Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][CH:6]([C:18]2[N:19]([CH3:26])[N:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[O:5][CH2:4]1.N([C@@H]1CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC[C@@H]1O)=[N+]=[N-]>>[CH3:1][O:2][C@@H:3]1[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH2:8][CH2:7][C@@H:6]([C:18]2[N:19]([CH3:26])[N:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[O:5][CH2:4]1
Reactant: COC1COC(c2c([N+](=O)[O-])cnn2C)CCC1NC(=O)OC(C)(C)C
Agent: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])[C@@H](O)CO1
Product: CO[C@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following the procedure for Intermediate 58 starting from (3R,4R,7S)-4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol gave tert-butyl N-[(3R,4R,7S)-3-methoxy-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate as a colourless oil (357 mg, 32% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 5.60-5.53 (m, 1H), 5.12-5.02 (m, 1H), 4.21-4.08 (m, 2H), 4.01 (s, 3H), 3.79 (dd, J=13.2, 4.4 Hz, 1H), 3.75-3.70 (m, 1H), 3.41 (s, 3H), 2.28-2.07 (m, 1H), 1.97-1.89 (m, 2H), 1.80-1.72 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C[Al](C)C.C1(C)C=CC=CC=1.C[O:27][C:28]([C:30]1[CH:53]=[CH:52][C:33]2[N:34]=[C:35]([C:37]3[CH:42]=[C:41]([C:43]4[C:44]([O:49][CH3:50])=[N:45][CH:46]=[CH:47][CH:48]=4)[CH:40]=[CH:39][C:38]=3[OH:51])[NH:36][C:32]=2[CH:31]=1)=O>ClCCCl.C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:28]([C:30]3[CH:53]=[CH:52][C:33]4[NH:34][C:35]([C:37]5[CH:42]=[C:41]([C:43]6[C:44]([O:49][CH3:50])=[N:45][CH:46]=[CH:47][CH:48]=6)[CH:40]=[CH:39][C:38]=5[OH:51])=[N:36][C:32]=4[CH:31]=3)=[O:27])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CO
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)Nc4ccc(N5CCN(C)CC5)nc4)ccc3[nH]2)c1
Temperature: 80 °C
Yield: 20 %

Procedure:
To a solution of 6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine (38.4 mg, 0.2 mmol) in dry DCE (1 mL) were added AlMe3 in toluene solution (2.0 M, 160 μL, 0.32 mmol), and then 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid methyl ester (37.5 mg, 0.1 mmol). The reaction mixture was heated at 80° C. for 16.5 h, cooled to the room, loaded on silica gel, and chromatographyed (250:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (10.7 mg, 20%). 1H NMR (MeOH-d4) δ 2.35 (s, 3H), 2.57 (m, 4H), 3.54 (m, 4H), 3.97 (s, 3H), 6.84 (d, J=9 Hz, 1H), 7.03-7.10 (2H), 7.58 (d, J=9 Hz, 1H), 7.68 (d, J=9 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 7.86-7.93 (2H), 8.13 (m, 1H), 8.17 (s, 1H), 8.22 (s, 1H), 8.41 (s, 1H). ESI-MS m/z 536.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=O.[CH3:18][NH:19][CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][N:19]([CH3:20])[CH3:18]
Reactant: O=CC1CCCN1c1ccc([N+](=O)[O-])cc1F
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC1CCCN1c1ccc([N+](=O)[O-])cc1F
Reaction time: 0.5 h
Yield: 69 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-pyrrolidine-2-carbaldehyde (100 mg, 0.42 mmol) and dimethylamine (large excess) is stirred at room temperature in CH2Cl2 for 5 min and NaBH(OAc)3 (120 mg, 0.57 mmol) is added. The reaction is stopped after 30 min as TLC suggested complete conversion and the desired product (77 mg, 69%) is isolated after chromatography.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>O>[OH:9][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:1][NH:13][CH2:12][CH2:10][OH:11]
Reactant: NCCO
Reactant: c1ccc(C2CO2)cc1
Solvent: O
Product: OCCNCC(O)c1ccccc1
Reaction time: 24 h
Yield: 30.9 %

Procedure:
Styrene oxide (1.2 g.), ethanolamine (0.6 g.) and water (0.05 g.) were heated at 70° with stirring for 24 hours. The mixture was cooled, evacuated and the oil formed triturated with ether to give title compound (550 mg.) m.p 93.5° - 95°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]=1[OH:37])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:25][C:24]=1[O:37][C:45](=[O:47])[CH3:46])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C=CC(=O)c2ccc(OCc3ccccc3)cc2O)c(OCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C=CC(=O)c2ccc(OCc3ccccc3)cc2OC(C)=O)c(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 92 %

