Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[NH:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:16](O)=[O:17]>ClCCl>[C:22]([O:21][C:19](=[O:20])[NH:14][CH2:15][C:16](=[O:17])[NH:13][CH:10]1[CH2:12][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NC1CC1
Reaction time: 17 h
Yield: 26.4 %

Procedure:
—TBTU (5.1 g, 16.5 mmol), DIPEA (2.9 ml, 16.5 mmol) and cyclopropylamine (2.2 ml, 33 mmol) were added to a solution of BOC-Gly-OH (2.63 g, 15 mmol) in dry dichloromethane (10 ml). After 17 h stirring, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The product was extracted into ethyl acetate. The combined organic phases were washed with an aqueous solution of 2M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-cyclopropylcarbamoylmethyl-carbamic acid tert-butyl ester (847 mg). The product was used in the following step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[F:15][CH2:16][C:17](=[O:20])[CH2:18][F:19].CC(=O)OCC>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:17]([OH:20])([CH2:18][F:19])[CH2:16][F:15]
Reactant: Cc1ccc(I)c(Br)c1
Reactant: O=C(CF)CF
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(CF)CF)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of 2-bromo-1-iodo-4-methylbenzene (18.5 g, 62.3 mmol) in THF (25 mL) at 0° C. was slowly added i-PrMgCl (24 mL, 24 mmol). After being stirred for 1 h at 0° C., the reaction mixture was cooled to −78° C. Then a solution of 1,3-difluoropropan-2-one (0.85 g, 9.04 mmol) in dry THF (25 mL) was added. The mixture was stirred at −70° C. for 1 h, and then dry ice bath was removed. The solution was acidified with HCl (2 N) and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, eluting with PE:EA (5:1) to give 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, yield 55%) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1 H), 7.46 (s, 1 H), 7.21 (d, 1 H), 6.21 (s, 1 H), 4.97-4.94 (m, 1 H), 4.85-4.82 (m, 2 H), 4.74-4.71 (m, 1 H), 2.26 (s, 3 H) ppm.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15].O>CN(C=O)C>[CH3:15][N:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: N#Cc1cnc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C#N)cnc21
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred solution of 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile (2.88 g, 20.1 mmol) in DMF (40 mL) was added 60% NaH (2.41 g, 60.4 mmol). After 20 minutes, iodomethane was added in one portion (6.3 mL, 101 mmol) and the resulting mixture was stirred overnight. The following day, water was carefully added drop-wise to quench the remaining NaH before additional water was added (50 mL) causing precipitation of the product. Filtration and drying in vacuo afforded 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (3.16 g, 20.1 mmol, 100% yield) which was subsequently used without further purification. ES MS (M+H+)=158.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][O:5][C:6]([C:8]1C(C2C=CC=CC=2Cl)C(C(OCC)=O)=C(C)[NH:12][C:13]=1[CH3:14])=[O:7]>C(O)C>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][O:5][C:6](=[O:7])/[CH:8]=[C:13](\[NH2:12])/[CH3:14]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccccc2Cl)C1c1ccccc1Cl
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1Cl
Yield: 63 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-chlorobenzylideneacetoacetic acid ethyl ester and 75 mmols of β-aminocrotonic acid 2-chlorobenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-ethoxycarbonyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-5-carboxylic acid 2-chlorobenzyl ester of melting point 120° C (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(O)(=O)C>O>[NH2:20][C:19]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccc(Cl)c(Cl)c1Cl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Temperature: 0 °C
Yield: 64.7 %

