Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([NH:18][C:19]1[N:20]=[N+:21]([O-:34])[C:22]2[C:31]([N:32]=1)=[CH:30][C:29]1[CH2:28][N:27]([CH3:33])[CH2:26][CH2:25][C:24]=1[CH:23]=2)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH2:16]([NH:18][C:19]1[N:20]=[N+:21]([O-:34])[C:22]2[C:31]([N+:32]=1[O-:4])=[CH:30][C:29]1[CH2:28][N:27]([CH3:33])[CH2:26][CH2:25][C:24]=1[CH:23]=2)[CH3:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CN(C)CC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
H2O2 (70%, 1.7 mL, ca. 17 mmol) was added dropwise to a stirred solution of TFAA (2.4 mL, 17 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 258 (440 mg, 1.7 mmol) and TFA (0.66 mL, 8.5 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-10%) of MeOH/DCM, to give 1,4-dioxide 259 (35 mg, 8%) as a red solid: mp 120-124° C.; 1H NMR δ 8.10 (s, 1H, H-10), 7.96 (s, 1H, H-5), 6.95 (br s, 1H, NH), 3.78 (s, 2H, H-6), 3.63 (dq, J=7.2, 6.0 Hz, 2H, CH2N), 3.10 (t, J=6.0 Hz, 2H, H-8), 2.75 (t, J=6.0 Hz, 2H, H-9), 2.50 (s, 3H, NCH3), 1.36 (t, J=7.2 Hz, 3H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 113.9, 58.1, 52.1, 45.8, 36.5, 29.1, 14.8; MS (APCI) m/z 276. (MH+, 100%); HRMS (FAB+) calcd for C13H18N5O2 (MH+) m/z 276.1461, found 276.1456.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([F:35])[CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[C:28]([F:35])[CH:27]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(Cl)cc1F
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(Cl)cc1F
Yield: 0.6 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 70 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (0.6 mg, 0.3%). The same compound was also prepared using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode when 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (63.6 mg, 53%). The second sample was characterized by 1H NMR: (300 MHz, DMSO-d6) δ 13.22 (br s, 1H), 8.50 (d, J=4.9 Hz, 2H), 8.26-8.37 (m, 2H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.37-7.60 (m, 4H).
Reaction SMILES: [Li+].[BH4-].[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=[C:5]12>C1COCC1.C(Cl)Cl.O=[Mn]=O>[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[C:14]([CH:16]=[O:17])[N:15]=[C:5]12
Reactant: CCOC(=O)c1cn2c3ccccc3n(C)c2n1
Agent: O=[Mn]=O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c2ccccc2n2cc(C=O)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To stirred solution of LiBH4 (1.79 g, 82 mmol) in THF at 0° C., ethyl 9-methyl-9H-imidazo[1,2-a]benzimidazole-2-carboxylate (2.5 g, 10.3 mmol) was added drop wise. The reaction mixture was refluxed for 2 hrs and cooled to room temperature. Ti was carefully quenched with icve cold water and acidified with Con. HCl to pH 4. The reaction mixture was stirred at room temperature for 1 hr and basified with K2CO3. The residue was extracted with chloroform;methanol (3:1) and dried over anhydrous MgSO4. It was filtered and concentrated. Yield. 1.3 g (65%). (M+H) 202. The resdue (1.3 g, 6.4 mmol) was oxidised with MnO2 (5.0 g) in CH2Cl2 under refluxing condition. After the completion, reaction mixture was filtered and concentrated. It was purified by SiO2 column chromatography by eluting it with 1:1 ethyl acetate:hexane. Brown solid. Yield. 330 mg (25%); (M+H) 200.
Reaction SMILES: [C:1]([OH:5])(=O)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:23]([N:25](CC)CC)C.[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH3:41])[C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1(C)C=CC=CC=1>[CH3:41][C:34]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:31]([NH:30][C:1]([NH:25][CH3:23])=[O:5])[S:32][CH:33]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: CCC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)csc1NC(=O)NC
Temperature: 25 °C

