Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@H:9]([C:14]1[CH:23]=[C:22]2[C:17]([O:18][CH2:19][C:20](=[O:24])[NH:21]2)=[N:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])C1C=CC=CC=1>CCO.O.CC(O)=O>[C:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH2:8])[C:14]1[CH:23]=[C:22]2[C:17]([O:18][CH2:19][C:20](=[O:24])[NH:21]2)=[N:16][CH:15]=1)([CH3:23])([CH3:15])[CH3:9]
Reactant: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)O)c1cnc2c(c1)NC(=O)CO2
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](N)c1cnc2c(c1)NC(=O)CO2
Reaction time: 18 h

Procedure:
A mixture of the dibenzylamine 20-6 (0.22 g, 0.44 mmol) in EtOH/H2O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (100 mg). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (20% 20:1:1 EtOH/NH4OH/H2O-80% EtOAc) to give the tert-butyl ester 20-7 as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7].COCCN(S(F)(F)[F:40])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:40][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: C/C(=N\OCCO)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C/C(=N\OCCF)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)ethanone O-2-hydroxyethyl oxime (example 54) (20 mg, 0.05 mmol) in dry DCM (4 mL) was added bis-(2-methoxyethyl)aminosulfur trifluoride (a 3.2 M solution in toluene, 0.13 mL, 0.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then at 35° C. overnight. LC-MS showed the reaction was complete, and 5 mL of saturated NaHCO3 solution was added. The mixture was extracted with DCM; the organic phase was dried over Na2SO4, filtered, concentrated, and purified by column chromatography to afford 6.8 mg (34%) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.95 (dd, 1H), 8.41 (dd, 1H), 8.00 (d, 1H), 7.81 (d, 1H), 7.66 (d, 1H), 7.46 (dd, 1H), 4.83 (s, 2H), 4.78 (dd, 1H), 4.67 (dd, 1H), 4.56 (dd, 1H), 4.49 (dd, 1H), 2.33 (s, 3H). LCMS (method A): [MH]+=401, tR=5.44 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C/[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C=C/[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a stirred solution of 3.2 (0.0313 g, 0.062 mmol) in THF (2.00 mL) and EtOH (2.00 mL) at 23° C. was added 1N lithium hydroxide (2.00 mL, 2.00 mmol). Stirring continued for 20 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give a clear oil (0.0241 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (I H, d, J=8.2 Hz), 7.40 (1H, dd, J=8.4, 2.2 Hz), 7.13 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=1.5 Hz), 7.00 (1H, t, J=8.6 Hz), 6.92 (2H, d, J=8.6 Hz), 6.86 (1H, m), 6.79 (1H, m), 5.57 (1H, m), 5.50 (1H, m), 4.99 (2H, s), 3.79 (3H, s), 3.76 (1H, dd, J=14.5, 7.8 Hz), 2.71 (2H, dd, J=7.8, 2.3 Hz), 1.66 (3H, d, J=6.3 Hz), 1.23 (9H, m). MS ESI (neg.) m/e: 951.4 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19]C(=O)C)[C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1CCO
Yield: 97.1 %

Procedure:
To 4-(2-acetoxy-ethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (925 mg) in methanol (10 ml) was added potassium carbonate (800 mg) in water (4 mL). After 2 hours at room temperature the mixture was diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2-hydroxy-ethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (780 mg). This material was dissolved in ethanol and stirred over 10% Pd/C under an atmosphere of hydrogen for 24 hours. The reaction mixture was then filtered through celite and the solvent removed in vacuo to give 1-(2-hydroxy-ethyl)-piperazin-2-one (413 mg), which was used in a standard reductive amination procedure with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde to give 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-(2-hydroxy-ethyl)-piperazin-2-one. This compound (150 mg) was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (96 mg) to give after flash silica purification the title compound (39 mg) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1>C(O)(C)C>[CH3:2][O:3][C:4]([C@H:5]1[NH:6][C@@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1
Temperature: 70 °C
Yield: 101.6 %

