Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[C:15]([C:17]3[N:18]=[C:19]([NH:22][CH3:23])[S:20][CH:21]=3)[O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:30][OH:31]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[C:15]([C:17]3[N:18]=[C:19]([NH:22][CH3:23])[S:20][CH:21]=3)[O:14][N:13]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNc1nc(-c2cc(C(=O)Nc3ccc(F)c(Cl)c3)no2)cs1
Reactant: NO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CNc1nc(-c2cc(C(=NO)Nc3ccc(F)c(Cl)c3)no2)cs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-5-[2-(methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboxamide (22 mg, 0.062 mmol) was suspended in benzene (1.5 mL) and phosphorus pentachloride (33 mg, 0.16 mmol) was added. The mixture was stirred for 3 h at 80° C. and evaporated in vacuo to give a tan solid. Benzene (2.0 mL) was added and the mixture was reevaporated twice. The solid was dissolved in tetrahydrofuran (1.5 mL) and 20 M aqueous hydroxylamine (70 μL, 1.0 mmol) was added and the mixture was stirred for 2 h. The mixture was evaporated in vacuo and triturated with methanol to give a white precipitate which was filtered and washed with methanol to give the desired product (12 mg, 35%). MF=C14H11ClFN5O2S; LCMS calculated for C14H11ClFN5O2S; (M+H)+: m/z=368. 1H NMR (400 MHz, DMSO-d6) δ: 11.20 (s, 1H), 8.75 (s, 1H), 7.82 (m, 1H), 7.32 (s, 1H), 7.20 (m, 1H), 6.92 (m, 1H), 6.65 (m, 1H), 2.82 (m, 3H).
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[C:31]4[N:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:27]=4[CH:26]=[C:25]([C:40]([F:43])([F:42])[F:41])[CH:24]=3)[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].O.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:13][N:10]1[CH2:11][CH2:12][C:7]([CH2:20][O:21][CH2:22][C:23]2[C:31]3[N:30]=[CH:29][NH:28][C:27]=3[CH:26]=[C:25]([C:40]([F:42])([F:41])[F:43])[CH:24]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1.[C:46]([OH:48])([C:45]([F:50])([F:49])[F:44])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c2ncn3COCC[Si](C)(C)C)(c2ccccc2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3[nH]cnc23)(c2ccccc2)CC1

Procedure:
tert-Butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate was treated with trifluoroacetic acid: water (9:1, 3 ml) at ambient temperature for 15 min at which time LC-MS analysis revealed completion of the reaction (HPLC method 10: tR=2.5 min, 520(MH)+). The volatiles were evaporated and dried under vacuo. The residue was treated with formaldehyde (0.1 mL, 3.6 mmol), acetic acid (cat.) and sodium cyanoborohydride (25 mg, 0.4 mmol) at ambient temperature for 2 h. The reaction was complete by LC-MS analysis (HPLC method 9: tR=2.7 min, 534(MH)+). The solvent was evaporated and the residue was treated with trifluoroacetic acid /dichloromethane (1:1, 4 ml) at ambient temperature for 3 h. LC-MS analysis (HPLC method 1: tR=2.0 min, 404(MH)+). The solvent was evaporated and the residue was purified by Prep HPLC (HPLC method 15). Fractions containing required product were combined and evaporated to give the title compound as a TFA salt. (6 mg, yield for 5 steps from (6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol, 13.2% yield). 