Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=Cc1ccncc1
Product: Cc1cccc(NCc2ccncc2)c1C(=O)O

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-6-methylbenzoic acid (Fluka) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 170.4, 149.5, 149.3, 147.8, 138.5, 131.2, 121.9, 118.7, 115.8, 109.1, 45.1, 22.1.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[CH3:22][S-:23].[Na+].O1CCOCC1>CO>[CH3:22][S:23][CH2:6][C@@H:7]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CSC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 45 °C
Yield: 76.1 %

Procedure:
(S)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate (600 mg, 1.902 mmol) and sodium thiomethoxide (593 mg, 7.61 mmol) were added to a 20 mL microwave tube equipped with mechanical stir bar and charged with Dioxane (10 ml). The reaction was allowed to heat overnight at 45° C. The reaction was poured into 5 mL MeOH and 5 g silica, and the solvents were evaporated in vacuo. The dry-loaded crude product was purified on 50 g SNAP column 10-50% EtOAc/hexanes to provide (S)-tert-butyl (2-(methylthio)-1-phenylethyl)carbamate (387 mg, 1.447 mmol, 76% yield).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=2)[CH2:19][CH2:18][O:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+]>CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)[CH2:19][CH2:18][O:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(CCCN2CCOC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCN2CCOC(CN[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 4-(3-(2-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)morpholino)propyl)benzoate (190 mg, 0.366 mmol) in methanol (3 mL) was added sodium hydroxide (6M, 0.5 mL, 3.00 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 110 mg of product (HCl salt) as white solid. MS: (M+H)+=395.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.35 (m, 1H), 1.47-1.61 (m, 1H), 2.00-2.17 (m, 2H), 2.65-3.22 (m, 9H), 3.25-3.51 (m, 3H), 3.60 (br. s., 1H), 3.88-4.15 (m, 2H), 4.38 (br. s., 1H), 7.14-7.26 (m, 3H), 7.27-7.34 (m, 2H), 7.38 (d, J=8.08 Hz, 2H), 7.90 (d, J=8.08 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([I:12])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:28])(=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])=[CH:16][CH:15]=1.Cl>C(#N)C.O1CCOCC1.O>[CH2:26]([O:25][C:23]([N:22]=[S:20]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([I:12])=[CH:4][N:3]=2)=[CH:19][CH:18]=1)([CH3:28])=[O:21])=[O:24])[CH3:27]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: C#CCNc1nc(Cl)ncc1I
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: C#CCNc1nc(Nc2ccc(S(C)(=O)=NC(=O)OCC)cc2)ncc1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
400 mg (1.65 mmol) of (2-chloro-5-iodopyrimidin-4-yl)-prop-2-in-1-yl-amine and 630 mg (2.15 mmol) of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl sulfoximide in 7 ml of acetonitrile are mixed with 0.6 ml of a 4N solution of HCl in dioxane and 1 ml of water. The batch is stirred for 24 hours at 50° C. The solvent is drawn off, and the remaining residue is purified by chromatography (DCM/EtOH 9:1). 279 mg (0.56 mmol, corresponding to 54% of theory) of the product is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[O:11][N:10]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29]1([O:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CCOC(C)=O>[C:29]1([O:35][C:36]([N:1]2[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=4)[O:11][N:10]=3)[CH2:3][CH2:2]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1cc(-c2nc(COC3CCNCC3)no2)ccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1cc(-c2nc(COC3CCN(C(=O)Oc4ccccc4)CC3)no2)ccn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[3-(piperidin-4-yloxymethyl)[1,2,4]oxadiazol-5-yl]pyridine-2-carbonitrile (Preparation 25, 700 mg, 2.5 mmol) in DCM (30 ml) was added triethylamine (0.7 ml, 4.9 mmol). The resulting solution was transferred to a stirred solution of phenylchloroformate (0.62 ml, 4.9 mmol) in DCM (30 ml) and stirring was continued for 30 min at rt. The reaction mixture was diluted with EtOAc (250 ml) then washed successively with water (100 mL), saturated aqueous sodium carbonate (100 ml) and brine (100 ml). The organics were dried (MgSO4) then adsorbed onto silica gel. Purification via chromatography (EtOAc-IH, 1:1 to 3:2) afforded the title compound: RT=3.63 nm in; m/z (ES+)=406.01 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]([OH:26])=O)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)=O.CN(C)CCN>C1COCC1>[CH3:27][N:29]([CH3:30])[CH2:33][CH2:32][NH:31][C:24]([C:19]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 59.9 %

