Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: OCc1ccc(B(O)O)cc1
Product: OCc1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cc1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 4-(hydroxymethyl)phenylboronic acid was prepared the title compound as a yellow foam, MS (ESI+): m/z=409.2 ([M+H]+).
Reaction SMILES: C([NH:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[N:14]1)=[O:12])C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[N:14]1)=[O:12]
Reactant: O=C(c1ccccc1NCc1ccccc1)n1nc(O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1C(=O)n1nc(O)c2ccccc21
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To 4.2 g. of 1(o-benzylaminobenzoyl)-1H-indazol-3-ol dissolved in 1 liter of absolute EtOH was added 1.4 g of 10% Pd/C and the mixture was hydrogenated in a Paar apparatus for 16 hrs. The catalyst was then filtered off, washed well with EtOH, and the filtrate evaporated to afford 2.3 g. of a yellow-green solid. Recrystallization from aqueous. EtOH afforded the desired amine as a light yellow solid in 66.7% yield; m.p. 181°-183° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[C:18](=[CH:22][N:23]([CH3:25])C)[C:19](=O)[CH3:20])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:31])([F:30])[F:29])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.C(N)=[NH:37].CC[O-].[Na+]>C(O)C>[CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:18]4[C:19]([CH3:20])=[N:37][CH:25]=[N:23][CH:22]=4)=[O:26])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:30])([F:29])[F:31])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: N=CN
Reactant: CC(=O)C(=CN(C)C)C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ncncc1C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Yield: 5 %

Procedure:
Step-3: N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (700 mg, 1.6 mmol) and formamidine acetate (282 mg, 2.7 mmol) were dissolved in ethanol and added NaOEt (120 mg, 3.4 mmol). The above mixture was refluxed for 3 hr. Ethanol was removed on rotavapour and worked up (H2O/AcOEt) to obtain the crude. Crude was purified by column on 60-120 mesh silica gel using AcOEt and Petether (35:65) as eluent to obtain the title compound (34 mg) as a pale-yellow solid. M.P.: 147-150° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.25 (s, 1H), 9.18 (s, 1H), 8.96 (s, 1H), 7.73 (d, J 9.9, 2H), 6.69 (s, 1H), 2.61 (s, 3H), 1.65-1.56 (m, 1H), 0.95-0.86 (m, 2H), 0.80-0.72 (m, 2H). MS (m/z): 424.09 [M+H]+.
Reaction SMILES: FC1C=CC(OC2C[N:9](CCCN)C2)=CC=1.[C:17]1([O:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C1C=CC=CN=1)C>ClCCl>[C:17]1([O:23][C:24](=[O:25])[NH2:9])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCN1CC(Oc2ccc(F)cc2)C1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: NC(=O)Oc1ccccc1