1H-NMR (CD3OD, 500 MHz) δ 8.85 (s, 1H), 7.99 (s, 2H), 7.57 (s, 1H), 7.43-7.27 (m, 5H), 4.85 (s, 2H), 3.52 (s, 2H), 3.45 (m, 2H), 2.85 (m, 2H), 2.75 (s, 3H), 2.69-2.66 (m, 2H), 2.19 (m, 2H); 19F NMR (471 MHz, CD3OD) δ −62.9, −77.6; LC/MS (HPLC method 1): tR=2.1 min, 404(MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][O:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[C@@H:17]([O:33][CH2:34][CH2:35][CH3:36])[C@H:16]([CH3:37])[O:15][C:14]2=[O:38])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].[CH2:47]([O:49][CH2:50][C:51]([O:53][CH2:54]Cl)=[O:52])[CH3:48]>CC(C)=O>[CH2:47]([O:49][CH2:50][C:51]([O:53][CH2:54][O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][O:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[C@@H:17]([O:33][CH2:34][CH2:35][CH3:36])[C@H:16]([CH3:37])[O:15][C:14]2=[O:38])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[O:52])[CH3:48]
Reactant: CCOCC(=O)OCCl
Reactant: CCCO[C@@H]1[C@@H](Cc2ccc(C(F)(F)F)cc2)COC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@H]1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCO[C@@H]1[C@@H](Cc2ccc(C(F)(F)F)cc2)COC[C@H](NC(=O)c2nccc(OC)c2OCOC(=O)COCC)C(=O)O[C@H]1C
Temperature: 40 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
To a solution of 3-hydroxy-4-methoxy-N-((3S,7S,8R,9S)-9-methyl-2-oxo-8-propoxy-7-(4-(trifluoromethyl)benzyl)-1,5-dioxonan-3-yl)picolinamide (83 mg, 0.154 mmol) in acetone (2 mL) were added Na2CO3 (24.4 mg, 0.230 mmol), NaI (4.60 mg, 0.031 mmol), and chloromethyl 2-ethoxyacetate (30.5 mg, 0.200 mmol), and the mixture was stirred for 7 hours at 40° C. The reaction was cooled to room temperature and purified directly by flash chromatography (SiO2, 0→100% EtOAc/hexanes) to give ((4-methoxy-2-(((3S,7S,8R,9S)-9-methyl-2-oxo-8-propoxy-7-(4-(trifluoromethyl)benzyl)-1,5-dioxonan-3-yl)carbamoyl)pyridin-3-yl)oxy)methyl 2-ethoxyacetate as a colorless oil (94 mg, 93%): 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=8.2 Hz, 1H), 8.26 (d, J=5.4 Hz, 1H), 7.61-7.50 (m, 2H), 7.32 (d, J=8.0 Hz, 2H), 6.95 (d, J=5.4 Hz, 1H), 5.80 (s, 2H), 5.04-4.95 (m, 2H), 4.08 (s, 2H), 4.03 (dd, J=11.7, 7.3 Hz, 1H), 3.90 (s, 3H), 3.66 (dt, J=8.6, 6.6 Hz, 1H), 3.63-3.47 (m, 3H), 3.47-3.36 (m, 3H), 3.23-3.12 (m, 2H), 2.43 (dd, J=13.7, 11.7 Hz, 1H), 2.01-1.90 (m, 1H), 1.69-1.58 (m, 2H), 1.51 (d, J=6.4 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −62.35; HRMS-ESI (m/z) [M]+ calcd for C31H39F3N2O10 expected, 656.2557. found, 656.2569.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1(C)C=CC=CC=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[Na+].[Na+]>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[N:4][CH:3]=2)=[CH:17]1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cncc(-c2ccsc2)c1
Temperature: 75 °C
Yield: 337.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5 g, 21 mmol), distilled water (35 mL), toluene (140 mL), ethyl alcohol (35 mL), 3-thiopheneboronic acid (2.8 g, 22 mmol), sodium carbonate (4.67 g, 44.1 mmol) and tetrakis(triphenylphosphine) palladium (1.22 g, 1.05 mmol) were stirred. This black suspension was heated at 75° C. for 20 h. After cooling to room temperature, the mixture was diluted with distilled water (200 mL) and extracted with ethyl acetate (2×200 mL, then 100 mL). The combined organic phases were dried with MgSO4, filtered and concentrated by rotary evaporation, producing 17 g of a purple oil. Purification by column chromatography on silica gel, using cyclohexane:ethyl acetate (95:5) as eluent, afforded 2.9 g (58%) of white crystals, mp 58° C.
