Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH2:33][CH2:34][OH:35])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>C(OCC)(=O)C>[CH3:8][S:9]([O:35][CH2:34][CH2:33][C:29]1[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:23][CH:22]=2)[CH:32]=[CH:31][N:30]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)Oc1ccc(CCCCn2ccnc2CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2CCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (3.16 ml) and methanesulfonyl chloride (1.40 ml) were added to a solution of 2-[1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]ethanol (4.77 g) in ethyl acetate (50 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 2-[1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]ethyl methanesulfonate. Sodium thiomethoxide (2.25 g) was added to a solution of the product in DMF (35 ml), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:3) to give the titled compound (4.22 g) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1.[OH-:14].[K+].Cl.C([OH:19])C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:19])=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CC1(c2ccc(Br)cc2F)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)C1(c2ccc(Br)cc2F)CC1
Temperature: 25 °C

Procedure:
A solution of the compound (24.6 g, 102 mmol) obtained in Example 14-2) and potassium hydroxide (46 g, 820 mmol) in ethanol (200 ml) and water (40 ml) was heated to reflux for 7 h. The reaction mixture was cooled to room temperature, and then 5 N hydrochloric acid was added until the reaction mixture was rendered acidic. The deposited solid was collected by filtration, washed with water, and then dried to obtain the title compound (28.7 g, quant.) as a colorless solid.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1.C([O-])(=[O:20])C.[Na+]>C(O)(=O)C>[CH3:17][C:13]1[CH:12]=[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:4]2)[CH:16]=[CH:15][N:14]=1
Reactant: O=C1CCCCN1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(Cl)ccn1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N2CCC(=O)CC2)ccn1
Yield: 83.1 %

Procedure:
A mixture of piperidone hydrochloride hydrate (68.98 g), 4-chloro-2-picolin (47.7 g) and sodium acetate (36.8 g) in acetic acid (500 ml) was refluxed for 15 hours and then the reaction mixture was concentrated, and the resultant residue was dissolved in water, combined with potassium hydroxide to make alkaline, and then extracted with dichloromethane, dried and concentrated. The residue obtained was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=30:1) to obtain the title compound (59.1 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].[C:21](Cl)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][O:20][C:21](=[O:23])[CH3:22])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2]
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)ON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
To a solution of 33 (1.0 g, 3.77 mmol) in dry pyridine (30 ml) cooled at 0° C., acetyl chloride (0.8 ml, 11.3 mmol) was added dropwise and the mixture was stirred 16 h at room temperature. Water (40 ml) was added and the precipitate was collected by filtration. The crude was purified by flash chromatography (CH2Cl2/acetone/MeOH 8:2:0.5) and triturated with Et2O/CH2Cl2/MeOH, affording 35 (251 mg, 21%) as yellow solid as single isomer. 1H NMR (300 MHz, DMSO d6): δ 8.12 (d, 1H), 7.91 (m, 2H), 7.77 (ddd, 1H), 7.43 (bs, 2H), 2.27 (s, 3H). ESI+MS: calcd for C15H9N5O3: 307.27; found: 308.1 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:12]C)=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][OH:11])[C:3]=1[OH:12]
Reactant: COc1c(F)cc(F)cc1CCO
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: OCCc1cc(F)cc(F)c1O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 2-(3,5-difluoro-2-methoxyphenyl)ethanol (850 mg, 4.52 mmol) in DCM (30 mL) at 0° C. was added 1M BBr3 (13.55 mL, 13.55 mmol) solution. The resulting mixture was slowly warmed to room temp and stir for 3 h. water (dropwise) was then added and after the bubbling stops mixture was diluted with DCM and washed with water, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-50%, EtOAc/hexane) to afford 2,4-difluoro-6-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol, 57.2% yield) as clear viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.14 (br. s., 1H), 6.80-6.73 (m, 1H), 6.66 (dt, J=8.8, 2.4 Hz, 1H), 4.01-3.95 (m, 2H), 2.93 (t, J=5.5 Hz, 2H), 2.32 (br. s., 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
