Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17]([O:19]CC)=O)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:36]O.Cl>CO.O.C(Cl)Cl>[C:30]([C:28]1[CH:27]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:22][NH:36][C:17](=[O:19])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:33])([CH3:32])[CH3:31]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
Cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.03 g, 4.42 mmol) was dissolved in MeOH (16 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.177 g, 4.42 mmol) dissolved in water (1.600 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.271 mL, 4.42 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (20 mL, 120.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-50% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.358 g, 72%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.22-1.33 (m, 18H), 1.80-2.10 (m, 4H), 2.59-2.67 (m, 1H), 2.71-2.78 (m, 1H), 2.92-2.98 (m, 1H), 3.07-3.15 (m, 1H), 3.55 (s, 3H), 3.97 (dd, 1H), 4.18-4.27 (m, 1H), 5.68 (s, 1H), 6.92 (d, 2H), 7.22 (s, 1H). MS m/z 429 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.C([O-])(=[O:20])C.[K+]>C(O)(=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:20])=[CH:4][CH:5]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A solution of 4-bromomethyl-2'-nitro-1,1'-biphenyl (7.27 g, 24.8 mmol) in acetic acid (50 mL) was treated with potassium acetate (4.88 g, 49.1 mmol). The reaction mixture was heated at reflux for 2 hours. After cooling, the reaction mixture was filtered and the precipitate was washed with acetic acid (2×). The filtrate was evaporated under vacuum and the residue was triturated with ethyl ether. The ether layer was washed consecutively with water, saturated aqueous sodium bicarbonate (3×) and water. The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was dissolved in methanol (50 mL) and treated with a 6N methanolic potassium hydroxide solution (5 mL). After stirring for 1 hour at room temperature, thin layer chromatography indicated the absence of starting material. The reaction mixture was acidified with acetic acid and evaporated under vacuum. The residue was washed free of acetic acid by washing an etheral solution with aqueous sodium bicarbonate and water. After drying over magnesium sulfate, the ethereal solution was evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 2'-nitro-1,1'-biphenyl-4-carboxaldehyde (620 mg) followed by 4-hydroxymethyl-2'-nitro-1,1'-biphenyl (3.06 g, 13.4 mmol, 54%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH2:51][CH2:52][CH3:53])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH2:51][CH2:52][CH3:53])[CH2:45][N:46]2[CH2:47][CH:48]([OH:50])[CH2:49]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CCC[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (1.580 mL, 9.07 mmol) was added to a stirred suspension of 4-chlorobenzoic acid (0.473 g, 3.02 mmol) and TBTU (0.971 g, 3.02 mmol) in DCM (10 mL) at rt. The suspension was stirred for about 5 min before a solution of (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4) (0.62 g, 3.02 mmol) in DCM (3 mL) was added. The reaction was stirred at rt overnight. The reaction mixture was washed with an 8% aq. sol. of NaHCO3 (20 mL). The organic layer was dried through a phase separator and concentrated on the rotary evaporator. The residue was purified by preparative HPLC affording the title compound (0.760 g, 81%) as an oil. Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.80-0.88, 0.94-1.01, 1.09-1.65, 2.39-2.53, 2.62-2.99, 3.28-3.62, 3.65-3.76, 4.22-4.39, 4.64-4.76, 7.39-7.52. HRMS (M+H)+: calculated 311.1526. found 311.1539.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[N:30]([CH3:36])[C:31]([Br:35])=[C:32]([Br:34])[CH:33]=1)=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]3[N:30]([CH3:36])[C:31]([Br:35])=[C:32]([Br:34])[CH:33]=3)=[O:28])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: Cn1c(C(=O)NCCN=[N+]=[N-])cc(Br)c1Br
Product: Cn1c(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc(Br)c1Br

