Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)S(O[CH2:34][C:35]([F:43])([F:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=O)=O.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:34][C:35]([F:43])([F:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCC(F)(F)c3ccccc3)c2CC1
Temperature: 40 °C
Yield: 55.9 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL) and add potassium hydroxide (0.934 g, 16.64 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.163 g). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.163 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine (0.43 mL, 3.12 mmol) and 2,2-difluoro-2-phenylethyl trifluoromethanesulfonate (151 mg, 0.52 mmol). Heat the solution at 40° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1, 9:1 and 4:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (132 mg, 56%).
Reaction SMILES: [C:1]1([C@H:7]([NH:32][C:33]([O:35][C@@H:36]2[CH:41]3[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]3)[CH2:37]2)=[O:34])[C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[O:11][CH2:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([N:19]3[CH2:22][CH:21]([C:23](OC)=[O:24])[CH2:20]3)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl.[Cl:47][C:48]1[CH:49]=[N+:50]([O-:68])[CH:51]=[C:52]([Cl:67])[C:53]=1[CH2:54][C@@H:55]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=1)[OH:56].Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1>[Cl:67][C:52]1[CH:51]=[N+:50]([O-:68])[CH:49]=[C:48]([Cl:47])[C:53]=1[CH2:54][C@H:55]([O:56][C:23]([CH:21]1[CH2:22][N:19]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]3[CH:29]=[CH:30][CH:31]=[C:8]([C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:32][C:33]([O:35][C@@H:36]4[CH:41]5[CH2:40][CH2:39][N:38]([CH2:43][CH2:42]5)[CH2:37]4)=[O:34])[CH:9]=3)=[CH:28][CH:27]=2)[CH2:20]1)=[O:24])[C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: COC(=O)C1CN(C(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)C2CN(C(=O)c3ccc(COc4cccc([C@@H](NC(=O)O[C@H]5CN6CCC5CC6)c5ccccc5)c4)cc3)C2)cc1OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 2.6 %

Procedure:
To a solution of methyl 1-(4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoyl)azetidine-3-carboxylate (I23, 350 mg, 0.60 mmol) in THF (3 mL) and MeOH (3 mL) was added an aqueous solution of LiOH (1 N, 1.2 mL, 1.2 mmol) at room temperature. The resulting mixture was stirred for 16 h before being cooled to 0° C. and acidified with 2 N HCl to pH 2. The resulting mixture was then concentrated in vacuo and azeotroped to dryness with toluene. To a solution of the carboxylic acid in DMF (5 mL) was then added (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (248 mg, 0.72 mmol) followed by 4-(dimethylamino)-pyridine (37 mg, 0.30 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol). The resulting mixture was stirred at room temperature for 16 h and partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was dissolved in DMSO (3.0 mL) and purified by preparative HPLC to provide the title compound (14 mg, 3% over two steps) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[CH3:28])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:4].[Br:29]Br.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[CH3:28])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([Br:29])[CH:10]=[CH:9]2)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccc(Br)cc12
Reaction time: 2 h
Yield: 69.2 %

Procedure:
The compound of example 11, step 3, (550 mg, 1.47 mmol) was dissolved in a mixture of benzene (15 ml) and chloroform (15 ml) and treated at room temperature with bromine (235 mg, 1.47 mmol) under stirring. After 2 h, DBU (224 mg, 1.47 mmol) was added and the mixture stirred for 18 h at room temperature. The solvent was removed in vacuo and the remaining residue was purified by silica gel chromatography (HEP/EA). 460 mg of the title compound were obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([O:24]C)=O)[CH:9]=1)(=[O:3])[CH3:2].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.ClCCl>CS(C)=O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22](=[O:24])[N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Nc1cc(NCCNC(C)=O)nc(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)N2CCN(c3ccccc3)CC2)nc(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a well of a 96 well microtitre plate were added methyl [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate (30μl of a 0.3M solution in anhydrous DMSO) and 4-phenylpiperazine (30w1 of a 1.5M solution). This solution was left to shake on a plate shaker for 16 hrs. After this time 800 μl of dichloromethane were added, then 100 mg of PS-NCO. The plate was sealed, then mixed for 48 hrs. The slurry was filtered and the solvents removed in vacuo, to furnish the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:18][C:19](OC(C)=O)=[O:20]>N1C=CC=CC=1>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:20])[CH3:18])=[CH:7][CH:6]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of 5 g (19.3 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 25 mL of pyridine was treated with 2.2 mL (23.3 mmol) of Ac2O. The mixture was stirred at 60° C. for 2 hours and the solvent partially evaporated. The residue was distributed between a diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 5.7 g of crude N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide that was dissolved in 100 mL of DMF, treated with 3.4 mL (22.7 mmol) of DBU and then dropwise at 0° C. with 3.8 mL (22.7 mmol) of TESCl. The mixture was stirred at RT for 10 hours and then poured into a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 8.3 g of crude N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide which was dissolved in 100 mL of THF and treated with 3.4 mL of a 1M BH3*THF-solution in THF. The mixture was kept at reflux for 4 hours and the solvent partially evaporated. After addition of a saturated aqueous solution of NH4Cl and Et2O, the phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 9:1 yielded 7.5 g (96%) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine, light yellow oil, MS: 402 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2n(Cc2ccc(F)cc2)c1=O