To a stirred solution of 6-hydroxy-3-oxo-2,3-dihydrobenzofuran of Example 6(a) (32 kg, 213 moles) in DMF (192 L) was added potassium carbonate (31.0 kg, 224 moles). After stirring for 5 min. at room temperature, benzyl bromide (145.2 kg, 264 moles) was added and the resulting mixture was stirred for 2 hours at room temperature. The mixture was poured into water (651 L), stirred for 30 minutes and the product collected by centrifugation. The crude solid was washed with water (580 L), 80% ethanol (100 L) and dried under vacuum to afford the desired product (49.1 kg; 95%) which was used without any further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1(O)C=CC=CC=1.Cl.[N:24]([O-])=[O:25].[Na+]>O.C(O)C>[C:11]([C:7]1[CH:8]=[C:9]([N:24]=[O:25])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 500 ml round flask equipped with a thermometer, stirrer and nitrogen inlet was added 2,6-ditertbutylphenol (50 g, 0.243 moles) and ethanol (95%, I00 ml). The solution was stirred until all of the phenol dissolved. The solution was then cooled to 0° C and concentrated hydrochloric acid (26.3 g, 0.267 moles) was slowly added. A solution of sodium nitrite (17.56 g, 0.254 moles) in water (75 ml) was then added dropwise so as to keep the temperature of the reaction between 0 °and 10° C. (1 hr). The solution became quite thick and more ethanol was added accordingly, for efficient stirring. After the addition was completed, the reaction mixture was stirred for 1 hr and it was then poured into a beaker of ice water (~5 L). The yellow green precipitate was filtered off washed, with water and air dried. The yield was 98 wt%. (210-213° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:37][CH3:38])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)=[CH:13][N:12]=[C:11]([C:30]#[C:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:10]=3[N:36]=2)=[N:4][O:5][N:6]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:37][CH3:38])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:30]#[C:31][C:32]([CH3:33])([OH:35])[CH3:34])[C:10]=3[N:36]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CN(C(=O)OC(C)(C)C)CCO3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CNCCO3)c21
Temperature: 65 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a suspension of 1,1-Dimethylethyl (2S)-2-({[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4-morpholinecarboxylate (14.2 g, 0.027 mol) in methylene chloride (150 mL) was added trifluoroacetic acid (40 mL). After 1 h, the solvent was removed in vacuo. The residue was evaporated from ethyl acetate (2×) to give a solid. The residue was suspended in water and treated with 1N NaOH in an ice bath until the mixture was basic (pH 8). The precipitate was isolated by filtration, washed with water, ethyl acetate and dried in a vacuum oven at 40° C. for 4 h. The resulting solid was treated with ethyl acetate (250 ml) and stirred at 65° C. then allowed to cool to RT and then placed in an ice bath and then filtered and the solid dried in a vacuum oven at 40° C. The resulting solid was suspended in 20% tetrahydrofuran/ethanol (1.2 L). Darco G60 activated charcoal (3.9 g) was added and the mixture heated at reflux for 90 min. and filtered while hot through celite. The solvent was removed and retreated with ethanol and removed in vacuo (2×). The resulting solid was dried under high vacuum for 24 hr at 40° C. to afford the title compound (7.24 g, 64%). MS (ES)+ m/e 428 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:6]=[C:7]([C:20]2[CH:25]=[C:24]([S:26](=[O:33])(=[O:32])[NH:27]C(C)(C)C)[CH:23]=[CH:22][C:21]=2[O:34]C)[C:8]([O:13]COCCOC)=[C:9]([CH:11]=O)[CH:10]=1.Cl.[NH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[NH2:48])[C:42]([NH2:44])=[NH:43].C1(=O)C=CC(=O)C=C1.Cl.N1C=CC=CC=1>CO>[C:42]([C:41]1[CH:45]=[CH:46][C:47]2[NH:48][C:11]([C:9]3[CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:36])[CH:6]=[C:7]([C:20]4[CH:25]=[C:24]([S:26](=[O:32])(=[O:33])[NH2:27])[CH:23]=[CH:22][C:21]=4[OH:34])[C:8]=3[OH:13])=[N:38][C:39]=2[CH:40]=1)(=[NH:43])[NH2:44]
