Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:31][C:30]=2[CH:40]=1)(=[O:25])=[O:24])[CH3:22]>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:37]2[CH2:38][CH2:39][N:34]([C:32]3[O:33][C:29]4[CH:28]=[CH:27][C:26]([S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:40][C:30]=4[N:31]=3)[CH2:35][CH2:36]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCS(=O)(=O)c1ccc2oc(N3CCNCC3)nc2c1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Product: CCS(=O)(=O)c1ccc2oc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC4CCCC4)CC3)nc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example 2.3) and 5-ethanesulfonyl-2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.[CH3:35][NH2:36]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:36][CH3:35])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:30])([F:29])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Reactant: CN
Solvent: C1CCOC1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)NC)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A round bottom flask was mixed with 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoyl chloride (Example 295B) (0.037 g, 0.07 mmol) and 1.0M MeNH2 in THF (10.0 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The resulting solid was crystallized with Et2O, filtered in vacuo and dried under high vacuum to afford a pure solid (0.022 g, 59% yield): MS (ES) m/z 501 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([F:13])[CH:5]=1)[CH3:2].O.NN>CCO.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOc1ccc(N)c(F)c1
Temperature: 90 °C

Procedure:
To a solution of 4-ethoxy-2-fluoro-1-nitro benzene (1.0 g, 5.4 mmol) in absolute EtOH (25 mL) at rt was added 250 mg of Pd/C (Aldrich, 10 wt. % on activated carbon), followed by slow addition of hydrazine hydrate (2.5 mL). The resulting reaction mixture was refluxed at 90° C. for 30 min. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford 4-ethoxy-2-fluoro-phenyl amine as a pale yellow oil: MS (ESI) 156 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[C:35]([F:36])=[C:34]([F:37])[N:33]=[C:32]([F:38])[C:31]=2[F:39])=[CH:24][CH:23]=1)[C@@H:3]([NH:13]C(=O)OC(C)(C)C)[CH2:4][NH:5]C(=O)OC(C)(C)C.NCCCC[C@H](NC(=O)[C@@H](N)C)C(NC1C=CC(C#CC2C(F)=C(F)N=C(F)C=2F)=CC=1)=O>>[NH2:13][C@@H:3]([CH2:4][NH2:5])[C:2]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[C:35]([F:36])=[C:34]([F:37])[N:33]=[C:32]([F:38])[C:31]=2[F:39])=[CH:24][CH:23]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Agent: C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Product: NC[C@H](N)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Yield: 85 %

Procedure:
The compound (29) was prepared from compound (28) by using the same procedure as synthesis of compound (23) from compound (21), in 85% yield;1H NMR (400 MHz, CD3OD): 7.81 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 4.11 (t, J=5.8 Hz, 1H), 3.47-3.42 (m, 2H).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29](O)=[O:30].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:42][CH:43]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([NH:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:30]
Reactant: Nc1ccccc1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)Nc1ccccc1
Yield: 67 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with aniline, the title compound was obtained as a white powder in 67% yield: mp 187-188° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=6.0 Hz, 2H), 7.42 (br s, 1H), 7.36-7.28 (m, 4H), 7.19 (d, J=6.0 Hz, 2H), 7.15-7.08 (m, 1H), 4.47 (s, 2H), 4.12-4.07 (m, 2H), 3.50-3.44 (m, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.6, 157.3, 155.4, 154.1, 149.0, 137.8, 134.3, 129.7, 129.0, 124.4, 121.4, 120.3, 120.2, 117.5, 47.3, 42.0, 41.8, 17.3; MS (ES+) m/z 477.3 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[H][H]>[Ru](Cl)(Cl)Cl.CC(O)C>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: [H][H]
Agent: Cl[Ru](Cl)Cl
Agent: *C(F)(F)C(*)(F)F
Agent: [BH4-]