Procedure:
Prepared in the same manner as described for example 1. A solution of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.70 g, 1.92 mmol, 1 eq.) in anhydrous THF was treated with 1,1′-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.) and warmed as described. The reaction was allowed to cool and then treated with N,N-dimethylethylenediamine (0.20 g, 2.35 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give a yellow oil. The oil was purified by silica gel flash chromatography using 5% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (2-dimethylamino-ethyl)-amide (0.50 g, 60% yield) as a bright yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([CH:12]3[O:20][CH:19]4[CH:14]([O:15][Si](C(C)(C)C)(C(C)(C)C)[O:17][CH2:18]4)[CH:13]3[O:29][C:30](=[O:32])[CH3:31])[C:6]=2[N:7]=1.N1C=CC=CC=1>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([CH:12]3[CH:13]([O:29][C:30](=[O:32])[CH3:31])[CH:14]([OH:15])[CH:19]([CH2:18][OH:17])[O:20]3)[C:6]=2[N:7]=1
Reactant: CC(=O)OC1C2O[Si](C(C)(C)C)(C(C)(C)C)OCC2OC1n1c(=O)sc2cnc(N)nc21
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OC1C(O)C(CO)OC1n1c(=O)sc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 17 (2.28 g, 4.73 mmol) in 10 mL anhydrous methanol was added 327 μL HF/Pyridine. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated and purified by flash chromatography (0-10% MeOH—CH2Cl2) yielding 1.47 g (90%) 18: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (1H, s), 6.86 (2H, bs), 5.82 (1H, d, J=4.68 Hz), 5.76-5.78 (1H, m), 5.34 (1H, d, J=7.8 Hz), 4.60 (1H, t, J=5.46 Hz), 4.27-4.31 (1H, m), 3.96-4.00 (1H, m), 3.61-3.72 (2H, m), 2.03 (3H, s); [M]+ @ m/z 343.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[OH:13])([O-:3])=[O:2].[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1>N1C=CC=CC=1>[CH3:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:13][C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][N:8]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: c1ccncc1
Product: CC1CCN(C(=O)Oc2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 8 h

Procedure:
200 mg (1.12 mmol) of 5-nitro-1H-indazol-3-ol and 180.4 mg (1.67 mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 20 ml of pyridin were heated under reflux for 5 h and left to stand overnight. Pyridine was distilled off in vacuo, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 48 mg (14%), M+H+: 304.99.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Reaction time: 1 h

Procedure:
A mixture of 3-butyryl-4-chloro-8-methoxyquinoline (6.0 g, 023 mol) and o-toluidine (6.0 ml, 0.056 mol) in 1,4-dioxan (100 ml) was heated under reflux with stirring for 1 hour. The mixture was evaporated and chromatographed (silica gel, 2% methanol in dichloromethane) to give 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline as an oil which was isolated as the hydrochloride salt (2.12 g, 25.1%), m.p. 215°-217° by crystallisation from ethyl acetate and then recrystallisation from acetone.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.CC(C)=O.Cl.[CH2:24]([N+:28]([O-:30])=[O:29])/[CH:25]=N\O>O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:25][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])C/C=N\O
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c2ncc([N+](=O)[O-])c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (1 g), acetone (50 ml), 20 % hydrochloric acid (20 ml) and methazonic acid (4.5 g, wet) was stirred for 2 hrs. at room temperature and refluxed for 4 hrs. The mixture was diluted with water, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by a column chromatography on silica gel to give 4-(2-chlorophenyl)-6,8-dimethyl-3-nitroquinoline as crystals, which was recrystallized from a mixture of methanol and chloroform. m.p. 130°-131° C. Yield 1.95 g (54.2 %).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=O.ClC(OCC(C)C)=O.[C:29]([NH:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(N(CC)CC)C>[C:29]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[C:5](=[O:7])[CH2:6][CH:2]([OH:1])[CH:3]=2)=[CH:40][CH:39]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC1=CC(O)CC1=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.326 g. of 7-(3-Hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoic acid were dissolved in 20 ml. of dry acetone. At -20° C., 0.23 ml. of triehtylamine were added and then 0.216 ml. isobutyl chloroformate. After 5 minutes, the temperature was permitted to increase to 25° C., and 0.4 g. of p-benzoylaminophenol dissolved in 10 ml. of dry pyridine was added dropwise. After 2 hours, the solvent was distilled off; the residue was extracted in ethyl acetate; the organic phase was washed with water and dried over sodium sulphate. The solvent was distilled off. After chromatographic purification of the residue (silica gel/ethyl acetate), 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-heptanoic acid p-benzoylaminophenyl ester (m.p. 168°-169° C.) was obtained.
Reaction SMILES: C(#N)C.Cl.[CH2:5]([O:7][C:8]1[C:27]([C@H:28]2[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]2)=[CH:26][C:11]([CH2:12][C:13]2[CH:22]=[C:21]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20]3)[C:14]=2C(O)=O)=[CH:10][C:9]=1[O:39][CH3:40])[CH3:6]>C(OCC)(=O)C>[CH:14]1[C:15]2[C:21]([CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][C:13]=1[CH2:12][C:11]1[CH:10]=[C:9]([O:39][CH3:40])[C:8]([O:7][CH2:5][CH3:6])=[C:27]([C@@H:28]2[O:29][C@H:30]([CH2:37][OH:38])[C@@H:31]([OH:36])[C@H:32]([OH:35])[C@H:33]2[OH:34])[CH:26]=1
Reactant: CCOc1c(OC)cc(Cc2cc3cccccc-3c2C(=O)O)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1c(OC)cc(Cc2cc3cccccc-3c2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 92.1 %