Procedure:
To a solution of 2-benzyloxy-4-methoxymethyloxy-4′-benzyloxy-2′-hydroxy-chalcone (0.496 g, 1 mmol), in 10 mL of acetic anhydride was added triethylamine (0.25 mL, 2 mmol) and the solution heated at 60° C. for ca. 6 hrs. After disappearance of starting material (TLC), the hot reaction mixture was poured into ice water:methanol (1:1) ca. 50 mL. A solid precipitated upon vigorous stirring. The solid was filtered, dried and recrystallized from methanol (ca. 15 mL) to obtain 0.495 g (92%) of white solid: mp 94-96° C.; TLC Rf0.21 in hexanes:EtOAc (3:1); 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.75 (m, 2H), 7.71-7.69 (d, 1H, J=8.8 Hz, Ar—H6′), 7.49-7.36 (m, 10+1H, 2×C6H6+Ar—H8), 6.99-6.96 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5′), 6.90 (d, 1H, J=2.4 Hz, Ar—H3′), 6.85 (d, 1H, J=2 Hz, Ar—H3), 6.72-6.69 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5), 5.26 (s, 2H, O—CH2), 5.20 (s, 4H, O—CH2), 3.39 (s, 3H, OCH3), 2.18 (s, 3H, CH3CO); 13C NMR (100 MHz, DMSO-d6) δ 189, 169.5, 162.5, 160.9, 159.6, 151.4, 139.5, 137.2, 136.9, 132.3, 131.7, 129.3, 129.2, 128.8, 128.6, 128.6, 125.2, 123.3, 117.6, 113, 110.8, 109.1, 102.2, 94.5, 70.7, 70.5, 56.6, 21.5; analysis calc'd. for C33H30O7: C, 73.60; H, 5.61; O, 20.81. found: C, 73.86; H, 5.62; O, 20.79.
Reaction SMILES: [N:1]1([C:6]2[CH:40]=[CH:39][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][C:15]=4[CH3:37])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:41][S:42]([OH:44])=[O:43]>CN(C=O)C>[Cl:21][C:20]1[C:19]2[C:14](=[C:15]([CH3:37])[CH:16]=[C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])[CH:18]=2)[N:13]=[C:12]([S:42]([CH3:41])(=[O:44])=[O:43])[C:11]=1[CH2:10][C:9]1[CH:39]=[CH:40][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Reactant: CS(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(S(C)(=O)=O)nc12
Temperature: 100 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.17 mmol, Intermediate 67), methanesulfinic acid (16.3 mg, 0.20 mmol), and DMF (2 mL) were combined in a reaction tube then sealed and heated to 100° C. and allowed to react at that temperature overnight. Analysis after overnight reaction showed only partial conversion, so additional methanesulfinic acid (13.3 mg, 0.17 mmol) was added and the vessel was resealed and heated to 100° C. for an additional 24 hours. The reaction vessel was then cooled to room temperature and solvent was removed by reduced pressure distillation. The crude residue was taken up into EtOAc, then extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C32H27Cl2N5O3S, 631.1. m/z found, 632.5 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.73-8.69 (m, 1H), 7.87 (dd, J=2.5, 0.6 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.65 (dd, J=1.9, 1.0 Hz, 1H), 7.60-7.57 (m, 2H), 7.37 (s, 1H), 7.35-7.30 (m, 4H), 7.20-7.16 (m, 2H), 6.44 (dd, J=2.5, 1.8 Hz, 1H), 6.37 (s, 1H), 5.06 (s, 2H), 4.48 (s, 1H), 3.39 (s, 3H), 2.92 (s, 3H), 2.74 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:31]=[N:32][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Product: COc1cc(-c2cncc(CN(c3ccc(OC(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=2)=[C:5]([O:23]C)[CH:4]=1)#N.C[S-].[Na+].O.Cl.[CH3:30][N:31](C)C=O>C(OCC)C>[C:30]([C:8]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:21])([CH3:22])[CH:10]=2)[CH:7]=1)#[N:31]
Reactant: CN(C)C=O
Reactant: COc1cc(C#N)ccc1C1=CC(C)(C)Oc2ccc(C#N)cc21
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)C=C(c2cc(C#N)ccc2O)c2cc(C#N)ccc2O1
Temperature: 25 °C