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A ruthenium hydride complex was then prepared using the ruthenium chloride thus obtained, and this complex was used without isolation to carry out chiral hydrogenation of acetophenone. That is, trans-RuCl2[(S)-xylbinap][(S)-daipen] (1.5 mg; 0.00125 mmol) and sodium borohydride (0.9 mg; 0.025 mmol) were weighed and placed in a 100 mL glass autoclave equipped with a stirrer coated with polytetrafluoroethylene, and after depressurizing the interior of the vessel to eliminate air, argon was introduced. 2-propanol (1 mL) , which had been deaerated by argon bubbling in advance, was then added into the vessel by means of a syringe and under an argon gas flow. The procedure of performing pressure reduction and argon introduction while stirring the solution obtained was then repeated 5 times for deaeration, and then upon immersing in an oil bath for 5 minutes at 65° C., vigorous stirring was subsequently performed for 30 minutes at room temperature. Acetophenone (600 mg; 5.0 mmol) and 2-propanol (1.5 mL) were then added into the vessel by means of a syringe and under an argon gas flow. The procedure of performing pressure reduction and argon introduction while stirring the solution obtained was then repeated 5 times for deaeration. A hydrogen tank was then connected to the autoclave using a hydrogen introduction tube and the replacement of the air inside the introduction tube with hydrogen at 2 atmospheres was performed 5 times. The pressure inside the autoclave was then adjusted to 5 atmospheres and then hydrogen was released carefully until the pressure dropped to 1 atmosphere. After repeating this procedure 10 times, the hydrogen pressure was adjusted to 8 atmospheres and vigorous stirring at 25° C. was performed for 12 hours. After completion of reaction, by concentrating the solution obtained by depressurization and subjecting the same to simple distillation under reduced pressure (1 mmHg), (R)-1-phenylethanol (579 mg; 4.75 mmol; yield: 95%; enantiomeric excess: 98%) was obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)(O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.N1C=CN=C1.S(Cl)([Cl:39])=O>C(#N)C>[F:1][C:2]([F:31])([F:30])[C:3]([Cl:39])([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(O)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCOc1ccc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propan-2-ol (0.65 g) and imidazole (0.612 g) were dissolved in dry acetonitrile (30 cm3), and the solution cooled to ca. 0° C. Thionyl chloride (1.21 g) was added dropwise, with stirring. The reaction mixture was allowed to warm to the ambient temperature (ca. 22° C.) and was stirred for a further three hours. Analysis of the reaction mixture by thin layer chromatography and gas liquid chromatography at that time showed no starting tertiary alcohol to be present. The reaction mixture was quenched with water, and a small volume of saturated sodium chloride solution was added. The aqueous mixture was extracted four times with diethyl ether and, finally, once with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation of the solvent under reduced pressure to give an oil. The product was purified by column chromatography on a silica gel support, using n-hexane containing 6% by volume ethyl acetate as eluent, to give 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.48 g) as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1.[CH:12](N=C=NC(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:2]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: O=C(O)CCc1cccnc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCc1cccnc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 3-(3-pyridinyl)propanoic acid (2.50 g, 16.5 mmol) in CH2Cl2 (110 mL) and MeOH (1 mL) was added DMAP (0.010 g, 0.082 mmol) and diisopropylcarbodiimide (4.17 g, 33.1 mmol). The reaction was stirred for 2 hours at 23° C. then saturated aqueous NaHCO3 (100 mL) was added. The mixture was extracted with CH2Cl2 (100 mL) and the combined extracts were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 60% EtOAc/hexanes) to provide 2.70 g (99%) of the desired product. MS (DCI/NH3) m/z 166 (M+H)30 .
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([O:16][CH3:17])=[O:15])[C:8]1=[O:18])[CH3:6])C.COC(N1CC(=O)N2C(C(OCC)=O)CCC2C1)=O>>[CH3:17][O:16][C:14]([NH:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH:5]([CH3:6])[C:4]([OH:19])=[O:3])[C:8]1=[O:18])=[O:15]
Reactant: CCOC(=O)C(C)N1CCCC(NC(=O)OC)C1=O
Agent: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Product: COC(=O)NC1CCCN(C(C)C(=O)O)C1=O

Procedure:
2-(3-Methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid was prepared by method 801 substituting 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester for 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester. C10H16N2O5 calculated 244.1 observed [M+1]+ 245.1; rt=1.53 min.