Procedure:
D-Tryptophan methyl ester hydrochloride (50.0 kg, 196 mol) was suspended in isopropyl alcohol (500 L) and treated with piperonal (32.4 kg, 216 mol) at ambient temperature under an N2 atmosphere. The mixture was stirred between 70° C. and reflux (82° C.) for 16 to 18 hours. At this time, the reaction mixture contained less than 3% Compound IIa. The reaction mixture then was cooled to 0° C., filtered, and washed with cold isopropyl alcohol (150 L). The product was dried under vacuum at less than 60° C. to yield 69.8 kg (92%) of cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (Compound II)). 1H NMR (400 MHz DMSO) δ: 10.81 (1H, s), 10.67 (1H, exch.), 10.21 (1H, exch.), 7.52 (1H, d, J=8.0 Hz), 7.27 (1H, d, J=8.0 Hz), 7.11 (1H, m), 7.05-6.95 (4H, m), 6.08 (2H, s); 5.85 (1H, m), 4.71 (1H, m), 3.82 (3H, s), 3.39-3.23 (2H, m). HPLC Details: Column: SB-Phenyl 4.6×250 mm; ACN/(H2O+0.1% TFA) gradient; Temperature: 40° C.; Flow Rate=1 mL/min; UV Det.=285 μm; Injection Volume=20 μL; Diluent=1:1 ACN/H2O; Sample concentration: about 0.1 mg/mL; and Retention time=6.0 min.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:39]>CO.ClCCl>[ClH:39].[ClH:39].[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1

Procedure:
The free base was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 28) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1. The free base was dissolved in methanol/dichloromethane and treated with hydrogen chloride gas. After concentrated the solvents the product was obtained as a yellowish solid; mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.90 (m, 2 H), 2.05-2.25 (m, 2 H), 2.80-3.30 (m, 7H), 3.60-4.40 (m, 11H), 6.90-7.10(m, 3 H), 7.14(d, J=8.7 Hz, 2 H), 7.51 (d, J=8.7 Hz, 2 H), 7.57 (s, 1 H), 8.92(brs, 1 H), 9.36(brs, 1 H); MS (ES) m/z: 262.1 ((M+2 H)2+, 100%); 523.1(MH+, 30%); HRMS Calcd. for C28H35N4O3S (MH+): 523.2379. Found: 523.2394.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6]C=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[CH2:24][C:25]#N.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:25]([CH2:24][C:18]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: N#CCc1c(F)cccc1F
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Cc2c(F)cccc2F)cc1=O
Yield: 88 %

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 63, starting from 4,5-dichloro-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and (2,6-difluoro-phenyl)-acetonitrile and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-benzyl)-6-oxo-6H-pyridazin-1-yl]-propionic acid (175 mg, 88% for Step 5) as an off-white solid; ES+-HRMS m/e calcd for C20H21N2O3F3 [M+H+] 395.1577, found 395.1576. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-1.21 (m, 2H), 1.33-1.75 (m, 7H), 1.82-2.04 (m, 1H), 2.07-2.24 (m, 1H), 3.96 (s, 2H), 5.31 (d, J=6.3 Hz, 1H), 6.48 (s, 1H), 7.09-7.25 (m, 2H), 7.37-7.53 (m, 1H), 7.90 (s, 1H), 12.97 (br s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12]>C1(C)C=CC=CC=1>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][N:12]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: COC(CN=Cc1cccs1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.5 %

Procedure:
A solution of thiophene-2-carboxaldehyde (7.5 mL, 82.3 mmol, Alfa Aesar), aminoacetaldehyde dimethyl acetal (8.82 mL, 82.3 mmol, Alfa Aesar) in 100 mL toluene was heated to 115° C. using a Dean-Stark trap to remove water. After 3 hours, the reaction was cooled to room temperature. The reaction was placed on a rotary evaporator to evaporate the toluene, which yielded a brown liquid (about 17.3 g), which was used without further manipulation in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.42 (6H, s), 3.73 (1H, d, J=5.3 Hz), 4.65 (1H, t, J=5.3 Hz), 7.07-7.41 (3H, m).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B(O)O>>[O:7]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])[CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccncc1B(O)O
Product: COc1ccncc1-c1cncc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c1