Procedure:
1.58 g of 4-(4-cyano-2-methoxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 1.05 g of sodium methanethiolate were heated at 100° C. for 20 minutes in 15 ml of dimethylformamide. The mixture was allowed to cool to room temperature and then poured into water and diethyl ether. The aqueous phase was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed three times with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (2:3) for the elution. After o recrystallization of the product from toluene there were obtained 1,1 g of 4-(5-cyano-2-hydroxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile of melting point 213°-215° C.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:16][C:17]([CH2:20][Si](C)(C)C)=[C:18]=[CH2:19])[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:20]=[C:17]1[C:18](=[CH2:19])[C:11]23[O:15][CH:7]([CH2:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12]3)[CH2:16]1
Reactant: C=C=C(CC(O)CCC1CCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C1CC2CCC3CCCC3(O2)C1=C
Temperature: -78 °C

Procedure:
1.50 mL of diethyl ether was added to 2-(3-hydroxy-5-trimethylsilanylmethyl-hepta-5,6-dienyl)-cyclopentanone (98 mg, 0.35 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (63 μL, 0.35 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane={fraction (1/15)}) to obtain 60 mg of the pro duct (91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC(C)(C)C)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65][O:66][C:67]([NH:69][CH:70]([C:74]1[CH:79]=[CH:78][CH:77]=[C:76]([O:80][CH3:81])[CH:75]=1)[C:71]([OH:73])=O)=[O:68]>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:71](=[O:73])[CH:70]([NH:69][C:67]([O:66][CH3:65])=[O:68])[C:74]6[CH:79]=[CH:78][CH:77]=[C:76]([O:80][CH3:81])[CH:75]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)c1cccc(OC)c1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1cccc(OC)c1
Yield: 5 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-(3-methoxy-phenyl)-acetic acid (0.049 g, 0.206 mmol) to provide {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(3-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.006 g, 5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:14]>ClCCCl>[Br:1][C:2]1[C:3]([Cl:8])=[N+:4]([O-:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ncccc1Br
Solvent: ClCCCl
Product: [O-][n+]1cccc(Br)c1Cl

Procedure:
A solution of 3-bromo-2-chloropyridine (50 g, 0.26 mol) and 3-chloroperoxybenzoic acid (70-75% wet with water; 67.3 g, 0.39 mol) in 1,2-dichloroethane (600 mL) was heated under reflux for 7 hours. The reaction was then concentrated under reduced pressure to an approximate volume of 200 mL and purified by chromatography on silica gel (Gradient: 80% to 100% ethyl acetate in heptane, followed by 5% to 10% methanol in ethyl acetate) to yield the title compound as a brown solid. Yield: 32.9 g, 0.158 mol, 61%. LCMS m/z 210.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J=7.8, 6.9 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 8.33 (d, J=6.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:3]=1.I[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:18][CH:17]=1.N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N+:28]([O-:30])=[O:29])=[CH:20][CH:21]=3)[CH:9]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2cccc(O)c2)n1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(C)n(-c2cccc(Oc3ccc(-c4ccccc4[N+](=O)[O-])cc3)c2)n1
Temperature: 85 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
A mixture of 3-(3,5-dimethyl-1H-pyrazol-1-yl)phenol 2 (5.00 g, 26.56 mmol, 1.0 eq), 4′-iodo-2-nitrobiphenyl (10.38 g, 31.92 mmol, 1.2 eq), CuI (0.25 g, 1.33 mmol, 0.05 eq), picolinic acid (0.33 g, 2.66 mmol, 0.1 eq) and K3PO4 (11.28 g, 53.12 mmol, 2.0 eq) in DMSO (60 mL) was stirred at a temperature of 80-90° C. for three days under a nitrogen atmosphere, then cooled to ambient temperature. The solid was filtered off and washed with plenty of ethyl acetate (250 mL). The filtrate was washed with water three times and then dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-5:1-3:1) as an eluent to obtain the desired product as a sticky liquid (9.38 g in 92% yield). 1HNMR (DMSO-d6, 400 MHz): δ 2.15 (s, 3H), 2.30 (s, 3H), 6.06 (s, 1H), 7.07 (dd, J=8.0, 2.4 Hz, 1H), 7.13-7.16 (m, 3H), 7.30-7.32 (m, 1H), 7.36-7.40 (m, 2H), 7.52 (t, J=8.0, 1H), 7.57 (dd, J=7.6, 1.2 Hz, 1H), 7.59-7.64 (m, 1H), 7.75 (td, J=7.6, 1.2 Hz, 1H), 7.97 (dd, J=8.0, 1.2 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 12.30, 13.27, 107.63, 114.22, 117.18, 118.91, 118.97, 124.10, 128.81, 129.73, 130.61, 131.84, 132.28, 132.92, 134.33, 139.35, 141.11, 148.20, 148.92, 156.52, 156.67.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:31]1[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(F)ccc1Br
Reactant: OB(O)c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(F)ccc1-c1ccncc1
Yield: 79 %