Reaction SMILES: [CH:1]([C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]([O:7][C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1)=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].C[O-].[Li+].Cl>CN(C)C=O.CO.O>[C:9]([C:8]([CH3:13])([O:7][C:6]1[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][C:3](/[CH:1]=[CH:24]/[C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:25])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:12])([OH:11])=[O:10]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
2-(4-Formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-47, 0.23 g, 0.72 mmol) and 4-acetylbenzoic acid (0.12 g, 0.72 mmol) were dissolved in a dimethylformamide-methanol solution (5 mL, 7:3). After complete dissolution, lithium methoxide (0.11 g, 2.9 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (4×25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in a tetrahydrofuran-heptane solution (5 mL, 10:1) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.30 g (90%) of the title compound as a dark yellow solid, mp 135–137° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.23 (d, 2H, J=8.4 Hz), 8.10 (d, 2H, J=8.4 Hz), 7.99 (d, 2H, J=15.6 Hz), 7.71 (d, 1H, J=3.0 Hz), 7.54 (d, 1H, J=5.1 Hz), 7.14 (dd, 1H, J=5.1, 3.0 Hz), 6.49 (s, 1H), 3.85 (s, 3H), 1.69 (s, 6H). MS (ESI) m/z=467 ([M+H]+, 100%). Anal. Calcd. for C25H28O8S.EtOH: C, 63.27; H, 5.51; S, 6.26. Found: C, 63.40; H, 5.19; S, 6.38.
Reaction SMILES: O.[N:2]1(O)C2C=CC=CC=2N=[N:3]1.Cl.C(N=C=NCCCN(C)C)C.[I:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=2)[N:27]([S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:26]=1.NN>CN(C=O)C>[I:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([NH:2][NH2:3])=[O:35])[CH:32]=2)[N:27]([S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.471 g, 3.07 mmol) (Aldrich), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.589 g, 3.07 mmol) (Sigma-Aldrich), and 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.13 g, 2.56 mmol) were weighed into a 100 mL round bottomed flask and dissolved in DMF (12 mL). The solution was stirred at RT for 30 min. Hydrazine (1.4 mL, 44.6 mmol) (Aldrich) was added, and the reaction was stirred at RT for 1.5 h. The solution was partially concentrated. The concentrate was diluted with H2O and a precipitate formed. The solid was collected by filtration, washed with H2O, and dried to give 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (0.802 g, 1.762 mmol, 68.8%) as a beige solid. MS (ESI, pos. ion) m/z: 455.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.15 (s, 1H), 7.97-8.02 (m, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.82-7.92 (m, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.52 (br. s., 1H), 2.33 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].N1C2C=CC=CC=2N=N1.[C:21](=O)([O:27]C1C=CC=CC=1)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>O.C1COCC1>[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Agent: Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of L-lysine monohydrochloride (20.0 g, 109.5 mmol) and benzotriazole (14.3 g, 120.0 mmol) in a mixture of water (66.6 mL) and THF (111.0 mL) at pH 12 was treated with t-butyl phenyl carbonate (24.3 mL, 131.4 mmol) and stirred 18 hours at 60° C. The mixture, initially 2 layers, became a clear orange solution and the product was approximately 75% (NMR).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH:15]([CH3:17])[O:16][C:12]=2[C:11]([C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1>>[Cl:1][S:2]([C:9]1[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12]2[O:16][CH:15]([CH3:17])[CH2:14][C:13]=2[C:8]=1[O:7][CH3:6])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)O)c2c1CC(C)O2
Product: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1CC(C)O2
Temperature: 50 °C

Procedure:
218 g of chlorosulphonic acid were introduced into a 500 ml round-bottomed flask and 65 g of finely ground 4-methoxy-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were added in small amounts. The temperature rose to 38° C. The contents were then heated to 50° C. After cooling, the solution obtained was poured, in small amounts, onto ice, with stirring.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[N:5][C:6](Cl)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[N:5][C:6]([C:22]2[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: CN(C)c1cc(-c2ccccc2)c(Cl)nn1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Temperature: 110 °C

Procedure:
N,N-dimethyl 6-chloro-5-phenylpyridazin-3-amine (1-2; 120 mg, 0.51 mmol) was dissolved in dry dioxane (3 mL) and 4-formylphenyl boronic acid (136 mg, 0.91 mmol). 2 M aqueous Na2CO3 (0.75 mL) and palladium(0) tetrakis-triphenylphosphine (66 mg, 0.058 mmol) were then added. This mixture was degassed, the vessel sealed and heated at 110° C. for 24 hours. The cooled reaction was diluted with water and the product extracted into ethyl acetate, the extract dried over anhydrous NaSO4, filtered and evaporated. The product was purified by chromatography on silica gel and elution with a 25-65% ethyl acetate/hexane gradient to give 4-[6-(Dimethylamino)-4-phenylpyridazin-3-yl]benzaldehyde (1-3). NMR (CDCl3): δ9.98 (1H, s), 7.74 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.35 (3H, m), 7.19 (2H, d, J=8 Hz), 6.76 (1H, s), 3.29 (6H, s); m/e (m+1): 304.2
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.CC(C)=CCC[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:36])[C:22]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[OH:23])[CH2:16][CH2:15]1.Cl.Cl.NC1CCN([CH2:47][CH:48]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)CC1>>[CH:48]1([CH2:47][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:36])[C:22]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[OH:23])[CH2:16][CH2:15]2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccc(F)cc2)C2CCCC2)CC1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccc(F)cc1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-(4-fluorophenyl)-2-hydroxyacetic acid obtained in Example 55 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:27][C@@H:28]1[CH2:32][NH:31][CH2:30][C@H:29]1[OH:33]>>[F:27][C@H:28]1[C@H:29]([OH:33])[CH2:30][N:31]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:32]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: O[C@@H]1CNC[C@H]1F
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@H](F)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 38 using 6-chloro-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1) and trans-4-fluoropyrrolidin-3-ol (Stage 74.1). The product was purified by chromatography on Silica gel, preparative TLC (eluent EtOAc), followed by preparative SFC (Column 2-EP, from 17-22% in 6 min) to afford the title product as a white solid. UPLC-MS (Condition 8) tR=0.94 min, m/z=452.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.07 (d, J=12.42 Hz, 1H) 3.30-3.51 (m, 2H) 3.56-3.74 (m, 1H) 4.17 (br. s, 1H) 4.86-5.00 (m, 1H) 5.42-5.52 (m, 1H) 6.38-6.46 (m, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.53-7.91 (m, 3H) 8.03-8.13 (m, 1H) 8.71-8.82 (m, 1H) 10.24 (s, 1H).
Reaction SMILES: [Br-].[C:2]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)([O:4][CH3:5])=[O:3].[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=O.C1(C)C=CC=CC=1.C[O-].[Na+]>CO>[C:38]([C:37]1[CH:42]=[CH:43][C:34]([CH:32]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:2]([O:4][CH3:5])=[O:3])=[CH:31][CH:30]=2)=[CH:35][CH:36]=1)([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a 2 L 3-neck round bottom flask fitted with a glass stopper, rubber septum, and reflux condenser with a nitrogen inlet tube, was added 126.35 g (251 mmol) (4-carbomethoxy)benzyltriphenylphosphonium bromide, 49.45 g (302 mmol) methyl 4-formylbenzoate, and 632 mL 2:1 methanol:toluene. After the starting material dissolved, 63.2 mL (277 mmol) 25% sodium methoxide solution in methanol was added dropwise over several minutes. The reaction vessel was heated at reflux for 30 minutes. After cooling to room temperature, the reaction vessel was cooled at 0° C. for several hours. The resulting precipitate was filtered and dried in a vacuum oven to afford 59.0 g (79%) 4,4'-bis(carbomethoxy)stilbene as a 7:3 mixture of cis:trans isomers.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[CH:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[OH:36])=[O:3].[C:37](OCC)(=O)C.CCCCCC>>[NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[CH:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[O:36][CH3:37])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2

Procedure:
The compound of Example 67 is exposed to the conditions described in Example 25. Chromatography of the crude product on silica gel using ethyl acetate/hexane, (3:7) as eluant affords the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]([OH:16])=[O:15]>[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1ccc(C=CC(=O)O)c(Cl)c1OC
Agent: [Pd]
Product: COc1ccc(CCC(=O)O)c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 3-(2-Chloro-3,4-dimethoxy-phenyl)-acrylic acid and Pd—C to give 3-(2-Chloro-3,4-dimethoxy-phenyl)-propionic acid. LC-MS: m/e 243 (M−1).