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.116 g, 0.417 mmol) was reacted with N-(2-azidoethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide (0.145 g, 0.417 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), δ 7.32 (s, 1H), δ 6.81 (s, 1H), δ 6.49 (s, 1H), δ 6.17 (s, 2H), δ 4.52 (s, 2H), δ 3.94 (s, 3H), δ 3.84 (s, 2H), δ 2.65 (t, 2H), δ 2.30 (m, 2H), δ 1.58 (m, 13H), δ 1.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.2, 149.6, 148.2, 138.8, 127.4, 122.2, 114.9, 111.9, 106.5, 98.2, 84.5, 49.5, 39.7, 35.9, 29.3, 28.9, 28.2, 28.0, 27.7, 25.6 ppm; HRMS (ESI) calcd for C23H32N8O3 (M+) 626.0964, found 626.0960, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (0.151 g, 64% yield). 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), δ 6.86 (s, 1H), δ 6.56 (s, 1H), δ 4.71 (s, 2H), δ 3.81 (s, 5H), 2.78 (s, 2H), δ 2.44 (t, 2H), δ 1.69 (s, 2H), δ 1.59 (s, 2H), δ 1.37 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 161.4, 150.2, 159.8, 159.4, 147.3, 127.6, 127.3, 114.9, 111.6, 108.4, 97.9, 51.3, 39.0, 35.2, 28.3, 28.0, 27.6, 24.2, 23.8 ppm; HRMS (ESI) calcd for C18H24Br2N8O (M+) 526.0439, found 526.0425.
Reaction SMILES: [CH3:1][N:2]([C:4]1[O:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)[CH3:3].C([Li])CCC.[C:21](=[O:23])=[O:22]>>[CH3:1][N:2]([CH3:3])[C:4]1[O:8][N:7]=[C:6]([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:21]([OH:23])=[O:22])[N:5]=1
Reactant: CN(C)c1nc(Cc2ccccc2)no1
Reactant: O=C=O
Agent: [Li]CCCC
Product: CN(C)c1nc(C(C(=O)O)c2ccccc2)no1

Procedure:
5-(Dimethylamino-3-(phenylmethyl)-1,2,4-oxadiazole from part (a) is treated with a solution of butyl lithium and carbon dioxide according to the procedure of Example 1 (b) to yield 5-(dimethylamino)-α-phenyl-1,2,4-oxadiazole-3-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11](=O)[CH3:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:11]([CH3:12])[CH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9]
Reactant: CON
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of crude 1-(2,4,6-trichloro-phenyl)-propan-2-one prepared as described in example P1, (12 g, 0.050 mol) in methanol (100 ml) was added pyridine (6.8 ml, 0.084 mol), followed by O-methyl-hydroxylamine hydrochloride (6.70 g, 0.080 mol). The resulting mixture was stirred at ambient temperature for 18 hours. Methanol was removed under reduced pressure and the residue poured in 1N hydrochloric acid (300 ml) which was extracted with ethyl acetate (3×100 ml). Organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime E/Z-mixture (12.3 g, 92%), which was taken up for the next reduction step.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1>[C:14]([N:12]1[CH:8]([O:7][CH3:6])[CH2:9][CH2:10][C:11]1=[O:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1CCC(=O)N1C(=O)c1ccccc1
Yield: 41.5 %

Procedure:
20.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.8 g of 5-methoxy pyrrolidin-2-one in 160 cm3 of tetrahydrofuran. This temperature is maintained for 20 minutes, then 4.69 g of benzoyl chloride in solution in tetrahydrofuran is added. After allowing to return to ambient temperature, the mixture is concentrated to dryness and chromatographed on silica (eluent: hexane-ethyl acetate 1-1). 3 g of expected product is obtained. m.p. =92°-94° C. crystallized from isopropyl ether.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: BrCCCCOC1CCCCO1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
3,4-Dihydro-2H-pyran (8.5 mL, 90.96 mmol) was added dropwise to the dichloromethane (20 mL) solution of 1 (10.7 g, 69.93 mmol) and p-toluenesulfonic acid monohydrate (26.5 mg, 0.1372 mmol). The mixture was stirred at room temperature over night. After removing the solvent, the residue was purified by flash chromatography on silica gel with 5:1 hexanes/ethyl acetate as the eluent to yield product 2 as a colorless oil (15.3 g, 92%). 1H NMR (400 MHz, CDCl3): δ 1.48-1.62 (m, 4H), 1.68-1.85 (m, 4H), 1.94-2.02 (m, 2H), 3.40-3.53 (m, 4H), 3.74-3.88 (m, 2H), 4.57-4.59 (m, 1H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][C:4]2[C:9]=1[CH:8]=[CH:7][C:6](=O)[N:5]=2.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:6]1[N:5]=[C:4]2[CH:3]=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1C=CC2=NC=CC2=N1
Product: Clc1ccc2[nH]ccc2n1

