2 L), then 1:1:1 hexanes/Et2O/CH2Cl2 (1.5 L), then Et2O/CH2Cl2) gave the title compound (3.3387 g, 72%): 1H NMR (250 MHz, CDCl3) δ 3.85 (s, 3H), 4.06 (d, 2H), 5.18 (s, 2H), 5.61 (t, 1H), 7.2-7.4 (m, 6H), 7.65 (d, 1H), 8.63 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO.CCCCCC>[Cl:12][C:4]1[N:3]=[C:2]([O:14][CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (20.0 g, 96.1 mmol) in MeOH (100 mL) was added 0.5 M NaOMe in MeOH (423 mL, 211 mmol) dropwise. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was then concentrated to ca. ⅓ of the volume and slowly poured into saturated NH4Cl solution (200 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined EtOAc extracts were dried (Na2SO4), and concentrated in vacuo to yield a tan solid which was suspended in hexane (500 mL) and sonicated for 10 min. The resulting solid was collected by suction filtration and dried under suction to yield 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a powder. 1H-NMR (400 MHz, CDCl3) δ: 6.39 (s, 1H), 6.28 (br s, 2H), 4.05 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: BrCCOC1CCCCO1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccccc1SCCOC1CCCCO1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 2-bromobenzenethiol (3.0 ml, 24.9 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 1.10 g, 27.5 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To this reaction mixture was added 2-(2-bromoethoxy)tetrahydropyran (4.5 ml, 29.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Aqueous sodium carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give 2-[2-(2-bromophenylsulfanyl)ethoxy]tetrahydropyran (7.91 g, yield 100%).