Reactant: COCCOCOc1c(C=O)cc(CC(=O)OC)cc1-c1cc(S(=O)(=O)NC(C)(C)C)ccc1OC
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: c1ccncc1
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Temperature: 180 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Methyl[5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-6-(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (0.496 g, 1.1 mmol), prepared as in Reference 8, was dissolved in methanol (20 mL) and the solution was charged with 3,4-diaminobenzamidine-HCl (1.25 mmol, 0.23 g) and 1,4-benzoquinone (1.25 mmol, 0.135 g). The mixture was refluxed for 2 hours and then concentrated by evaporation. This residue was taken up in trifluoroacetic acid (10 mL) and the mixture was stirred for 1 hour. Evaporation and further pumping down yielded a purple amorphous residue. Pyridine hydrochloride (5.0 g) was added and the reaction mixture was heated at 180° C. for 30 minutes. The mixture was cooled and a resulting solid was dissolved in 20 mL of preparative hplc sample solvent (20% acetonitrile/20 mmol HCl). The product was purified by preparative hplc (C-18, 2,2,25 acetonitrile). The fractions containing the pure product were collected and lyophilized to give [5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetic acid (0.31 g, 59%). LCMS: Calcd 481.49; Obsd (MH+)=482.0, (MH−)=480.2. NMR (DMSO-d6) d 3.621 (s, 2H), 7.07 (d, J=8 Hz, 1H), 7.15 (br s, 2H), 7.27 (d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.65 (m, 2H), 7.73 (d of d, J=2, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.08 (d, J=2 Hz, 1H), 8.17 (s, 1H), 9.10, 9.39 (2s, 4H).
Reaction SMILES: CO[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:21]3[C:22]4[S:35][C:34]([CH2:36][O:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:33][C:23]=4[N:24](C(OC(C)(C)C)=O)[N:25]=3)[N:11]2C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)=[O:4].[CH2:45]([Mg]Br)[CH3:46].O1CC[CH2:51][CH2:50]1>>[CH2:38]([O:37][CH2:36][C:34]1[S:35][C:22]2[C:21]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[CH:7][CH:6]=[C:5]([C:3]([OH:4])([CH2:45][CH3:46])[CH2:50][CH3:51])[CH:13]=4)=[N:25][NH:24][C:23]=2[CH:33]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)c1ccc2cc(-c3nn(C(=O)OC(C)(C)C)c4cc(COCc5ccccc5)sc34)n(C(=O)OC(C)(C)C)c2c1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Product: CCC(O)(CC)c1ccc2cc(-c3n[nH]c4cc(COCc5ccccc5)sc34)[nH]c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To 2-(5-benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester [0.35 g, 0.68 mmol, Intermediate (95)] in tetrahydrofuran (5 mL) at −78° C. under nitrogen was added a 1.0M solution of ethylmagnesium bromide in tetrahydrofuran (1.7 mL, 1.7 mmol). The mixture was stirred at −78° C. for 1 hour. An additional 1.7 mL of 1.0M ethyl magnesium bromide solution was added. The temperature was raised to −45° C. and the mixture was stirred for 1 hour. It was then allowed to warm up to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (dichloromethane/ethyl acetate, 50/50 as eluant) to produce 3-[2-(5-benzyloxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yl]-pentan-3-ol [95 mg, 61%, Example 71] as a beige powder. LC/MS: 446.3 (M+H), RT=3.19 minutes. 1H NMR [300 Mhz, (CD3)2SO]: δ 13.18 (s, 1H), 11.44 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.36 (m, 5H), 7.21 (s, 1H), 6.93 (m, 1H), 6.55 (d, J=1.2 Hz, 1H), 4.78 (s, 2H), 4.59 (s, 2H), 4.43 (s, 1H), 1.75 (m, 4H), 0.66 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:41])([CH3:40])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:28]([F:39])[CH:27]=1)[CH2:19][C:20](O)=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.Cl.[NH2:52][OH:53].C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]([CH3:40])([CH3:41])[C@H:3]([NH:15][C:16](=[O:17])[C@H:18]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:28]([F:39])[CH:27]=1)[CH2:19][C:20]([NH:52][OH:53])=[O:21])[C:4]([NH:6][C@@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:5]
