Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[F:7][C:8]([F:58])([F:57])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:49]([CH3:50])=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:51])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:56])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:41]([CH3:51])=[CH:42][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:48][C:49]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:5]4[CH2:6][CH:3]([F:2])[CH2:4]4)[N:27]=3)[C@H:20]2[CH3:56])[CH:10]=[C:9]([C:8]([F:7])([F:58])[F:57])[CH:14]=1
Reactant: FC1CNC1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
3-Fluoroazetidine hydrochloride (26.7 mg, 0.239 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 44, 60 mg, 0.080 mmol), THF (800 μl) and triethylamine (55.6 μl, 0.399 mmol) were stirred at 100° C. for 10 minutes in the microwave reactor. Once complete, the reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ8.15 (s, 1H), 68.02 (d, 1H), 67.89 (s, 1H), 67.80 (s, 2H), 67.74 (s, 2H), 67.28 (d, 1H), 65.71 (d, 1H), 65.51 (m, 0.5H), 65.40 (m, 0.5H), 64.71 (d, 1H), 64.45 (m, 3H), 64.30 (m, 2H), 64.00 (d, s, 4H), 63.93 (s, 3H), 62.14 (d, 6H), 60.74 (d, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[CH3:19][C:20]([CH3:22])=O>[Pt]=O.C(O)C>[CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:20]([CH3:22])[CH3:19]
Reactant: CC(C)=O
Reactant: COc1ccc(CCN(C)CCCN)cc1OC
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCN(C)CCCNC(C)C)cc1OC
Yield: 100 %

Procedure:
3.87 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamine and 15 ml of acetone were dissolved into 50 ml of ethanol. To this was added 0.1 g of platinum oxide and then hydrogenetion was made at room temperature and under pressure of 3 kg/cm2. At the end of 3 hours catalyst was concentrated after filtering and 4.52 g of marked compound was obtained as yellow oily matter (yield: 100%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH3:22])=O.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:31][O:30][C:23](=[O:29])[CH2:24][C:25]1[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:22])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:28]
Reactant: COC(=O)CCC(C)=O
Reactant: Cc1[nH]c2ccccc2c1C(=O)c1c(N)sc2c1CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1c(C)[nH]c2ccccc12)CCCC3
Yield: 57.6 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-methyl-1H-indol-3-yl)methanone (0.310 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-70%) in heptane furnished 0.233 g (57%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-])=[O:8])[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.CO>C1COCC1>[OH:8][CH2:7][C:5]1[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[C:1]([CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1

Procedure:
A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) and borane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20-25 degrees C. overnight. The mixture is then treated with methanol, concentrated to dryness, and chouromatographed (silica gel) to give diethyl 5-(hydroxymethyl)isophthalate. Diethyl 5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and water with lithium hydroxide monohydrate (0.57 g) at 20-25 degrees C. for 3.5 hours at which time the solvents are removed under reduced pressure. Water (100 mL) is added and the mixture is acidified to pH=4 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried over magnesium sulfate, filtered, and concentrated to give 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolution MS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3 g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL), dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20-25 degrees C. overnight. The mixture is then partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate, filtered, and concentrated. Chromatography (silica gel) gives ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl3) δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[O:12][CH2:11][CH2:10][O:9]1>CCOCC>[CH3:7][C:8]1([C:13]2[CH:14]=[C:15]([CH2:16][NH2:17])[CH:18]=[CH:19][CH:20]=2)[O:9][CH2:10][CH2:11][O:12]1
Reactant: CC1(c2cccc(C#N)c2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(c2cccc(CN)c2)OCCO1
Reaction time: 4 h
Yield: 57.6 %

Procedure:
To a stirred solution of LiAlH4 (114 mg, 3.6 mmol) in ether at 0° C. was added 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (0.57 g, 3.0 mmol). The reaction mixture was stirred for 4 h and quenched with H2O (0.2 mL), 20% NaOH (0.2 mL), brine (0.6 mL). The resulting mixture was stirred for 1 h and filtered over celite and concentrated. The residue was purified by column chromatography (10% MeOH in CHCl3) to provide (3-(2-methyl-1,3-dioxolan-2-yl)phenyl)methanamine (334 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[N:10]([CH3:21])[CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[N:10]([CH3:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)cn(C)c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(F)cc2)c2ccc(C(=O)O)cc21
Yield: 100.6 %

Procedure:
To a solution compound 53f (264 mg, 0.93 mmol), and LiOH.H2O (156.4 mg, 3.73 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give compound 53g (252 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 270.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:11](=[O:34])[NH:12][C:13](=[O:33])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24]CC4C=CC=CC=4)[CH:22]=3)[N:17]([CH3:32])[CH:16]=2)=[CH:2]1.B(Br)(Br)Br>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:11](=[O:34])[NH:12][C:13](=[O:33])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[N:17]([CH3:32])[CH:16]=2)=[CH:2]1
Reactant: Cn1cc(C2=C(c3coc4ccccc34)C(=O)NC2=O)c2cc(OCc3ccccc3)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cc(C2=C(c3coc4ccccc34)C(=O)NC2=O)c2cc(O)ccc21
Reaction time: 0.75 h
Yield: 69.8 %