Procedure:
A mixture of pyrrolo[3,2-b]pyrid-5-one (prepared according to the procedure described in J. Med. Chem. 1990, 33, 2087) (1.33 g, 9.91 mmol) and 20 mL of phosphorous oxychloride is heated in a sealed Parr high pressure stainless steel vessel at 180° C. for 2.5 hours. After cooling, excess phosphorous oxychloride is removed in vacuo. The residue is cooled in an ice bath and quenched with ice water. The resulting mixture is neutralized by addition of saturated NaHCO3 solution and extracted with EtOAc (3×). The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. The crude product (1.07 g, 7.01 mmol) is used in the subsequent step without further purification.
Reaction SMILES: O=[C:2]1[C:7]([O:8]B(O)O)=[CH:6][CH2:5][CH2:4][CH2:3]1.Br[C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:18][N:17]1[C:13]([C:2]2[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:14][N:15]=[CH:16]1
Reactant: Cn1cncc1Br
Reactant: O=C1CCCC=C1OB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cncc1C1=CCCCC1=O
Yield: 8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using (6-oxocyclohex-1-en-1-yl)boric acid (J. Org. Chem. 2011, 76, 3946-3959; 790 mg, 5.65 mmol), 5-bromo-1-methyl-1H-imidazole (910 mg, 5.65 mmol), tetrakis(triphenylphosphine)palladium (0) (326 mg, 0.282 mmol), cesium carbonate (4.00 g, 12.3 mmol), 1,4-dioxane (10 mL) and water (5 mL), to yield the title compound (80 mg, 8%) as a brown oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[CH:9][CH:8]=2)=[C:4]([CH3:24])[CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:6][C:2]([CH2:26][CH2:25][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:3][C:4]=2[CH3:24])=[CH:8][CH:9]=1)=[O:23]
Reactant: C#Cc1cccnc1
Reactant: Cc1cc(Br)sc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CCc2cccnc2)sc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1

Procedure:
N-(4-(5-bromo-3-methylthiophen-2-yl)phenyl)-2,6-difluorobenzamide (a, 1 mmol), 3-ethynylpyridine (1 mmol), CuI (0.05 mmol), PdCl2(PPh3)2 (0.05 mmol) in THF (6 mL), and Et3N (3 mL) was heated in sealed tube at 100° C. for 1 h. The mixture was filtered through celite and purified by column chromatography to give a white solid (b, 46 mg).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:10]1=[O:31].Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].Cl.Cl.[O:47]=[C:48]1[NH:56][C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[N:49]1[CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:10](=[O:31])[C@H:9]([NH:8][C:33]([N:60]2[CH2:61][CH2:62][CH:57]([N:49]3[C:50]4[C:51](=[N:52][CH:53]=[CH:54][CH:55]=4)[NH:56][C:48]3=[O:47])[CH2:58][CH2:59]2)=[O:34])[CH2:15][CH2:14]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Triethylamine (0.065 mL, 0.468 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(pyridin-2-ylmethyl)azepan-2-one (180 mg, 0.417 mmol) and 4-nitrophenyl chloroformate (94 mg, 0.468 mmol) in tetrahydrofuran (3 mL) at 0° C. After 1 h, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (136 mg, 0.468 mmol) and triethylamine (0.195 mL, 1.404 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (240 mg). The title compound was converted to the HCl salt with 2M HCl in ether. MS 576.3 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.78 (d, J=5.9 Hz, 1H), 8.62-8.59 (m, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.03-7.98 (m, 3H), 7.32 (dd, J=8.1 Hz, 6.1, 1H), 7.18-7.15 (m, 3H), 5.43 (d, J=16.9 Hz, 1H), 4.75 (d, J=17.1 Hz, 1H), 4.56-4.51 (m, 1H), 4.36-4.28 (m, 3H), 3.51 (d, J=15.1 Hz, 1H), 3.48 (s, 1H), 3.22-3.17 (m, 1H), 3.05-2.98 (m, 2H), 2.44-2.40 (m, 1H), 2.34-2.23 (m, 2H), 2.18-2.14 (m, 2H), 1.97-1.92 (m, 1H), 1.89-1.88 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][CH:52]([CH3:61])[CH:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[OH:54]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:54][CH:53]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:52]([CH3:61])[CH3:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(c4ccccc4)C(C)C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 55.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-methyl-1-phenyl-1-propanol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (69 mg, yield 52%).
Reaction SMILES: Cl.CN.[CH2:4]([C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=O)[CH2:18][N:19]=1)=[CH:11]2)[CH3:5].O[N:36]1[C:40]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[CH2:4]([C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:36][CH3:40])=[O:23])[CH2:18][N:19]=1)=[CH:11]2)[CH3:5]
Reactant: On1nnc2ccccc21
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC)S3)[nH]c12
Reaction time: 48 h
Yield: 95.3 %