Procedure:
A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.05 g, 0.223 mmol), phenylchloroformate (0.056 ml, 0.446 mmol) and dimethylaminopyridine (0.027 g, 0.223 mmol) in dichloromethane (4 ml) is stirred at ambient temperature for 24 hours. The reaction mixture is evaporated and the crude product purified by flash silica chromatography (elution 5:95 methanol/dichloromethane) to afford 3-[3-(4-Fluoro-phenoxy)-azetidin-1-yl]-propyl)-carbamic acid phenyl ester. [MH]+ 344.9.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].C(OC(=O)[CH2:21][Si:22](C)([CH3:24])[CH3:23])C>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:6]2[O:5][C:4]([C:1]([O:3][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH2:2])=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: CC(=O)c1ccc(Cc2ccc(F)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 2-acetyl-5-(4-fluorobenzyl)furan (10 g, 46 mmol) and trimethylsilylacetic acid ethyl ester (10.9 g, 68 mmol) in anhydrous THF (30 ml) was cooled at −20° C. To a solution was added anhydrous tetrabutylammoniumfluoride (0.2 g). The reaction mixture was gradually warmed up to room temperature and stirred for 15 minutes at 50° C. The THF was evaporated under reduced pressure. The residue was distilled under reduced pressure. The fraction showing b.p. 130° C. (0.5 mmHg) was collected to give [1-[5-(4-fluorobenzyl)furan-2-yl]vinyloxy]-trimethylsilane (11.7 g). Yield 88%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O)([O-])=O>C(O)C.C(OCC)(=O)C.[Pd]>[CH:14]1[N:10]2[C:5]3[C:4]([NH:1][CH2:15][C:11]2=[CH:12][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)NCc1cccn1-2
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1.0 g of 1-(2-nitrophenyl)-1H-pyrrole-2-carboxaldehyde in 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, is added 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for 2 hours and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in ether and treated with hexanes to give 0.35 g of the desired product as a beige solid m.p. 108°-110° C.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][C:15]1[CH:27]=[CH:26][C:18]([O:19][CH:20]([CH3:25])[C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=1)[CH:8]=[N:7]2.[OH-].[Na+]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:25])[C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)[CH:8]=[N:7]2
Reactant: COC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)O
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Into a mixture of methanol (10 ml) and tetrahydrofuran (14 ml), methyl 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propionate (0.6 g) was dissolved, and lN sodium hydroxide solution (2.5 ml) was added thereto. The reaction was carried out at room temperature while stirring for 2 hours. After removal of methanol and tetrahydrofuran by distillation, the aqueous layer was washed with dichloromethane (1 ml), made acidic with conc. hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to remove ethyl acetate to give 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propionic acid (0.44 g). Yield, 76%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1.CCN(CC)CC>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[C:3]([C:4](=[O:5])[NH2:6])[CH:7]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1cc(Br)cc(C(N)=O)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C(N)=O)c1NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-bromo-3-methylbenzamide (820 mg, 3.55 mmol, 1.0 eq.) in THF (15 mL) and Et3N (0.7 nit) was added nicotinoyl chloride (551 mg, 3.91 mmol, 1.1 eq.) in anhydrous THF (15 mL) dropwise. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the resultant precipitate was filtered and dried in vacuo to give 1.74 g of crude iii-e as a yellow solid. LCMS m/z=333.8, 335.8 (M+1) (Method B) (retention time=1.42 min).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:35][CH2:34][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH:33]=[CH:32][C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:36]I>C1COCC1.Cl>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:35][CH2:34][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([N:28]([CH:29]([CH3:31])[CH3:30])[CH3:36])=[O:27])=[CH:32][CH:33]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: CI
Reactant: CC(C)NC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(C)C(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To NaH (0.04 g, 55% suspension in oil, washed with pentane) was added at RT and under an argon atmosphere and at RT 4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-N-isopropyl-benzamide (0.04 g), product of example 160), in THF (4 ml). The reaction mixture was stirred 1 hour at RT, then MeI (0.232 g) was added and stirring was continued overnight at RT until the conversion was complete. The reaction mixture was made acidic with 1M HCl (one drop) and stirred for one minute. The solvent was removed in vacuo, the residue adsorbed on silica gel and chromtographed over silica gel (eluent: AcoEt/CH2Cl2, gradient from 0 to 30%) to give the desired product as off-white solid. MS (ESI): 504.1 MH+).
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][NH:4][C@H:5]([CH3:21])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.S(=O)(=O)(O)O.[CH2:33](O)[CH3:34]>>[OH:1][C@H:2]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][NH:4][C@H:5]([CH3:21])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][C:18]([O:20][CH2:33][CH3:34])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1cccnc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12

Procedure:
{3-[(2R)-2-((2R)-2-Hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetic acid (65 mg, 0.176 mmol) is dissolved in ethanol (5 mL), and thereto are added conc. sulfuric acid (0.1 mL) and Molecular Sieves 4A powder (trade name, 0.3 g), and the mixture is refluxed for 20 hours. After cooling, the insoluble materials are removed by filtration, and a saturated aqueous sodium hydrogen carbonate solution is added to the filtrate. The mixture is evaporated under reduced pressure to remove ethanol, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (ethanol/chloroform=1/5→1/1). The obtained purified product is dissolved in ethanol (3 mL), and thereto is added 1N HCl/diethyl ether (0.5 mL). The mixture is concentrated under reduced pressure to give the desired ethyl {3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetate.2 hydrochloride (63 mg, yield: 76%).
Reaction SMILES: [N-]=[N+]=[N-].[Na+].C(O)(=O)C.[N:9]1([C:18](=[NH:33])[N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]2)C2C=CC=CC=2[N:11]=[N:10]1>C(Cl)(Cl)Cl>[NH:33]1[C:18]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]2)=[N:9][N:10]=[N:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=N)n2nnc3ccccc32)CC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(c2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 99.5 %

Procedure:
Sodium azide (2.00 g, 30.7 mmol) and acetic acid (1.70 ml, 30.7 mmol) were added to a chloroform (300 ml) solution of the compound (10.6 g, 30.7 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 25 hours. Insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography [chloroform:methanol=30:1→10:1 (v/v)] to give 8.20 g (94%) of the title compound as a solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 1-bromo-4-fluorobenzene
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][N:14]=1.[Cl:16]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Cl:16][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: Nc1nccnc1-c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1ncc(Cl)nc1-c1ccc(Cl)cc1Cl
Yield: 93.5 %

Procedure:
3-(2,4-Dichlorophenyl)-2-pyrazinamine (1.43 g, 6.0 mmol) was dissolved in chloroform (9 mL), N-chlorosuccinimide (0.96 g, 7.2 mmol) was added thereto, and the mixture was stirred by heating under reflux for 4 hours. After being allowed to cool, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (1.54 g) as yellow crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:34])[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:38]([OH:47])=[O:37])=[CH:40][CH:41]=3)=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:33])[F:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(COc2ccc(Oc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from 4-{3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]-phen-oxy}phenol (0.1 g, 0.0002 mole) and 4-Bromomethyl-benzoic acid methyl ester (0.057 g, 0.00024 mole) with subsequent hydrolysis following the procedure of Example 515: MS (ES) m/z 603.9; HRMS: calcd for C37H26F3NO4+H+, 606.18867; found (ESI, [M+H]+), 606.1894.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:32](O)(=[O:37])[CH2:33][CH2:34][CH2:35][CH3:36].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][CH3:36])[C:27]([F:30])([F:28])[F:29])=[CH:20][N:19]=3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: CCCCCc1ccc(-c2ccc(-c3ncc(OCC(O)C(F)(F)F)cn3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(-c3ncc(OCC(OC(=O)CCCC)C(F)(F)F)cn3)cc2)cc1
Yield: 94.1 %