Procedure:
By carrying out the operation analogously to example 3, starting from 2-bromo-5-fluoro-phenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation V, and 4-pyridineboronic acid, the expected product is obtained in the form of a white solid with a yield of 79%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.Cl[C:32]([O:34][CH3:35])=[O:33].O>C(Cl)Cl>[CH3:35][O:34][C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:33]
Reactant: CN(CCN(CCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCCN(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 2-((3-aminopropyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (300 mg, 0.88 mmol) in dry CH2Cl2 (5 mL), Et3N (583 mg, 5.3 mmol) was added. The resulting mixture was cooled to 0-5° C. and a solution of methyl chloroformate (965 mg, 10.3 mmol, 5 eq) in dry CH2Cl2 (5 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Upon completion of the reaction, water (10 mL) was added, the aqueous layer was extracted with CH2Cl2 (3×8 mL), the combined organic layers were washed with 10% citric acid (2×5 mL) and brine, then dried over Na2SO4. The filtrate was concentrated to the crude product which was purified by preparative HPLC to tert-butyl 2-((3-(methoxycarbonylamino)propyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (200 mg, yield 83%).
Reaction SMILES: C([N:5]([CH2:9][CH2:10][C:11]([NH:13][NH:14][C:15]([C@@H:17]1[CH2:23][CH2:22][C@@H:21]2[CH2:24][N:18]1[C:19](=[O:30])[N:20]2[O:25][S:26]([OH:29])(=[O:28])=[O:27])=[O:16])=[O:12])C(=O)[O-])(C)(C)C.[NH+]1C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:5][CH2:9][CH2:10][C:11]([NH:13][NH:14][C:15]([C@@H:17]1[CH2:23][CH2:22][C@@H:21]2[CH2:24][N:18]1[C:19](=[O:30])[N:20]2[O:25][S:26]([OH:29])(=[O:27])=[O:28])=[O:16])=[O:12]
Reactant: CC(C)(C)N(CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)C(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Yield: 72.3 %

Procedure:
All the amount of the above pyridine salt was deprotected with trifluoroacetic acid, and purified by octadecyl silica gel column chromatography to afford 191 mg of the title compound (yield 72.3%).
Reaction SMILES: Br[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10]>O1CCCC1>[Br:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: BrC#CCCCCCCBr
Solvent: C1CCOC1
Product: CCCCC=CCCC#CCCCCCCBr

Procedure:
On the other hand, 1,8-dibromo-1-octyne and a copper halide as the catalyst are dissolved in tetrahydrofuran in a reaction vessel to form a reaction mixture, into which the above prepared Grignard reagent in tetrahydrofuran is added dropwise to effect the reaction between the reactants followed by hydrolysis and distillation to give 1-bromohexadeca-11-en-7-yne. The reaction is expressed by the following reaction equation:
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C1COCC1.O>[CH3:20][N:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
NaH 60% dispersed in mineral oil (0.030 g; 0.745 mmol) was added to a solution of methyl 4-(phenylamino)benzoate (0.113 g; 0.497 mmol) in THF (3 mL). After stirring the resulting solution for 10 minutes, methyl iodide (0.062 mL; 0.994 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted in water and extracted with ethyl acetate. The organic layer was washed with brine and dried to yield 0.045 g (40%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.I[CH3:17]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:17])[C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: CI
Reactant: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Yield: 88.9 %

Procedure:
8-Fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 3.13 g, 0.0149 mol) and iodomethane (1.39 ml, 0.0223 mol) in DMF (25 ml) are stirred at room temperature overnight. The reaction is diluted with water and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum to give the title compound as an orange solid (2.97 g, 89%); 1H NMR (300 MHz, CDCl3) δ 2.56-2.61 (m, 2H), 2.99-3.04 (m, 2H), 3.32 (s, 3H), overlapping 8.06 (s, 1H) and 8.08 (dd, 1H); [M+H]+=225.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]1[N:28]=[C:27]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:18][CH:19]=2)[CH:32]=[CH:31][N:30]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccccc1O
Product: Oc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 42.8 %

Procedure:
Using the procedure of example 1, 2-aminophenol (88 mg) was reacted with compound 1f (100 mg) to provide compound 30 (35 mg, 43%). 1H NMR (400 MHz, CD3OD) δ 8.83 (d, J=8.0 Hz, 1H), 8.28 (m, 2H), 8.25 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.22 (m, 2H), 6.97 (m, 1H), 6.91 (m, 2H). MS (ESI) m/z: 304 (M+H)+.