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)O)C(C)(C)C)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(Oc2ccccc2)c(F)c1)CC(=O)NO)C(C)(C)C)c1ccccc1
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 36.6 %

Procedure:
N-[(Dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethaninium hexafluorophosphate N-oxide (740 mg, 1.95 mmol) was added to a stirred solution of (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-fluoro-4-phenoxyphenyl)hexanoic acid (Preparation 5) (731 mg, 1.30 mmol) and diisopropylethylamine (220 μL, 1.30 mmol) in anhydrous dimethylformamide (10 mL) at 0° C. under nitrogen. After 25 min, hydroxylamine hydrochloride (271 mg, 3.90 mmol) was added followed by diisopropylethylamine (880 μL, 5.20 mmol). The resulting mixture was stirred at 20° C. for 16 h, poured into ethyl acetate (150 mL) and washed with pH 7 phosphate buffer solution (3×50 mL), saturated aqueous sodium chloride (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/diisopropyl ether to give the title compound as a colourless solid (275 mg, 24%). Further purification of a sample (130 mg) by preparative hplc (Phenomenex C18 Magellan column, 150×20 mm, 5μ packing, 20 mL/min acetonitrile:aqueous phosphate buffer (8.3 mM, pH 7.2)=1:1, retention time 13.5 min), then trituration with diisopropyl ether, filtration and drying in vacuo at 50° C. gave 50 mg of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]([F:29])([F:28])[F:27])[C:22]([F:30])=[C:21]([F:31])[C:18]=1[CH2:19]Br>CN(C=O)C>[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]([F:29])([F:27])[F:28])[C:22]([F:30])=[C:21]([F:31])[C:18]=1[CH2:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:13])([F:14])[F:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(OC(F)(F)F)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1OC(F)(F)F
Yield: 81 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-trifluoromethoxybenzoic acid (1.35 g, 6.23 mmole), DMF (50 ml), TEA (6 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.10 ml, 6.7.3 mmole), 2.25 g (81.0% yield) of 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid was obtained as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].IC.[H-].[Na+]>CN(C=O)C>[CH3:15][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][C:7]1=2
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCCN2
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A solution of 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (192 mg, 1.0 mmol) in DMF (10 mL) was treated with potassium carbonate (345 mg, 2.5 eq), and iodomethane (0.08 mL, 1.25 eq) and stirred at room temperature for 30 min. Sodium hydride was added (1.5 eq) and the mixture stirred for 30 min, quenched with water and extracted with ether. The organic layers washed with brine and dried (MgSO4), filtered and concentrated to give 1-Methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (206 mg, 100%) as a yellow solid. MP: 52-54° C.; 1H-NMR (CDCl3) δ 7.97 (s, 1H), 7.89 (dd, J=2.6, 8.7 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.42 (br s, 1H), 2.88-2.84 (m, 2H), 1.89-1.78 (m, 4H); LC/MS (ESI+): 207.04 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[Br:17][CH2:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][N:27]2[S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:23][CH:22]=1)=O>C(O)C>[BrH:17].[C:33]1([S:30]([N:27]2[C:28]3[C:24](=[CH:23][CH:22]=[C:21]([C:19]4[N:15]=[C:12]5[CH:11]=[CH:10][C:9]([B:4]6[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]6)=[CH:14][N:13]5[CH:18]=4)[CH:29]=3)[CH:25]=[CH:26]2)(=[O:32])=[O:31])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C(CBr)c1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Solvent: CCO
Product: Br
Product: CC1(C)OB(c2ccc3nc(-c4ccc5ccn(S(=O)(=O)c6ccccc6)c5c4)cn3c2)OC1(C)C
Yield: 55.5 %

Procedure:
1.6 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine and 2.7 g of 2-bromo-1-[1-(phenylsulphonyl)indol-6-yl]ethanone are placed in 70 ml of ethanol and the mixture is refluxed for 20 h. A precipitate forms and is recovered by filtration, washed with diethyl ether and oven-dried under reduced pressure. 2.3 g of compound are obtained.