Procedure:
A mixture of propionic acid (3.8 ml, 50.64 mmol), diphenylphosphoryl azide (10.9 ml, 50.64 mmol), and triethylamine (7.1 ml, 50.64 mmol) in toluene (30 ml) was refluxed for 1 hour. After cooling to room temperature, ethyl 2-amino-4-methylthiophene-3-carboxylate (3.13 g, 16.88 mmol) was added, and the mixture was refluxed for 18 hours. The product was partitioned between ethyl acetate and water, the organic layer washed with brine, dried over sodium sulfate, and solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexane 1:1, to provide ethyl 4-methyl-2-[(methylamino)carbonylamino]-thiophene-3-carboxylate as pink crystals.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[Na+].[Na+].[I:18][CH2:19][CH2:20][CH2:21]I.C(OCC)(=O)C.CCCCCC>CC(C)=O>[I:18][CH2:19][CH2:20][CH2:21][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1O
Reactant: ICCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccccc1OCCCI
Reaction time: 18 h

Procedure:
Combine methyl salicylate (5.09 g, 33.2 mmol), sodium carbonate (10.56 g, 99.67 mmol), and 1,3-diiodopropane (29.49 g, 99.67 mmol) in acetone (200 mL). Heat to reflux. After 18 hours, add sodium carbonate (10.56 g, 99.67 mmol) and continue to heat at reflux. After 18 hours, add 1,3-diiodopropane (29.49 g, 99.67 mmol) and continue to heat at reflux. After 18 hours. filter the reaction mixture and concentrate the filtrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/10 ethyl acetate/hexane to give the title compound: Rf=0.29 (silica gel, 1/10 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][NH:3][CH2:2][CH2:1][C:7]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-1H-benzo[d]azepine (535 mg/3.63 mmol, neat) was cooled to −10° C. (acetone/ice bath), treated with neat fuming nitric acid (ca. 10 mL, precooled to −10° C.), and allowed to stir for 30 minutes. The yellow solution was then poured onto ice with vigorous stirring. The resulting white solid was collected by filtration and washed with ice cold water and dried in vacuo to afford the nitrate salt of 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (650 mg/70%). The filtrate was basified with 1 N sodium hydroxide and extracted with methylene chloride (2×20 mL). The extracts were dried and concentrated to yield an additional 200 mg (25%) of the free base 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (br s, 2 H), 8.13 (s, 1H), 8.08 (dd, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 3.21 (m, 8H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br-].[CH2:8]([O:10][C:11]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12])[CH3:9].[C:32]1([CH:42]=O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:32]1([C:42](=[CH2:1])[C:11]([O:10][CH2:8][CH3:9])=[O:12])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
220 ml of a 1N solution of potassium tert-butoxide in tetrahyclrofuran are added dropwise to a solution of 0.219 mol of ethoxycarbonyltriphenylphosphonium bromide in 200 ml of tetrahydrofuran. The medium is stirred for 1 h at room temperature, after which a solution of 0.22 mol of naphthalene-1-carboxaldehyde in tetrahydrofuran is added dropwise. The medium is stirred for 4 h at room temperature, filtered, the solvent is evaporated off and the residue is taken up in 400 ml of methylene chloride. The organic phase is washed with 100 ml of water, dried and concentrated. The residue is taken up in diisopropyl ether, the precipitate is filtered off and the expected product is obtained after concentration of the solvent.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl[CH2:14][C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[F:11][C:5]1[CH:6]=[C:7]([O:10][CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[CH2:26][N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[CH3:20])=[O:12]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: ClCc1ccsc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccsc2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 3-chloromethyl-thiophene [CAS 2746-23-8], and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 403.3
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([O:24][CH2:25][C:26]1[C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][C:41]([F:44])([F:43])[F:42])=[N:28][O:29][C:30]=1[CH:31]1[CH2:33][CH2:32]1)[CH2:17]2.[F-].[K+].O>CN1C(=O)CCC1>[CH:31]1([C:30]2[O:29][N:28]=[C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][C:41]([F:42])([F:43])[F:44])[C:26]=2[CH2:25][O:24][CH:18]2[CH2:17][CH:16]3[N:23]([C:2]4[CH:3]=[CH:4][C:5]5[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=5)[N:7]=4)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH2:32][CH2:33]1.[C:11]([OH:13])([C:41]([F:42])([F:43])[F:44])=[O:12]
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cn2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)ccc2n1
Product: O=C(O)C(F)(F)F
Temperature: 200 °C