Procedure:
To a mixed solution of methylamine hydrochloride (147 mg), triethylamine (0.31 mL), and N,N-dimethylformamide (25 mL) were added [2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-hydroxybenzotriazole (300 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (420 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (490 mg, yield 95%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C@H]2[C@H](N3C4N=CN=C(NCC5C6C(=CC=CC=6)C=CC=5)C=4N=C3)O[C@H](CO)[C@H]2O)=[O:10])[CH:6]=[C:5](OC)[CH:4]=1.NCC1SC=CC=1.C(O)(=O)C1C(=CC=CC=1)O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[OH:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][CH:4]=1)[C:9]([NH2:11])=[O:10]
Reactant: COc1cc(OC)cc(C(=O)N[C@@H]2[C@H](O)[C@@H](CO)O[C@H]2n2cnc3c(NCc4cccc5ccccc45)ncnc32)c1
Agent: NCc1cccs1
Agent: O=C(O)c1ccccc1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(O)c1
Yield: 73 %

Procedure:
A solution of the crude NMDBA salt of 18d (3.2 g, “5.1 mmol”), salicylic acid (987 mg, 7.14 mmol), HOBt (966 mg, 7.14 mmol), and EDC (1.37 g, 7.14 mmol) in DMF (69 ml) was stirred for 1 h at 23° C. The mixture was diluted with EtOAc (700 ml) and washed (3×H2O; brine). The aqueous layers were back-extracted with EtOAc (250 ml). The combined organic layers were concentrated and chromatographed (EtOAc:cyclohexane 1:1→2:1) to give 2.18 g (73%) of the title 3-hydroxybenzamide, which was further purified by preparative reverse-phase HPLC(H2O:CH3CN 70:40 →25:75 over 35 min, Rt=31 min) to give 1.50 g (50%) of a white powder: m.p. 174.5-175.5° C. 1H NMR (DMSO-d6) δ10.03 (s, 1H), 9.75-9.65 (br. d, 1H), 9.15 (t, J=6.0 Hz, 1H), 8.33-8.29 (br. s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.42 (d, J=3.8 Hz, 1H), 7.27-21 (m, 4H), 7.01 (d, J=3.8 Hz, 1H), 6.91 (dt, J=7.1, 2.2 Hz), 4.59 (d, J=5.8 Hz, 2H), 2.69 (q, J=7.0 Hz, 2H), 2.04 (t, J=6.9 Hz, 2H), 1.67 (quint, J=7.1 Hz, 2H). 13C NMR (DMSO-d6) δ169.65, 167.57, 158.49, 154.79, 149.06, 142.54 (q, J=4 Hz, C—C—CF3), 136.39, 132.80, 131.61, 126.91, 124.82, 122.93 (q, J=271 Hz, CF3), 117.66, 116.22, 114.01, 112.91, 112.01 (q, J=33 Hz, C—CF3), 39.19, 36.62, 29.42, 23.35. 19F NMR (DMSO-d6) δ-59.52 (s). M/Z APCI: 592 (M+1), 590 (M−1). Anal. HPLC: Rt=6.22 min (method a). C24H23F3N4O7S3 Calc.: C: 44.63%. H, 3.8%. N, 11.83%. Found: C, 44.68%, H, 3.59%, N: 11.90%.