Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(C(C)C)C(C)C)C.Cl[C:56]([O:58][CH2:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:57]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:61][C:60]([CH3:63])([CH3:62])[CH2:59][O:58][C:56](=[O:57])[NH:45][C@@H:20]1[CH2:21][C@H:22]([C:24](=[O:44])[N:25]([CH:41]2[CH2:43][CH2:42]2)[CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[CH2:23][NH:18][CH2:19]1
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC(C)(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)OCC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-yl-methyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (121.4 mg, 0.2 mmol) (Starting Material 6), N-ethyldiisopropylamine (171.2 μL, 1 mmol) and 4-dimethylaminopyridine (10 mg) in CH2Cl2 (3 mL), neopentyl chloroformate (52.1 μL, 0.35 mmol) is added. After stirring at RT for 14 h, the mixture is diluted with CH2Cl2. The organic layer is washed with 1N HCl and saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellowish solid. MS: 499.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.45 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][C:47]([N:49]1[CH2:54][CH2:53][N:52]([C:55](=[O:66])[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[C:62]([F:65])([F:64])[F:63])[CH2:51][CH2:50]1)=[O:48].Cl>CN(C=O)C.O>[O:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:45][CH2:46][C:47](=[O:48])[N:49]2[CH2:50][CH2:51][N:52]([C:55](=[O:66])[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:62]([F:63])([F:65])[F:64])[CH2:53][CH2:54]2)=[O:21])=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2nnco2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
DIPEA (80 mg, 0.1 mL, 0.64 mmol) was added drop wise to 4-[1,3,4]Oxadiazol-2-yl-benzoic acid (40 mg, 0.2 mmol) in DMF (2 mL). EDCI (45 mg, 0.24 mmol) and HOBT (32 mg, 0.24 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (70 mg, 0.2 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 10% EtOAc in Hexane as eluent) to afford 30 mg (33% yield) of 4-[1,3,4]oxadiazol-2-yl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 93.4%. 1H NMR (CDCl3): δ 8.5 (s, 1H), 8.2 (d, 2H), 8.0 (d, 2H), 7.8 (m, 3H), 7.3 (m, 2H), 4.2 (m, 2H), 3.8 (m, 5H), 3.4 (m, 1H), 3.2 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[S:27][C:26]([C:28]3([O:32]COC)[CH2:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:23]2[S:27][C:26]([C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OC6CCOC6)cc5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: OC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OC6CCOC6)cc5)cc34)s2)CCC1

Procedure:
The title compound was prepared as described in Example 22E, substituting 5-(5-chloro-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 69C) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.47 (s, 1H) 8.29 (s, 1H) 8.25 (s, 1H) 7.94 (d, 2H) 7.02 (d, 2H) 6.95 (d, 1H) 6.67 (s, 1H) 5.11 (m, 1H) 3.93-3.75 (m, 4H) 2.63 (m, 2H) 2.41 (m, 2H) 2.26 (m, 1H) 1.97 (m, 3H); MS ESI(+) m/z 468.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.[CH2:18]([S:20][C:21]1[C:22]([C:27](O)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:27]([C:22]2[C:21]([S:20][CH2:18][CH3:19])=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:28])=[CH:9][C:8]([C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: CCSc1cccnc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A mixture of N2-(2,2,2-trifluoroethyl)-5-trifluoromethylpyridin-2,3-diamine (0.52 g), 3-ethylsulfanylpyridin-2-carboxylic acid (0.37 g), WSC (0.46 g), HOBt (27 mg) and pyridine (2 ml) was stirred at room temperature for 3 hours. To the reaction mixture was poured aqueous 10% citric acid solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 3-ethylsulfanyl pyridin-2-carboxylic acid [2-(2,2,2-trifluoroethyl)amino-5-trifluoromethylpyridin-3-yl]amide (0.75 g), which is hereinafter referred to as “intermediate compound (M3-43)”.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](O)[C:3]=1[C:9]([F:12])([F:11])[F:10].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncnc(O)c1C(F)(F)F
Product: Nc1ncnc(Cl)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The mixture of 6-amino-5-(trifluoromethyl)pyrimidin-4-ol (N-4) (300 mg, 1.66 mmol) in POCl3 (8 mL) in a pressure vessel is stirred at 100° C. for 1 h. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is taken up in water (20 mL), basified with saturated NaHCO3 aqueous solution to pH=9 and then extracted with DCM (30 mL x3). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the desired product, 6-chloro-5-(trifluoromethyl)pyrimidin-4-amine (N-5) as a yellow solid.
Reaction SMILES: [CH:1]1([N:5]2C[CH2:9][N:8](C([C@@H]3C[C@H]3C3C=C(C=CC=3)C(N)=O)=O)[C@@H:7](C)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:26](O)([C:28](F)(F)F)=O.[CH2:33](Cl)Cl>>[CH:1]1([N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C:28]2([CH3:26])[CH3:33])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CN(C2CCC2)CCN1C(=O)[C@@H]1C[C@H]1c1cccc(C(N)=O)c1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Product: CC1(C)CNCCN1C1CCC1
Reaction time: 1.5 h