Procedure:
By carrying out the operation analogously to example 239, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 4-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=23%).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][Mg]Br.O>C(OCC)C.Cl>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@:10]1([CH3:22])[OH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C[C@@]1(O)CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a solution of (2S)-2-(dibenzylamino)cyclopentanone (8.31 g, 29.7 mmol) in diethyl ether (149 mL) at −78° C. is added methyl magnesium bromide (29.7 mL, 89.1 mmol, 3 M in diethyl ether) slowly. The mixture is stirred at −78° C. for 4 h and then the reaction is allowed to warm to room temperature. Water is added to the reaction, resulting in an emulsion. Aqueous 1 M hydrochloric acid is added to break up the emulsion while keeping the aqueous phase basic. The aqueous phase is extracted twice with EtOAc. The combined organic portions are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (10% EtOAc/hexanes) to obtain the product. The material is dissolved in 1 M hydrochloric acid and extracted four times with EtOAc. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as an orange solid (3.49 g, 40%). ES/MS m/z 296 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl.[Ni].C(O)C>[N:10]1[CH:11]=[CH:12][C:7]([C@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:21])=[CH:8][N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=C(c2ccnnc2)CCCC1
Agent: [Ni]
Solvent: CCO
Solvent: ClCCl
Product: O[C@H]1CCCC[C@@H]1c1ccnnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
To a solution of the 4-(cyclohex-1-en-1-yl)pyridazine (0.15 g, 0.94 mmol) prepared in Example 53a in dichloromethane (9.4 mL), 3-chloroperbenzoic acid (0.76 g, 3.09 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 4 hours. A highly polar compound was removed with a silica gel pad (dichloromethane) to yield crude epoxide. A solution of the crude epoxide and Raney nickel in ethanol (3.0 mL) was stirred at 70° C. for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, and the residue was then purified with silica gel chromatography to yield the title compound (35 mg, 31%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester (1.69 g, 7.4 mmol) in DMF (20 ml) was added 1-(4-aminophenyl)ethanone (1 g, 7.4 mmol), NEM (0.852 g, 7.4 mmol) and TOTU (2.427 g, 7.4 mmol). The solution was stirred for 16 h at room temperature. The solvent was removed and the residue was dissolved in ethyl acetate (50 ml) and washed with saturated aqueous NaHCO3 solution (5 ml) and HCl (1 N, 10 ml). The organic phase was dried (MgSO4) and filtered. The solvent was removed to give 1.344 g (52%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[CH3:17]OC(=O)C1C=CC(C(F)(F)F)=CC=1I.[Br-].C1([Zn+])CCC1>>[CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2][CH2:17]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Agent: [Br-]
Agent: [Zn+]C1CCC1
Product: O=C(O)c1ccc(C(F)(F)F)cc1C1CCC1

Procedure:
The title compound, white solid, MS: m/e=243.0 [(M−H)−], was prepared in accordance with the general method of intermediate K from 2-iodo-4-trifluoromethyl-benzoic acid methyl Ester and cyclobutylzincbromide followed by saponification with sodium hydroxide.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH3:30])=[C:13]([C:15]2[N:16]=[C:17]([CH3:28])[S:18][C:19]=2[NH:20]C(=O)OC(C)(C)C)[CH:14]=1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH3:30])=[C:13]([C:15]2[N:16]=[C:17]([CH3:28])[S:18][C:19]=2[NH2:20])[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1nc(C)sc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1nc(C)sc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
TFA (4.0 mL) was added to a solution of tert-butyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-ylcarbamate (315 mg, 0.89 mmol) in DCM (10 mL) and water (3 drops). The reaction mixture was stirred for 1.5 hours at room temperature, then evaporated to dryness to give 215 mg (95%) of 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-amine as a yellow solid. LCMS (ESI) m+H=255.2.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.[CH:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20].O>O1CCCC1>[CH3:20][CH:19]([CH3:21])[CH2:18][C:17]([C:10]1[S:9][CH:13]=[CH:12][C:11]=1[C:14]([OH:16])=[O:15])=[O:22]
Reactant: O=C(O)c1ccsc1
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(=O)c1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium diisopropylamide (86 mmol) in tetrahydrofuran (30 ml) was added at 0° C. to a solution of thiophene-3-carboxylic acid (5 g) in tetrahydrofuran (50 ml). Isovaleraldehyde (4.6 ml) was added as a solution in tetrahydrofuran (30 ml) at 0° C. The reaction mixture was stirred at 25° C. for 3 hours and then water (100 ml) was added and the tetrahydrofuran was removed in vacuo. The aqueous residue obtained was extracted with ethyl acetate and the aqueous phase added to potassium permanganate (12.3 g) and warmed to 60° C. for 1.5 hours. The mixture was filtered, allowed to cool to ambient temperature, and then acidified with dilute hydrochloric acid. The acidic aqueous mixture was extracted with ethyl acetate and the organic extract dried and evaporated to give the sub-title compound as an oil (5.3 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[CH:8][CH:7]=1.[S:31]1[CH:35]=[C:34]([CH:36]=O)[N:33]=[CH:32]1>>[OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:34]3[N:33]=[CH:32][S:31][CH:35]=3)[CH2:25][CH2:24]2)=[CH:10][CH:11]=1
Reactant: O=Cc1cscn1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(Cc3cscn3)CC2)c2cccc3cccnc23)cc1