Procedure:
To a solution of 3-benzofuran-3-yl-4-(5-benzyloxy-1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (31) (22 mg, 0.044 mmol) in 2 ml of dry dichloromethane was added dropwise boron tribromide (44 mg, 0.178 mmol) at −10° C. After 45 min, the reaction was quenched with saturated NaHCO3, and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC (ethyl acetate:hexane; 2:3) to afford product (11 mg, 68%). 1H NMR (DMSO-d6, 400 MHz) 3.81 (s, 3H), 6.21 (d, J=2.1 Hz, 1H), 6.59 (dd, J=2.2, 8.5 Hz, 1H), 6.96 (m, 2H), 7.18 (m, 2H), 7.60 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 8.23 (s, 1H), 8.67 (s, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) 14.5, 103.6, 106.1, 111.2, 111.8, 111.9, 112.5, 121.1, 122.2, 123.0, 125.0, 126.1, 127.0, 131.6, 133.2, 134.9, 147.3, 152.1, 154.6, 172.4, 172.7. FAB-HRMS calcd for C21H14N2O4+Na+: 381.0846; found: 381.0844.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N1CCNCC1)C1C=CC=CC=1.[BH4-].[Na+].[H][H]>C(O)C.[Pd]>[N:11]1([C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:20])[CH2:18][CH2:19]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O[C@H]1CC[C@H](N2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1CC[C@H](N2CCNCC2)CC1
Reaction time: 72 h

Procedure:
trans-4-(4-Benzylpiperazin-1-yl)cyclohexanol (prepared from benzylpiperazine according to the process described in Example 1 using, in Stage e, NaBH4 in ethanol) (15 g, 54.6 mmol) is placed in 150 ml of ethanol under 4 bar of hydrogen in the presence of 10% palladium-on-charcoal (1 g) . After stirring for 72 h, the catalyst is filtered off on celite and the filtrate is concentrated to dryness. 9.6 g of light-colored oil are isolated.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)C.[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34][CH2:35]OS(C)(=O)=O>>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:35][CH2:34][CH2:33][C:23]1[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=1[CH3:21])[C:11]([CH3:16])=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCCOS(C)(=O)=O
Product: CCOC(Cc1ccc2c(c1)cc(C)n2CCCc1nc(-c2ccccc2)oc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with methanesulfonic acid 3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl ester to give rac-2-ethoxy-3-{2-methyl-1-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-1H-indol-5-yl}-propionic acid as orange viscous oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[CH2:5][CH:6]([OH:9])CO.O>ClCCl>[OH:10][C:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH2:3][O:2][CH3:1])[CH2:5][CH:6]=[O:9]
Reactant: COCC(O)(CC(O)CO)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: COCC(O)(CC=O)c1ccccc1
Temperature: 25 °C

Procedure:
NaIO4 (5.20 g) was added to a mixture of 5-methoxy-4-phenyl-pentane-1,2,4-triol (1.10 g), dichloromethane (10 mL), and water (5 mL) chilled in an ice bath. The mixture was stirred vigorously while warming to ambient temperature in the cooling bath and further stirred at this temperature overnight. Then, water (20 mL) and dichloromethane (50 mL) were added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with water and dried (MgSO4). After removal of the solvent, the title compound was yielded which was directly submitted to the next reaction step (glycol cleavage).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:11][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1.C(Cl)(=O)C(Cl)=O.C[N:31](C=O)C.N>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:11][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([NH2:31])=[O:23])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1
Reactant: C[C@H]1CCCCN1[C@H]1C[C@H](c2nc3ccc(C(=O)O)cc3s2)C1
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CCCCN1[C@H]1C[C@H](c2nc3ccc(C(N)=O)cc3s2)C1
Reaction time: 1 h

Procedure:
2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylic acid (Example 143B, 20 mg, 0.062 mmol) was added to a solution of oxalyl chloride (17 mg, 0.13 mmol) in CH2Cl2 (1 mL) at 23° C., followed by 1 drop of catalytic amount of DMF. The reaction mixture was allowed to stir for 1 h. Solvent and excess of oxalyl chloride were removed under vacuum, the residue solid was re-dissolved in CH2Cl2 (0.5 mL). Excess of ammonia (2 mL, 1.2 mmol) in CH2Cl2 (2 mL) was then added to the reaction vial. The reaction mixture was then stirred overnight. Solvent was removed, and the crude product was purified via HPLC (C-18 column, 0.1% TFA in acetonitrile) to give 16 mg product as a TFA salt (65%). 1H NMR (500 MHz, CD3OD): δ=8.51 ppm (m, 1H), 8.01 (m, 2H), 4.00 (m, 1H), 3.80 (m, 1H), 3.83 (m, 2H), 2.80-3.15 (m, 5H), 2.74 (m, 1H), 1.94 (m, 3H), 1.75 (m, 3H), 1.41 (m, 3H). MS (ESI, M+H+): 330.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:12][C:13](O)([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1F
Yield: 64.8 %