Reaction SMILES: [C:1]([C@H:5]1[C:9](=[O:10])OC(=O)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1>C(O)C>[NH2:6][C@@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]([N:13]1[CH2:16][CH2:15][CH2:14]1)=[O:10]
Reactant: CC(C)(C)[C@@H]1NC(=O)OC1=O
Reactant: C1CNC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)[C@H](N)C(=O)N1CCC1
Yield: 98.7 %

Procedure:
(S)-4-tert-butyloxazolidine-2,5-dione (1.59 g, 10.12 mmol) and azetidine hydrochloride (0.946 g, 10.12 mmol) were combined in ethanol (5 mL) in a 2 mL microwave vial. The vial was capped and subjected to microwave irradiation at 150° C. for 10 min. The reaction was concentrated under reduced pressure and azeotroped with twice with toluene (5 mL) to provide the desired (S)-2-amino-1-(azetidin-1-yl)-3,3-dimethylbutan-1-one as a brown oil (1.7 g, 99%) that was used without further purification. LCMS (+ESI) m/z: 171.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.[F:19][CH:20]([F:23])[CH2:21]I.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:21][CH:20]([F:23])[F:19])[CH2:11]1
Reactant: FC(F)CI
Reactant: NS(=O)(=O)c1cnc(OC[C@@H]2CCNC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(OC[C@@H]2CCN(CC(F)F)C2)c(Cl)c1
Temperature: 25 °C

Procedure:
A reaction mixture of EXAMPLE 400B (353 mg), 1,1-difluoro-2-iodoethane (268 mg) and Na2CO3 (283 mg) in N,N-dimethylformamide (10 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Flash column purification with 2.5-3% methanol/dichloromethane provided the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[O:11])=[CH:8][CH:7]=1>C(NCCCC)CCC>[CH2:12]([N:13]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:14][CH2:19][CH2:18][CH3:17])[CH2:10][CH2:9][CH3:8]
Reactant: Cc1cccn2cc(C(=O)c3ccc(OCCCCl)cc3)nc12
Solvent: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cn3cccc(C)c3n2)cc1
Yield: 197.7 %

Procedure:
A mixture of 2-(4-chloropropoxybenzoyl)-8-methylimidazo-[1,2-a]pyridine (2.4 g, 6.0 mmol) in dibutylamine (30 ml) was stirred at reflux for 8 hours. The excess dibutylamine was removed by distillation and the resulting oil was flash chromatographed (silica gel, acetone) to give the free base of the title compound (2.5 g, 100% yield) as a thick oil. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the title compound in methanol, concentrated and recrystallized from methanol-acetone, mp 159 to 161° C. IR(KBr): 3420, 1650 cm−1. MS: 421 (M+). 1HNMR (CD3OD): δ8.89 (s, 1 H), 8.72 (d, J=6.6 Hz, 1H), 8.15 (d, J=8.9 Hz, 2H), 7.89 (d, J=7.3 Hz, 1H ), 7.48 (t, J=6.9 Hz, 1H ), 7.21 (d, J=8.9 Hz, 2H), 4.29 (t, J=7 Hz, 2H), 3.26 (m, 6H), 2.73 (s, 3H), 2.33 (m, 2H), 1.79-1.35 (m, 8H), 1.02 (m 6H).