Procedure:
Intermediate 1 (0.443 g, 1.65 mmol) was dissolved in DCM (10 mL) and TFA (5.00 mL) was added. The reaction mixture was stirred for 1.5 h, then was concentrated under reduced pressure and dried under vacuum. The crude title compound was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cnc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(CN2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
A mixture of 5-formyl-pyrazine-2-carboxylic acid methyl ester (0.400 g, 2.40 mmol), piperidine (0.204 g, 2.40 mmol), and NaB(OAc)3H (1.40 g, 3.60 mmol) in DCM (10 mL) was stirred for 18 h at rt. The reaction was quenched by the addition of 10% aq. NaOH (10 mL) and the mixture was stirred for 30 min. The mixture was extracted with DCM (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to yield the title compound (0.130 g, 23%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:23][CH2:24][CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].[H-].[Na+]>CN(C=O)C>[ClH:23].[ClH:23].[O:28]=[S:27]1(=[O:29])[CH2:26][CH2:25][CH2:24][N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:14]=[CH:15][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)N1CCN(c2cnc(-c3ccc(N)cc3)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2cnc(-c3ccc(N4CCCS4(=O)=O)cc3)cn2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A mixture of 4-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)phenylamine (0.34 g, 1.14 mmol), 3-chloro-1-propanesulfonyl chloride (0.20 g, 1.14 mmol) and TEA (0.12 g, 1.14 mmol) in DMF was stirred at rt for 1 h. NaH (0.055 g, 2.29 mmol) was added and stirring was continued for 5 h. The reaction mixture was transferred to a microwave vial (20 mL) and heated for 1000 s at 80° C. in a microwave oven. The reaction mixture was evaporated in vacuo and redissolved in a mixture of DCM and water. The phases were separated and the aqueous phase was extracted with DCM (2×25 mL). The combined organic extracts were evaporated in vacuo, redissolved in MeOH and purified by preparative HPLC Method B. This afforded 220 mg of a solid which was redissolved in MeOH and treated with HCl in diethyl ether. The volatiles were evaporated to give 126 mg (22%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([OH:14])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:35]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41]O)=[CH:36]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:14][CH2:41][CH2:40][C:37]2[CH:38]=[CH:39][S:35][CH:36]=2)[CH:7]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Reactant: OCCc1ccsc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCc2ccsc2)cc(OC(C)C)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
To a solution of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (71.4 mmol) in anhydrous THF (85 ml) is added under inert atmosphere successively triphenylphosphine (1.5 eq.) and 2-(3-thienyl)ethanol (1.3 eq.). The solution is chilled at 0° C. and DIAD [diisopropylazodicarboxylate] (21.65 g, 107.1 mmol, 1.5 eq.) is added dropwise. Then the reaction mixture is stirred at room temperature for 20 h and concentrated in vacuo. 3-Isopropoxy-5-(2-thiophene-3-yl-ethoxy)-benzoic acid methyl ester is obtained after column chromatography (cyclohexane/ethyl acetate) as yellow oil in a yield of 41%.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][N:32]([C:9](=[O:10])[CH2:8][CH2:7][C:4]5[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=5)[CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CCc3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from benzenepropanoyl chloride (Aldrich, Cat. #249440) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=457.2.
Reaction SMILES: C[Si](Br)(C)C.C[O:7][P:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)(=[O:10])[O-:9]>CN(C=O)C>[NH2:17][C:13]1[CH:12]=[C:11]([P:8](=[O:7])([OH:10])[OH:9])[CH:16]=[CH:15][CH:14]=1
Reactant: COP(=O)([O-])c1cccc([N+](=O)[O-])c1
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1cccc(P(=O)(O)O)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4 mL of DMF and trimethylsilyl bromide (1 mL) were added to the mixture (170 mg) of monomethyl(3-nitrophenyl)phosphonate and dimethyl ester, and stirred at 60° C. for 2 hours. After removing a solvent, the mixture was dissolved in a mixed solvent of water and methanol. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight. After filtering out the catalyst, a solvent was removed to obtain a crude product of (3-aminophenyl)phosphonic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8]
Reactant: [H][H]
Reactant: Nc1ccc(C(=O)c2nccs2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2nccs2)cc1N