Procedure:
This compound was prepared from 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) and 4-fluorobenzyl bromide according to General Procedure B. Yield 210 mg (55%), MP 132° C.; 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.2 Hz, 3H), 3.21 (m, 4H), 3.91 (m, 4H), 4.31 (q, J=7.2 Hz, 2H), 5.41 (s, 2H), 7.13-7.29 (m, 5H), 7.41 (d, J=6.0 Hz, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=4.8, 1.2 Hz, 1H), 8.57 (d, J=6.0 Hz, 1H), 9.09 (s, 1H); EIMS: 521 (M+1). Anal. (C27H25FN4O4S) C, H, N.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>CO>[Si:1]([O:8][CH2:9][C:10]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:11]1[OH:24])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)(c2ccc(Cl)c(Cl)c2)C(=O)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)(c2ccc(Cl)c(Cl)c2)C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution (25 mL) of tert-butyl 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3,4-dichlorophenyl)-6-oxo-1,4-oxazepane-4-carboxylate (1.34 g) in methanol was added sodium borohydride (221 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (303 mg) as a high-polar diastereomer. In addition, a less polar diastereomer (836 mg) was isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([Cl:20])[C:13]=1[N+:21]([O-:23])=[O:22]>>[F:18][C:17]1[C:12]([Cl:11])=[C:13]([N+:21]([O-:23])=[O:22])[C:14]([Cl:20])=[C:15]([F:19])[CH:16]=1.[F:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([Cl:10])=[C:5]([F:9])[C:6]=1[N+:21]([O-:23])=[O:22]
Reactant: Fc1cc(F)c(Cl)cc1Cl
Agent: O=[N+]([O-])c1c(Cl)c(F)cc(F)c1Cl
Product: O=[N+]([O-])c1c(F)c(Cl)cc(Cl)c1F

Procedure:
By nitration of 1,3-dichloro-4,6-difluorobenzene, the 2,6-dichloro-3,5-difluoronitrobenzene is available after stage 3 in good yields (75-95%) and selectivities (87:12; 3,5-difluoro-2,6-dichloronitrobenzene:2,6-difluoro-3,5-dichloronitrobenzene). (See also Trans. Ill. State Acad. Sci., 65, (1972) 75-80).
Reaction SMILES: [CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:37][C:36]6([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]6)[CH2:35][N:34]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C(N(CC)CC)C.[C:67](Cl)(=[O:69])[CH3:68].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:67]([N:40]1[CH2:39][CH2:38][C:36]2([CH2:35][N:34]([C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:46])[CH3:47])[CH:33]([C:30]3[NH:31][CH:32]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[CH:20]=[CH:21][C:16]([C:14]6[N:15]=[C:11]([C@@H:7]7[CH2:8][CH2:9][CH2:10][N:6]7[C:4]([C@@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:2]([CH3:59])[CH3:1])=[O:5])[NH:12][CH:13]=6)=[CH:17][CH:18]=5)=[CH:27][CH:26]=4)[N:29]=3)[CH2:37]2)[CH2:42][CH2:41]1)(=[O:69])[CH3:68]
Reactant: CC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCNCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(C)=O)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,8-diazaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 20) (19 mg, 0.02 mmol) in anhydrous CH2Cl2 (0.5 mL) was added triethylamine (0.016 mL, 0.12 mmol) followed by acetyl chloride (0.01 mL, 0.14 mmol) and the reaction stirred at room temperature for 1 h. The reaction is concentrated in vacuo and dissolved in methanol (0.7 mL) to which was added potassium carbonate (30 mg, 0.22 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and partitioned between CH2Cl2 and water (3 mL each) and the aqueous layer extracted with CH2Cl2 (3 mL) and the organic layers combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (18 mg, 90% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54-7.88 (m, 10H) 7.32 (br. s., 2H) 5.05-5.23 (m, 2H) 4.03-4.34 (m, 2H) 3.71-4.03 (m, 3H) 3.56-3.71 (m, 8H) 3.34-3.56 (m, 2H) 2.14-2.46 (m, 4H) 1.89-2.14 (m, 6H) 1.46-1.83 (m, 4H) 1.19-1.32 (m, 2H) 0.78-1.07 (m, 14H). HRMS for C46H60N9O7 (M+H)+ calc: 850.4616, found: 850.4617. Purity (LC-MS): 94%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CSc2cnc3ccccc3n2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(Cc1ccccn1)c1cnc2ccccc2n1
Yield: 11.6 %