Procedure:
A mixture of 2-(3-fluoro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Step 2 (3.4 g, 7.9 mmol) and p-toluenesulfonic acid monohydrate (700 mg) in toluene (200 mL) was heated to reflux for 72 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture (3.6 g) was purified by chromatography on silica gel using toluene/ethyl acetate (8/2) to give pure 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (2.12 g, 65%) as a white solid: mp (DSC) 182° C. Anal. Calc'd. for C18H14N2SO3F4: C, 52.17; H, 3.41; N, 6.76; S, 7.74. Found: C, 52.56; H, 3.65; N, 6.53; S, 8.01.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.BrBr.[Br:17](F)(F)F>>[Br:17][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=[C:2]([CH:11]=1)[C:1]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: BrBr
Product: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Yield: 55 %

Procedure:
Conventionally, it is known that selective bromination of aromatic compounds having an electron-attracting group is very difficult. As techniques related to such a reaction, it is known, for example as a method for preparing dialkyl 5-bromoisophtalate a method comprising brominating dimethyl isophthalate with bromine at the presence of bromine trifluoride (BrF3) to give dimethyl 5-bromoisophtalate in a 55% yield (J. Org. Chem., 58, 239 (1993)). This method, however, uses bromine trifluoride that is expensive and intractable, and leads an aimed product in a low yield. Therefore, the above-mentioned method is not practical.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>ClCCl>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:20])=[CH:17][CH:16]=1
Reactant: NCCCO
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A reaction vessel was charged with 7.51 g of 3-amino-1-propanol, 2.53 g of triethylamine and 50 ml of dichloromethane, and 5.21 g of 4-trifluoromethylbenzoyl chloride was slowly added dropwise under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was successively washed with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then concentrated, which afforded 5.25 g of 3-(4-trifluoromethylbenzamido)propan-1-ol (85% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(Br)c2cc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)c2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromo-7-methoxy indole (2 g, 8.8 mmol) was dissolved in CH2Cl2 (300 mL). PhSO2Cl (2.4 g, 9.4 mmol was added, followed by tetrabutylammonium hydrogen sulfate (0.34 g, 0.88 mmol) and 4M aqueous NaOH (17 mL), in that order. The reaction mixture was stirred at ambient temperature for 3 hrs. The layers were separated and the aqueous layer was extracted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and concentrated. The crude material was recrystallised from ethanol to give 4-bromo-7-methoxy-1-(phenylsulfonyl)-1H-indole, 0.9 g.
Reaction SMILES: [CH:1]([C:4]1[O:8][CH:7]=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26]([C:7]2[O:8][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][N:6]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: CC(C)c1cnco1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2ncc(C(C)C)o2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 5-isopropyl-oxazole (54 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (48 mg) as a yellow gum.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:30])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH:17]([F:30])[F:16])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCC(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)F
Yield: 48 %

Procedure:
The title compound is prepared in 48% yield (178 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (253 mg, 1.0 mmol, Amine-5, single enantiomer) in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19]Cl)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[CH2:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH:36][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCCl)C3)c1C
Reactant: CC(C)CN
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCNCC(C)C)C3)c1C
Yield: 62 %

Procedure:
Reaction and post-treatment were performed in the same manner as in Example 18 using 4-amino-N-(3-chloropropyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxamide of Example 17 (30 mg) and isobutylamine (2 mL), followed by purification by NH silica gel column chromatography (dichloromethane-methanol) to obtain the title compound (20 mg, 62%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33](=[O:34])[NH2:35])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: NC(=O)C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(N)=O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.1 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol), morpholine-3-carboxamide (0.78 g, 6 mmol) and potassium carbonate (1.66 g, 12 mmol) in anhydrous ethanol (70 mL) was stirred at 25° C. for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=100/1) to give the title compound as a yellow solid (1.66 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S-:9][C:10]#[N:11].[K+].Cl>C(O)C>[NH2:11][C:10]1[S:9][C:2]2[C:7]([N:8]=1)=[CH:6][CH:5]=[CH:4][N:3]=2
Reactant: Nc1cccnc1Cl
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Nc1nc2cccnc2s1

Procedure:
The method described in J. Het. Chem., 14(1), 129(1977) was followed to react 2-chloro-3-aminopyridine with potassium thiocyanate and hydrochloric acid in ethanol to produce 45.3 g of 2-aminothiazolo[5,4-b]pyridine. M+Theory 151; Found 151.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:9][N:10]2C(OCC)=O)=[CH:6][C:5]=1[O:24][CH3:25])(=[O:3])[CH3:2]>[OH-].[K+]>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1cc(CCNC(C)=O)c2cc(OC)c(C(C)=O)cc21
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(CCNC(C)=O)c[nH]c2cc1C(C)=O

Procedure:
N-[2-(6-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide is prepared by alkaline hydrolysis of N-[2-(6-acetyl- 1-carbethoxy- 5-methoxyindol-3-yl)ethyl]acetamide in alcoholic potassium hydroxide.