Reaction SMILES: [Li]CCCC.[Se:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[Se:12][CH:13]=[CH:14][CH:15]=1.CN(CCN(C)C)C.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26]>C1COCC1.CC#N>[CH3:24][Sn:25]([CH3:27])([CH3:26])[C:10]1[Se:6][C:7]([C:11]2[Se:12][C:13]([Sn:25]([CH3:27])([CH3:26])[CH3:24])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1c[se]c(-c2ccc[se]2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc(-c2ccc([Sn](C)(C)C)[se]2)[se]1
Temperature: 17 °C
Reaction time: 0.33 h

Procedure:
A solution of BuLi in hexanes (10.6 ml of a 1.6 M solution, 17 mmol) is added dropwise to a cooled (−78° C.) solution of 2,2′-biselenophene (2.00 g, 7.7 mmol) in THF (50 ml) and TMEDA (1.98 g, 17 mmol). On addition of the BuLi an immediate colour change is observed (dark red). After stirring for 20 min, the reaction mixture appeared dark yellow. The mixture is stirred for 6 h allowing to warm to 16-18° C. While warming the reaction mixture changed appearance to a green suspension. The reaction mixture is then cooled to −70° C. Trimethylstannyl chloride (3.38 g, 17 mmol) is added as a solid to the reaction mixture. After 10 min, the reaction mixture appeared brown. The reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with water (100 mL) and the mixture stirred for 1 h. Ethylacetate (100 mL) is added to the mixture. The layers are separated. The combined organic extracts are washed with water, brine and then dried (Na2SO4). After filtration the crude product is concentrated to yield a brown oil. MeCN is added and the mixture is stirred for 5 min. The mixture is recrystallized three times from acetonitrile. The material is used without further purification. MS (EI) 588 (M+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>CCOCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCc2ccc(OC)cc2)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Oc1ccc(CCCCCCc2ccc(O)cc2)cc1
Yield: 77.3 %

Procedure:
A mixture 40.0 g of 1,6-bis(4-methoxyphenyl)hexane of Example 2, 150 ml of HBr (48%) and 150 ml of glacial acetic acid was refluxed for 5 hours. It was concentrated by evaporation to give a dark brown semi-solid. This was dissolved in ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 28.0 g of dark brown semi-solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:33])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:34](O)=O>>[C:1]1([S:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[CH:34][N:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)[C:14]=3[CH:13]=2)=[O:33])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CO
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2ncn(Cc3ccc(-c4ccccc4)cc3)c2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 0.400 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide and 2 ml of formic acid was stirred at 90° C. for 3 hours. The reaction solution was concentrated, and was precipitated with methanol. The crystals precipitated were separated through filtration, and were dried to give 0.243 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole (241).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC#Cc1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COCCCc1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Yield: 59.2 %

Procedure:
A solution of 6-(3-Methoxy-prop-1-ynyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 83B) (30 mg, 0.075 mmol) and 10% platinum black (10 mg) in ethyl acetate (10 ml) was hydrogenated at room temperature under 1 atmosphere of hydrogen during 48 hours. The catalyst was removed by filtration over Celite® and the filtrates concentrated to dryness to yield the title compound (18 mg, 60%) as a yellow solid that was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[CH:16]([O-])([O-])[O:17][CH2:18][CH3:19].C(OC(=O)C)(=O)C>>[CH2:18]([O:17][CH:16]=[C:6]([C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:15])[C:11]([F:14])=[C:12]([F:13])[C:2]=1[F:1])[C:7]#[N:8])[CH3:19]
Reactant: CCOC([O-])[O-]