Procedure:
A mixed solution of 2-(4'-pentylbiphenyl-4-yl)-5-(2-hydroxy-3,3,3-trifluoropropoxy)-pyrimidine (80 mg), pentanoic acid (20 mg), DCC (50 mg), DMAP (10 mg) and methylene chloride (10 ml) was stirred at room temperature, followed by filtering off deposited solids, concentrating the mother liquid, purifying the residue by means of silica gel column chromatography and recrystalizing from ethanol to obtain the objective 2-(4'-pentylbiphenyl-4-yl)-5-(2-pentanoyloxy-3,3,3-trifluoropropoxy)-pyrimidine (90 mg). Cr 33° C. mesophase 84° C. iso
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[OH-].[Na+].O.Cl>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: CCCCCCC(=O)C=Cc1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCC(=O)C=Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
In 10 ml of methanol was dissolved 830 mg of 1-(3,4-diacetoxyphenyl)-1-nonen-3-one and after adding 7.5 ml of an aqueous 1N-sodium hydroxide solution to the solution, the mixture was stirred for 30 minutes at room temperature. Then, the reaction mixture was ice-cooled and after adding thereto 25 ml of water, the mixture was acidified with the addition of 5 ml of an aqueous 1N-hydrochloric acid solution to form crystals, which were collected by filtration and washed with water to provide 580 mg of 1-(3,4-dihydroxyphenyl)-1-nonen-3-one.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[C:4]([OH:6])=[O:5].[C:16]([OH:20])(=[O:19])[CH:17]=O.C([O-])([O-])=O.[K+].[K+]>O>[CH:17]1([C:16]([OH:20])=[O:19])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:3]([C:4]([OH:6])=[O:5])[CH2:2][NH:1]1
Reactant: NCC(C(=O)O)c1c[nH]c2ccccc12
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1CNC(C(=O)O)c2[nH]c3ccccc3c21
Reaction time: 72 h

Procedure:
3-Amino-2-(3-indolyl)propanoic acid (6 g; 0.03 mole) was mixed with 55 ml of water. Then glyoxalic acid (80% in water) (3 g; 30 mmole) dissolved in 50 ml of water was added and with rapid stirring 10% K2CO3 solution was added to pH 4.00. The mixture was stirred for a period of 3 days. A white precipitate was collected, washed with 400 ml of water and dried overnight with isopropyl alcohol. Yield 3 g (38%) mp 230°-231° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[CH2:6][CH2:5]2.[N:13](OCCC(C)C)=O.Cl.O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][CH:6]([NH2:13])[CH2:5]2
Reactant: O=C1CCc2cc(F)c(F)cc21
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC1Cc2cc(F)c(F)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][CH:15]=2)=[N:6]1.O=[C:27]([CH3:33])[C:28](OCC)=[O:29].S(=O)(=O)(O)O>C(O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:27]([CH3:33])[C:28](=[O:29])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: Nc1ccc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: CCOC(=O)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1nc2ccc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]c1=O
Temperature: 25 °C

Procedure:
146 mg (0.435 mmol) of the compound from example 43A were initially charged in ethanol (8 ml), then 56 mg (0.48 mmol) of ethyl 2-oxopropanoate were added and the reaction mixture was heated to reflux overnight. Thereafter, a catalytic amount of conc. sulfuric acid was added and the mixture was again heated to reflux overnight. Subsequently, the mixture was cooled to RT, and the solid formed was filtered off, washed with ethanol and dried under high vacuum. The crude product was dissolved in DMSO and separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient), and the product fractions were concentrated. This gave 30 mg (18% of theory) of the title compound in solid form.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6][NH:5]1.Br[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:24][C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[C:4]1=[O:3])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCCNC(=O)OC(C)(C)C)c(=O)c2c1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 0.30 g, 7.4 mmol) in DMF (10 mL) under an atmosphere of nitrogen was added methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.0 g, 4.9 mmol) in DMF (10 mL) dropwise. The mixture was stirred for 30 mins, then tert-butyl (3-bromopropyl)carbamate (1.76 g, 7.4 mmol) dissolved in DMF (5 mL) was added dropwise via cannula and the resulting solution was stirred at rt overnight. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20% to 90% EtOAc/hexanes) to afford methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.99 g, 56%). LC-MS: (FA) ES+ 361.