Procedure:
A suspension of 20 g. (0.082 mol) of 2-(3-nitro-4-aminobenzoyl)thiazole in 1 liter of tetrahydrofuran containing 5 g. of 5% palladium on carbon was reduced with hydrogen under a pressure of 3 atmospheres. The resulting mixture was filtered and concentrated in vacuo to yield 2-(3,4-diaminobenzoyl) thiazole as unstable red needles, mp. 125°-127° C. (dec.) (acetone-water).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:15])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>CO>[F:31][C:29]([F:30])([F:32])[C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH:14]([C:11]3[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[O:8])=[CH:13][CH:12]=3)[CH3:15])=[CH:22][CH:21]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(C)Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A solution of 3-({5-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (chiral Isomer 1) (170 mg, 0.356 mmol) in methanol (7.1 mL) is treated with 5N NaOH (0.712 mL) and shaken at rt for 2 h. The reaction is neutralized with 1N HCl (0.748 mL), and extracted into ethyl acetate (2×). The combined organic layers are dried and concentrated, giving the title compound (142 mg). MS (ES): 464.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([Cl:31])=[O:24])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 0 °C

Procedure:
A suspension of 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoic acid (1.50 g, 3.56 mmol) in DCM (35 mL) was stirred at 0° C. and oxalyl chloride (340 μL, 3.9 mmol) was added, followed by a catalytic amount of DMF (<50 μL). The mixture was allowed to warm to room temperature and stirred for two days, during which time the solid dissolved to form a light yellow clear solution. The mixture was evaporated under reduced pressure and the residue was azeotroped with toluene (3 mL), then hexane (10 mL) and the title compound obtained as a light brown, slightly gummy, solid (1.5 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:23]([OH:33])=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1>C1COCC1>[Cl:21][C:22]1[C:23]([OH:33])=[C:24]([S:29]([N:7]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: COC(=O)c1cccc(CNCc2ccc(F)cc2)n1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of methyl 6-((4-fluorobenzylamino)methyl)picolinate (140 mg, 0.51 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (147 mg, 0.56 mmol) and TEA (0.142 mL, 1.02 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated and lyophilized to give the desired product (0.19 g, 74%) as a white solid. 1H NMR (CD3OD) δ 7.93-7.80 (m, 2H), 7.65-7.53 (m, 3H), 7.27-7.25 (m, 2H), 6.94-6.90 (m, 2H), 4.68 (s, 2H), 4.65 (s, 2H), 3.98 (s, 3H). MS (ESI): 499.0 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([Cl:38])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([Cl:38])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cc1ccc(C(=O)CCCCCBr)cc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)c(Cl)c2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-chloro-4-methylphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-chloro-4-methylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:24][C@H:25]1[O:27][CH2:26]1)(=O)=O>>[CH2:24]([O:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:25]1[O:27][CH2:26]1
Reactant: Oc1cccc2cc(-c3nnc(C(F)(F)F)o3)oc12
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: FC(F)(F)c1nnc(-c2cc3cccc(OC[C@@H]4CO4)c3o2)o1
Yield: 36.1 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(7-hydroxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole (2.4 g) and (S)-glycidyl nosylate (2.2 g), the title compound (1.0 g) was obtained as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH2:11])=[N:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2]1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:21]([CH:18]3[CH2:20][CH2:19]3)=[O:22])=[N:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2]1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccoc2)s1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccoc2)s1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 μL of a 0.3M stock solution of 5-furan-3-yl-4-phenyl-thiazol-2-ylamine and 120 μL of a 0.3M stock solution of pyridine were mixed with 120 μL of a 0.3M stock solution of cyclopropanecarbonyl chloride. The reaction mixture was shaken overnight at ambient temperature. Purification was performed by preparative LC-MS.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[CH:24]=[CH:25][C:26](Br)=[CH:27][C:14]=2[N:13]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([N:16]1[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[N:13]=[C:12]1[CH:8]([NH2:7])[CH:9]([CH3:10])[CH3:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2n1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamic acid tert-butyl ester in DCM (2 ml), was added trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo to give the free amine product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1>O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH2:10][CH2:11][C:12]2=[O:14])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CCCC(=O)O)cc1
Solvent: O
Product: CSc1ccc2c(c1)C(=O)CCC2
Temperature: 60 °C

Procedure:
0.055 mol of the compound obtained in Step B and 100 g of polyphosphoric acid are introduced into a 500 ml round-bottomed flask. The reaction mixture is heated at 60° C. for 3 hours and is then cooled and poured into water. Extraction with ethyl ether is carried out; the organic phase is washed with water, dried over MgSO4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel. Yellow oil