Procedure:
In a mixture of 20 ml of chloroform and 5 ml of methanol was dissolved 2.51 g of 2-(2-pyridylmethylthio)-quinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was portionwise added 1.95 g of m-chloroperbenzoic acid (purity: 70%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (acetone/hexane), and recrystallized from ethanol/ether to give 0.27 g of 2-(2-pyridylmethylsulfinyl)quinoxaline as a pale brown crystalline powder, m.p. 117°-122° C. (decompn.).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.[H-].[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.CS(Cl)(=O)=O.CN(C)C=O>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:15][CH2:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:13]=2)=[CH:19][CH:18]=1
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: Oc1ccc(I)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Ic1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (6-phenoxypyridin-2-yl)methanol (100 mg) in ethyl acetate (4 ml), triethylamine (0.103 ml) and methanesulfonyl chloride (0.062 ml) were added under ice-cooling, the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a brown oil. To a solution of 4-iodophenol in dimethylformamide (1 ml), 24 mg of sodium hydride was added under ice-cooling, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., a solution of the crude product in dimethylformamide (1 ml) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with a saturated saline solution, extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-20:80)) to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[I-:13].[Na+].C(Cl)(=O)C>C(#N)C>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]([I:13])=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)ncc1Br
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: FC(F)(F)c1cc(I)ncc1Br
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
Prepared using General Procedure 17: To a stirred a solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). The reaction mixture was heated to 40° C. and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40° C. for 90 min. Once cooled, the reaction was quenched with NaHCO3 (5 mL) and extracted with EA (3×5 mL). The combined organics were washed with brine (10 mL), dried over MgSO4 and concentrated to give 80.0 mg (40%) of 5-bromo-2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (m/z) calculated for C6H2BrF3IN, 351.9; found 352.5 [M+H]+, tR=3.91 min. (Method 1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[OH:27].O>CN(C=O)C.CCOC(C)=O>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracated with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [CH2:1]([N:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]([CH2:8][C@@H:9]([C:22]([O:24]C)=[O:23])[NH:10][C:11](=[O:21])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([N:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]([CH2:8][C@@H:9]([C:22]([OH:24])=[O:23])[NH:10][C:11](=[O:21])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)OC)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)c2ccccc21
Yield: 88.7 %

Procedure:
The same procedures as in Example 149 were carried out from the compound obtained in Example 148 (2.1 g), 1 mol/L of an aqueous sodium hydroxide solution (7.5 mL), and methanol (75 mL), to give the captioned compound (1.8 g, 87%) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:4]([F:21])[CH:3]=1.[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:23]1([C:22](=[N:35][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[C:4]([F:21])[CH:3]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Br)cc2F)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2F)C1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (+)-(R)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (4.3 g) and benzophenone imine (2.2 ml) in toluene (20 ml) was added sodium tert-butoxide (1.84 g). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (743 mg) and tris(dibenzylideneacetone)dipalladium(0) (328 mg) were added and the reaction mixture was heated to 90° C. and stirred for 90 min. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 40% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(diphenylmethyleneamino)-2-fluorophenyl)morpholine-4-carboxylate 5.95 g, quant.) as a yellow amorphous solid. MS (ISP): 461.2 ([M+H]+).