Procedure:
Acetonitrile and a 4 M ethyl acetate solution (0.02 ml) of hydrochloric acid (5 ml) were added to 2-[4-ethoxy-3-methoxy-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylic acid (50 mg) and the mixture was refluxed with heating for 10 minutes. A 4 M ethyl acetate solution (0.02 ml) of hydrochloric acid was further added to the reaction mixture and the mixture was refluxed with heating for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxy-3-methoxyphenyl]-D-glucitol (42 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.O[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH:24]=1
Reactant: COC(=O)c1ccc(CCCc2ccccc2O)cc1
Reactant: OCc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCc2ccccc2OCc2cccnc2)cc1
Reaction time: 72 h
Yield: 57 %

Procedure:
Methyl 4-[3-(2-hydroxyphenyl)propyl]benzoate (1.35 g, 5 mmol) was dissolved in 0.2 ml of THF. The solution was treated with 3-hydroxymethylpyridine (0.6 g, 5.5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol). To this mixture was added slowly diethylazodicarboxylate (0.96 g, 5.5 mmol). The reaction mixture was stired for 72 hours and the solvent was evaporated. The amide residue was purified by chromatography (methanol, dichloromethane) to give methyl 4-[3-(2-(3-pyridylmethyloxy)phenyl)propyl]benzoate as a pink oil (1.03 g, 57%) MS (CI+):362 [M+H]+.
Reaction SMILES: [C:1]([NH:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC(C)([O-])C.[K+]>>[CH2:2]([C:1]1[NH:18][C:19]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1c(C)cccc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCc1cc2cccc(C(=O)O)c2[nH]1
Yield: 89.1 %