Reactant: N#CCC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 2-(2,3,4,5-tetrafluorobenzoyl)acetonitrile (13.1 g), ethyl orthoformate (13.4 g) and acetic anhydride (15.4 g) is heated at 100° C. with stirring for 3 hours. The reaction mixture is concentrated under vacuum to yield an orange brownish oily residue. When the oily residue is allowed to stand at room temperature, it crystallizes slowly. The resulting crystals are collected and washed successively with a 2:1 mixture of hexane and ethyl acetate, and a 5:1 mixture of hexane and ethyl acetate to give 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (14.5 g) as light orange crystals, m.p. 99°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C([Li])CCC.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O1CCCC1.[Cl-].[Na+].O>[C:11]([O:10][C:9]([NH:8][C:4]1[CH:3]=[C:2]([CH2:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:6][N:5]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: COC(=O)CBr
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: -78 °C
Yield: 59 %

Procedure:
tert-Butyl N-(4-methyl-2-pyridyl)carbamate (5 g, 24.0 mmol) was dissolved in tetrahydrofuran (120 ml), cooled to −78° C., and then added dropwise with n-butyl lithium (40 ml, 60 mmol). Then, the reaction solution was warmed and stirred at room temperature. The reaction mixture was stirred for 1 hour, then again cooled to −78° C., and added dropwise with methyl bromoacetate (3.4 ml) dissolved in tetrahydrofuran (10 ml). After the reaction mixture was stirred for 30 minutes, the reaction was stopped with saturated brine and the reaction mixture was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=3:1→5:1) to obtain 3.95 g (59%) of the title compound as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:26])([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[C:14]([C:27]([CH3:35])([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:13]=1[OH:36])([O-])=O.C1(C)C=CC=CC=1.[OH-].[Na+].Cl>[Zn].O.C(O)(C)C>[OH:36][C:13]1[C:14]([C:27]([CH3:35])([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:15][C:16]([C:18]([CH3:26])([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a 5-liter 3-necked flask fitted with a stirrer, thermometer, reflux condenser and nitrogen inlet was charged 386 grams (0.805 mol) of the o-nitroazobenzene intermediate of Example 2 and 1200 ml of toluene. To the resulting solution was added 240 ml of isopropanol and 240 ml of water. A nitrogen atmosphere was imposed and 160 ml of 50.15 aqueous sodium hydroxide was added. A flask containing 158.2 grams (2.42 gram-atoms) of zinc was connected to the reaction flask by Gooch rubber tubing and the zinc dust was added portionwise to the reaction mixture over a 90-minute period. The zinc was added at such a rate to keep the internal temperature between 40° and 45° C. After the zinc was all added, the reaction mixture was heated for 1 hour at 40° C. and then for 3 hours at 70° C. The mixture was cooled to room temperature and acidified with 600 ml of concentrated hydrochloric acid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].[C:18]([OH:21])(=S)[CH3:19]>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][NH:1][C:18](=[O:21])[CH3:19])[O:9][C:8]2=[O:10])=[N:12][CH:13]=1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Reactant: CC(O)=S
Product: CC(=O)NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(5R)-5-(Azidomethyl)-3-(5-bromopyrid-2-yl)-1,3-oxazolidin-2-one (5.60 g, 18.7 mM) was dissolved in thioacetic acid (10 ml) to give a yellow solution. The solution was degassed and stirred at room temperature for 20 hours. The thick slurry was concentrated and the desired product was crystallized from acetone (100 ml) to give the product as a light yellow solid (3.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1N=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[O:37]1C2C=CC(N3CCC(=O)CC3)=CC=2O[CH2:38]1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[O:2]1[C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=5)[CH2:16]4)[CH2:11][CH2:10]3)=[CH:7][C:38]=2[O:37][CH2:1]1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reactant: O=C1CCN(c2ccc3c(c2)OCO3)CC1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby 1-(1,3-benzodioxol-5-yl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.79-1.85 (m, 2H), 2.03-2.18 (m, 3H), 2.40-2.47 (m, 1H), 2.67 (t, J=11.4 Hz, 2H), 3.13-3.21 (m, 1H), 3.35-3.43 (m, 2H), 3.54-3.64 (m, 4H), 4.03 (s, 2H), 4.48-4.50 (m, 1H), 5.86 (s, 2H) 6.42 (dd, J=8.4, 2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.69 (m, J=8.4 Hz, 2H), 7.70 (t, J=7.9 Hz, 2H), 7.87 (d, J=7.5 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.21 (s, 1H), 8.33 (s, 2H). MS m/z: 519 (M+1)