Procedure:
To a suspension of commercially available ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (II Farmaco, 1997, 52, 4, 213) (66 mg, 0.255 mmol) in NMP (2.5 mL) was added 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-1) (120 mg, 0.29 mmol) and potassium fluoride (51 mg, 0.88 mmol). The mixture was heated at 200° C. for 30 minutes under microwave irradiation. The mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using mass-triggered reverse phase HPLC using gradient of 40 to 60% acetonitrile/water with 0.05% TFA as modifier to yield ethyl 6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazine-2-carboxylate as TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.67 (d, J=10.0 Hz, 1H), 7.54 (dd, J=7.6 and 2.0 Hz, 1H), 7.51 (dd, J=7.6 and 0.8 Hz, 1H), 7.40-7.37 (m, 2H), 6.72 (d, J=10.0 Hz, 1H), 4.43 (q, J=7.2 Hz, 4H), 4.32 (bs, 2H), 4.28 (bs, 2H), 3.48 (m, 1H), 2.14-2.07 (m, 1H), 2.05-1.86 (m, 6H), 1.69 (bs, 1H), 1.65 (bs, 1H), 1.42 (t, J=7.2 Hz, 3H), 1.25-1.20 (m, 2H), 1.13-1.08 (m, 2H). MS m/z 598.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([OH:17])[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C=O.[C:20](O)(=O)C.C(Cl)(Cl)Cl>C(O)C.O=[Pt]=O.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([OH:17])[CH2:15][CH2:14][CH2:13][N:12]2[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)O
Reactant: COc1ccc([C@@H]2NCCC[C@@H]2O)cc1OC
Agent: O=[Pt]=O
Agent: C=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc([C@H]2[C@@H](O)CCCN2C)cc1OC

Procedure:
A solution of cis-2-(3,4-dimethoxyphenyl)-3-piperidinol (19.0 g, 80 mmoles, described in Example 4), ethanol (200 ml), 37% aqueous formaldehyde (7.4 g, 91 mmoles) and glacial acetic acid (8.0 g, 131 mmoles) is stirred at room temperature for 2 hours. The solution is diluted to 300 ml with ethanol and hydrogenated in the presence of Adams catalyst (400 mg). The residue is subjected to chromatography on silica gel using chloroform, 5% methanol-chloroform and finally 20% methanol-chloroform. The appropriate eluates are evaporated and the residue is dissolved in acetone. Maleic acid is added, followed by ether. The precipitate is collected and crystallized from acetonitrile-ether to give the title compound as the maleate salt, mp 132°-134° C.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([NH2:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:10]([C:6]1[C:5]2[S:1][N:2]=[N:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)#[N:12]
Reactant: NC(=O)c1cccc2nnsc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cccc2nnsc12
Temperature: 3 °C
Reaction time: 22 h

Procedure:
4.0 g (0.022 mol) of benzo-1,2,3-thiadiazol-7-ylcarboxylic acid amide are dissolved in 35 ml of tetrahydrofuran, and 3.6 ml (0.045 mol) of pyridine are added. The batch is then cooled to 3° C. and a solution of 3.9 ml (0.028 mol) of trifluoroacetic acid anhydride in 12 ml of tetrahydrofuran is added dropwise. The reaction mixture is subsequently stirred for 22 hours at room temperature and then poured onto ice/water and extracted twice with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate and filtered through a layer of silica gel. Concentration by evaporation gives 3.5 g (99% of the theoretical yield) of crystalline product having a melting point of 119°-122° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:39]([O:44][CH2:45][C@@H:46]1[O:48]C1)(=[O:43])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][C@H:45]([CH2:46][OH:48])[O:44][C:39]4=[O:43])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC=C(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 2, 0.500 g) in dry tetrahydrofuran (5.7 mL) at −78° C. under N2 is treated with n-butyllithium (0.73 mL, 1.6M in hexanes) dropwise over five minutes. The resulting mixture is stirred at −78° C. for 45 minutes and is then treated with (R)-(−)-glycidyl butyrate dropwise. The resulting solution is allowed to warm to ambient temperature over approximately 45 minutes and is stirred for an additional 20 hours, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 40 g), eluting with methanol/methylene chloride (1/99). Pooling and concentration of those fractions with an Rf=0.37 by TLC (methanol/chloroform, 5/95) gives the title compound, mp 131.5-133.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]1([C:10]([C:12]2[CH:22]=[CH:21][C:15]([CH:16]([CH3:20])[C:17](Cl)=[O:18])=[CH:14][CH:13]=2)=[O:11])[S:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[OH:4][CH2:3][CH2:2][NH:1][C:17](=[O:18])[CH:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:5]2[S:9][CH:8]=[CH:7][CH:6]=2)=[CH:22][CH:21]=1)[CH3:20]
Reactant: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: CC(C(=O)NCCO)c1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred solution of 2.44 parts of 2-aminoethanol in 15 parts of chloroform is added dropwise a solution of 5.6 parts of p-(2-thenoyl)hydratropoyl chloride in 15 parts of chloroform at room temperature (highly exothermic reaction). Upon completion, the whole is stirred and refluxed for one hour. The reaction mixture is cooled and washed with a 1N hydrochloric acid solution. The organic layer is separated, washed twice with water, dried, filtered and evaporated. The oily residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from boiling ether, yielding N-(2-hydroxyethyl)-p-(2-thenoyl)hydratropamide; mp. 87.1° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:20])=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:22]>>[ClH:20].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:26]3[CH2:27][CH2:28][C@H:24]([O:23][CH2:21][CH3:22])[CH2:25]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2ccc(OCc3ccccc3)cc2n1
Reactant: CCO[C@H]1CCNC1
Product: CCO[C@H]1CCN(c2cc(C)nc3cc(OCc4ccccc4)ccc23)C1
Product: Cl
Temperature: 80 °C
Yield: 71 %