Procedure:
A mixture of 2-(n-hexadecanamido)-3-methylbenzoic acid (5.0 g) and potassium tert-butoxide (20 g) was treated in a similar manner to that described in Example 1 to give a solid, which was recrystallised from methanol to give 2-(n-pentadecyl)indole-7-carboxylic acid (4.25 g), in the form of a white solid, m.p. 93°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=O)[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].O=P(Cl)(Cl)[Cl:26]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:26])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)cc(Cl)c2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 11 step B from 6,8-dichloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester and POCl3. Light brown solid. MS (ESI): 366.0 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].C([N:42]=[C:43]=[S:44])(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2.N1CCCCC1>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:3](=[O:4])[C@@H:2]([NH:1][C:43]([NH2:42])=[S:44])[CH:22]([CH3:24])[CH3:23])=[N:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(N)=S)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-amino-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methylbutan-1-one (1.530 g, 3.91 mmol) in CH2Cl2 (10 mL) was added O-(9H-fluoren-9-yl)methyl carbonisothiocyanatidate (1.100 g, 3.91 mmol) as a solid in one portion. The mixture was allowed to stir at room temperature for 12 h. Piperidine (2 mL) was added to the mixture and it was allowed to stir at room temperature for 1 h. A further portion of piperidine (2 mL) was added and the solution allowed to stir 1 h. The solution was concentrated to dryness and the residue was purified by column chromatography (biotage, eluting with 5:4.5:0.5 hex:EtOAc:MeOH, and then 5% MeOH in EtOAc). The title compound as obtained as a light yellow glass (1.30 g, 74%). 1HNMR (300 MHz, DMSO-d6) δ 11.81 (s, H), 7.65 (d, J=8.8 Hz), 7.63-7.71 (m, overlap with previous peak, 2H total), 7.42-7.56 (m, 2H), 7.10-7.14 (m, 1H), 5.06 (dd, J=7.0, 3.0 Hz, 1H), 4.94 (app t, J=8.0 Hz, 1H), 4.72-4.76 and 4.56-4.62 (m, 1H, rotamers, 1:1 ratio), 3.77-3.90 (m, 1H), 2.07-2.14 (m, 2H), 1.90-1.98 (m, 3H), 0.93 (d, J=7.0 Hz, 3H), 0.84 (d, J=7.0 Hz, 3H). LCMS: Anal. Calcd. for C19H24BrN5OS: 449, 451. found: 450, 452 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[C:27]([F:35])[CH:26]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(C(F)(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-[4-(3-fluoro-4-trifluoromethylphenyl)-1,3-thiazol-2-yl]acetamide (128 mg, 0.334 mmol) in the presence of NaH (10 mg, 0.418 mmol) in dry DMF (5.0 mL) to give 75 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.40 (s, 3H), 5.33 (s, 2H), 6.24 (s, 1H), 7.36 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.90-8.01 (m, 3H), 12.77 (br s, 1H); APCI-MS (m/z) 482.07 (M+H)+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(OCC)(=O)C.O>[Cl:31][C:23]1[C:19]([C:20]([OH:22])=[O:21])=[C:18]([O:17][CH3:16])[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(C(F)(F)F)cc(Cl)c1C(=O)O
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
A solution of LiTMP was formed by cooling a solution of 2,2,6,6-tetramethylpiperidine (862 mg, 6.1 mmol) in THF (5 mL) to −50° C. then adding a solution of n-butyllithium (2.4 mL of 2.5 M in hexanes, 6.1 mmol) dropwise and stirring the mixture for 10 minutes at −50° C. This solution was then cooled to −78° C. and a solution of 2-methoxy-6-(trifluoromethyl)nicotinic acid (300 mg, 1.35 mmol) in THF (5 mL) was added dropwise. This mixture was stirred at −78° C. for 2 hours then added via cannula to a pre-cooled solution of hexachloroethane (1.44 g, 6.1 mmol) in THF (5 mL) at −50° C. This mixture was allowed to warm to room temperature over 1 hour then poured into water (20 mL), ethyl acetate (100 mL) added, then washed with hydrochloric acid (2 N, aq, 100 mL). The organic phase was dried over magnesium sulphate, filtered and evaporated to give 4-chloro-2-methoxy-6-(trifluoromethyl)nicotinic acid (312 mg) as an orange solid: 1H NMR (360 MHz, CDCl3): δ 7.36 (1H, s), 4.08 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]#[N:19].B1([O-])OO1.O.O.O.O.[Na+]>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:16][N:1]=[C:2]3[C:3]([CH2:17][C:18]#[N:19])=[CH:4][CH:5]=[CH:6][C:7]=23)=[CH:10][CH:11]=1
Reactant: N#CCc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3)onc12
Temperature: 0 °C

Procedure:
Following the procedure of Intermediate 59, 2-amino-3-(4-chlorobenzoyl)benzeneacetonitrile is reacted with sodium perborate tetrahydrate in acetic acid at 70° C. and thereafter mixed with ice-water to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=1.[H][H]>[C].[Pd].CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Yield: 84.6 %

Procedure:
A solution of 8.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-nitrobenzamide and 0.8 g of 10% palladium carbon added to 50 ml of methanol was stirred in a hydrogen atmosphere at room temperature. After disappearance of the starting raw material was confirmed by means of TLC, the reaction solution was filtered and the obtained filtrate was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent (development solvent; hexane:ethyl acetate=3:1) to obtain 6.3 g of the desired product (Yield: 85%) in the form of powder.