Reaction SMILES: CC(C)=O.C(O)(=O)C.[S-:9][C:10]#[N:11].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][CH2:20][C@H:21]1[O:36][C:34](=[O:35])[C@H:33]([CH3:37])[C@@H:32]([O:38][C@@H:39]2[O:44][C@@H:43]([CH3:45])[C@H:42]([OH:46])[C@@:41]([O:48][CH3:49])([CH3:47])[CH2:40]2)[C@H:31]([CH3:50])[C@@H:30]([O:51][C@@H:52]2[O:57][C@H:56]([CH3:58])[CH2:55][C@H:54]([N:59]([CH3:61])[CH3:60])[C@H:53]2[OH:62])[C@@:29]([OH:64])([CH3:63])[CH2:28][C@@H:27]([CH3:65])[C:25](=[O:26])[C@H:24]([CH3:66])[C@@H:23]([OH:67])[C@@:22]1([OH:69])[CH3:68]>C(OCCCC)(=O)C.O>[CH3:19][CH2:20][C@H:21]1[O:36][C:34](=[O:35])[C@H:33]([CH3:37])[C@@H:32]([O:38][C@@H:39]2[O:44][C@@H:43]([CH3:45])[C@H:42]([OH:46])[C@@:41]([O:48][CH3:49])([CH3:47])[CH2:40]2)[C@H:31]([CH3:50])[C@@H:30]([O:51][C@@H:52]2[O:57][C@H:56]([CH3:58])[CH2:55][C@H:54]([N:59]([CH3:60])[CH3:61])[C@H:53]2[OH:62])[C@@:29]([OH:64])([CH3:63])[CH2:28][C@@H:27]([CH3:65])[C:25](=[O:26])[C@H:24]([CH3:66])[C@@H:23]([OH:67])[C@@:22]1([OH:69])[CH3:68].[C:10]([SH:9])#[N:11]
Reactant: N#C[S-]
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCOC(C)=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: N#CS
Temperature: 37.5 °C

Procedure:
In a three-necked flask, 12 g of erythromycin was dissolved in butyl acetate or acetone, added with 2M acetic acid aqueous solution and 10% sodium thiocyanate solution (in a molar ratio to erythromycin of 1:1:1-1.2), and stirred continuously at 15-60° C. After complete reaction, the mixture was added with water, cooled to a temperature between −25° C. and 10° C., filtered, the resultant solid was washed with water, filtered under a reduced pressure, and dried at 60° C. for about 4 h to obtain an off-white crystal powder. HPLC analysis: the main peak of the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 88.46% (the theoretical value: 88.54%); melting point: 165.8-169.8° C. (not corrected), water content by Karl Fischer method was 4.62% (the theoretical value: 4.35%), TG-DTG: weight loss before 140° C. was about 4.51%, which was in the error range of the sample having 2 crystal water (see FIG. 6), MS (ESI, FAB) m/z: 793, 792, 734, 733, 59, 58. Element analysis: found: C, 54.93; H, 8.87; N, 3.29; S, 3.76; calculated: C, 55.05; H, 8.75; N, 3.38; S, 3.87. The obtained sample having 2 crystal water was added to a sodium carbonate solution to generate a precipitate, the precipitate was washed with water, recrystallized from water-ethanol, and the product was consistent with raw material erythromycin in terms of specific optical rotation and MS data.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1nn(N)c(=O)c2ccccc12
Product: CCOC(=O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 51B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.49 (d, J=8.0, 1H), 8.35 (d, J=7.9, 1H), 8.10-8.01 (m, 1H), 7.97 (dd, J=11.8, 4.3, 1H), 7.47-7.35 (m, 4H), 4.42 (q, J=7.1, 2H), 3.73 (s, 2H), 1.35 (t, J=7.1, 3H); MS (ESI−) M/Z 384 (M−H)−.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:15][C@H:16]([CH:27]1[CH2:30][CH2:29][CH2:28]1)[C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18].[Cl:31][C:32]1[N:39]=[C:38](Cl)[C:37]([F:41])=[CH:36][C:33]=1[C:34]#[N:35]>O>[Cl:31][C:32]1[N:39]=[C:38]([NH:15][C@H:16]([CH:27]2[CH2:28][CH2:29][CH2:30]2)[C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH3:18])[C:37]([F:41])=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H](N)C1CCC1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](Nc1nc(Cl)c(C#N)cc1F)C1CCC1
Reaction time: 3 h

Procedure:
DIPEA (17 ml) was added to a DMF (30 ml) solution containing tert-butyl ((1R,2S)-1-amino-1-cyclobutylpropan-2-yl)carbamate and 2,6-dichloro-5-fluoronicotinonitrile (16.2 g) obtained in the 5th step at 70° C., followed by stirring for 3 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and the organic layers were dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 1:1). A white solid of tert-butyl ((1R,2S)-1-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1-cyclobutylpropan-2-yl)carbamate (16.5 g) was thus obtained.