Procedure:
A mixture of 436 mg (1.5 mmol) of 7-Benzyloxy-4-chloro-2-methyl-quinoline, product of example 1d), and 1.75 g (15 mmol) of (S)-3-ethoxypyrrolidine, prepared according to Tetrahedron Lett., 1995, 2745, was heated at 80° C. (oil bath temperature) under an argon atmosphere for 18 h after which time the reaction was completed according to HPLC analysis. The excess (S)-3-ethoxy-pyrrolidine was distilled off, and the residue was partitioned between EtOAc and water. The layers were separated, the organic layer was washed with water then saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo. The residue was taken-up in MeOH (1 ml) diluted with diethyl ether (30 ml) and then treated dropwise at RT under stirring with 0.7 ml of 3N HCL in MeOH. The solvent was removed and the remaining salt triturated with diethyl ether, then filtered off by suction and dried in a high vacuum to give 425 mg (69.7%) of the (S)-7-benzyloxy-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinoline hydrochloride as a light yellow solid. ISP mass spectrum, m/e: 363.2 (M+1 calculated for C23H26N2O2: 363).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][C:2]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(=O)c1cccc(O)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c, which was used without purification. MS m/z (M+H+) 290.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.2 %

Procedure:
The product from Step B (52 mmol) was treated with tetrabutylammonium tribromide (25.5 g, 52.9 mmol) in methanol/methylene chloride (1/3, 240 ml) under nitrogen. After stirring 3 days at room temperature, the solvents were removed in vacuo, and the residue dissolved in diethyl ether (200 ml), washed with water (4×50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (120 g) eluting with hexanes/ethyl acetate (30/1) afforded the desired □-bromoacetophenone (6.23 g) as a crystalline solid: 1H NMR (300 MHz, CDCl3) δ 7.70–7.81 (m, 2H), 7.55 (t, J=7.7 Hz, 1H), 4.39 (s, 2H); CI MS m/z=251 [C8H5BrClFO+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH3:30])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[Li+].[OH-]>O.O1CCOCC1>[CH2:29]([CH:3]([CH2:1][CH3:2])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:30]
Reactant: CCC(CC)C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)C(c1ccc2nc(-c3ccc(C(=O)O)cc3)sc2c1)n1ccnc1
Reaction time: 8 h

Procedure:
A solution of methyl 4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate (74 mg, 0.176 mmol) and LiOH (37 mg, 0.882 mmol) in water (1.5 mL) and dioxane (3 mL) was heated to 50° C. and stirred overnight. The solvent was evaporated, water was added and neutralized to pH 7 using 1 N HCl and evaporated. The crude product was purified by preparative TLC using 30% MeOH in DCM as eluent to afford to 4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoic acid as white solid. MS (ES+): m/z 406.28 (MH+).