Procedure:
An even further embodiment is directed to reacting the N-(2-hydroxy-ethyl)-N-methyl-4-(piperidin-4-ylidene-quinolin-8-yl-methyl)-benzamide with thiazole-4-carbaldehyde to form N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])=[C:23]([C:31](O)=[O:32])[N:22]=[N:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])=[C:23]([C:31]([NH:37][CH:34]2[CH2:36][CH2:35]2)=[O:32])[N:22]=[N:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCF)c(OCc2ccccc2)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCCCF)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-{2-(benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-(5-fluoropentyl)-1H-1,2,3-triazole-4-carboxylic acid (0.49 g) obtained in Example 137b) in acetonitrile (5 ml) were successively added cyclopropylamine (0.09 ml), triethylamine (0.18 ml), HOBt (0.20 g) and WSC (0.25 g), and the reaction mixture was stirred at room temperature for 3.5 hr, and then at 60° C. for 1 hr. After allowing the reaction mixture to cool, the solvent was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a colorless amorphous substance (0.31 g, 59%).
Reaction SMILES: C(O[CH:4]([O:21]CC)[CH2:5][CH:6]1[CH2:20][O:19][C:10]2=[CH:11][C:12]3[CH2:13][NH:14][C:15](=[NH:18])[C:16]=3[CH:17]=[C:9]2[O:8][CH2:7]1)C.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:31]([OH:38])=[C:30]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:29]=1)=[O:27].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>CN(C=O)C.C(Cl)Cl>[C:34]([C:32]1[CH:33]=[C:28]([C:26](=[O:27])[CH2:25][N:14]2[CH2:13][C:12]3[CH:11]=[C:10]4[O:19][CH2:20][CH:6]([CH2:5][CH:4]=[O:21])[CH2:7][O:8][C:9]4=[CH:17][C:16]=3[C:15]2=[NH:18])[CH:29]=[C:30]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:31]=1[OH:38])([CH3:37])([CH3:35])[CH3:36].[F:46][C:45]([F:48])([F:47])[C:43]([O-:49])=[O:44]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(CC1COc2cc3c(cc2OC1)C(=N)NC3)OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)CN2Cc3cc4c(cc3C2=N)OCC(CC=O)CO4)cc(C(C)(C)C)c1O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The residue prepared in STEP B above (850 mg, 2.65 mmol) in DMF (10 mL) was combined with 2-bromo-1-[3,5-di(tert-butyl)-4-hydroxyphenyl]ethan-1-one (1.04 g, 3.18 mmol) and stirred at room temperature for 18 h. The resulting mixture was evaporated in vacuo to yield an oil, which was treated with 50% TFA in DCM at 0° C. The solvent was then evaporated, and the residue purified via reverse phase HPLC to yield 2-(8-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-7-imino-2,3,4,7,8,9-hexahydro-[1,4]dioxepino[2,3-f]isoindol-3-yl)acetaldehyde as its corresponding trifluoroacetate salt, as a residue. MS MH+=493; 1H NMR (CDCl3): d 8.88 (bs, 1H), 7.83 (s, 2H), 7.66 (s, 1H), 7.05 (s, 1H), 5.85 (bs, 1H), 4.67 (s, 2H), 4.36 (m, 2H), 4.11 (m, 4H), 2.91 (m, 1H), 2.76 (m, 2H), 1.45 (s, 18H).