Procedure:
A solution of 15 g of 2,3,4-trichlorophenylhydrazine, 8.7 g of (ethoxymethylene)malononitrile, 100 ml of glacial acetic acid and 50 ml of water was refluxed for 3 hours. The reaction mixture was cooled, poured into ice water and the precipitated solid was collected by filtration and dried. This solid was dissolved in ethyl acetate and the resulting solution was washed twice with saturated sodium bicarbonate, once with 100 ml of water, once with 100 ml of saturated brine and dried over anhydrous magnesium sulfate. The organic phase was evaporated under reduced pressure and the residue was recrystallized from ethanol to give 13.2 g of 5-amino-1-(2,3,4-trichlorophenyl)-1H-pyrazole-4-carbonitrile. Yield 66%. mp=140°-142° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[C:7]([C:10]1[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12](=[O:25])[CH:11]=1)[CH:6]=[N:5]2.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:26][C:3]1[N:4]2[N:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[C:12](=[O:25])[CH:11]=3)=[CH:8][C:9]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2cnn3ccnc3c2)ccn1CCCN1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(-c2cnn3c(Br)cnc3c2)ccn1CCCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Imidazo[1,2-b]pyridazin-7-yl-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (1 eq, 0.122 mmol, 41.3 mg) is dissolved in DMF (10 ml) and N-bromosuccinimide (1.1 eq, 0.135 mmol, 24.2 mg) is added. The reaction mixture is then stirred at 0° C. for 30 min. The reaction is diluted with EtOAc and washed with NaHCO3 and brine. The organic phase is then dried over MgSO4, filtered and evaporated to dryness to give 4-(3-bromo-imidazo[1,2-b]pyridazin-7-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one as a brown solid which did not require any further purification; [M+H]+=417
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:16]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a solution of 3-hydroxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (360 mg, 0.863 mmol) (obtained as described in Reference Example 75(2)) in methylene chloride (18 ml) were added methanesulfonyl chloride (200 μl, 2.59 mmol) and triethylamine (363 μl, 2.59 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride→methylene chloride:methanol (95:5) as the eluant to afford 3-methanesulfonyloxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (390 mg, yield 91%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH3:23][N:24]([CH3:43])[S:25]([N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:29]1)(=[O:27])=[O:26]>C1COCC1.CCCCCC.[Cl-].[NH4+]>[CH3:23][N:24]([CH3:43])[S:25]([N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([C:37]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:42])[C:38]([F:39])([F:41])[F:40])=[CH:29]1)(=[O:26])=[O:27]
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: CN(C)S(=O)(=O)n1cc(C(=O)C(F)(F)F)c2cccnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
To a chilled (−78° C.) solution of 80 mg (0.27 mmol) of 5-bromo-1-(4-fluorophenyl)-1H-indazole in 1 mL of anhydrous THF was added 110 μL (0.28 mmol) of a solution of 2.5 M n-BuLi in hexane in one portion. This solution was then added to a chilled (−78° C.) solution of 88 mg (0.27 mmol) of 3-(2,2,2-trifluoro-acetyl)pyrrolo[2,3-b]pyridine-1-sulfonic acid dimethylamide in 3 mL of THF. The reaction was monitored by TLC (ethyl acetate-hexanes 4:6). After 30 minutes, the mixture was diluted with 7 mL of saturated aqueous ammonium chloride and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with three 10 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel (prep. plate, 2×1 mm, ethyl acetate-hexanes 30:70). The material from the prep plate was washed from the silica gel with ethyl acetate and concentrated. The residue was triturated with ether-hexanes to afford 42 mg (28%) of the title compound. MS m/z 534.22 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=O.[Cl:19][C:20]1[N:21]=[N:22][C:23]([NH:26][NH2:27])=[CH:24][CH:25]=1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[N:26]([C:23]2[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[N:27]=1)=[O:18]
Reactant: NNc1ccc(Cl)nn1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(N(C)C)cc1
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(N(C)C)cc2)n(-c2ccc(Cl)nn2)n1

Procedure:
The above-obtained 4-(4-dimethylaminophenyl)-2,4-dioxobutanoic acid methyl ester (742 mg) and 3-chloro-6-hydrazinopyridazine (473 mg) in methanol (30 mL) was refluxed under heat for 18 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give 1-(6-chloro-3-pyridazinyl)-5-(4-dimethylaminophenyl)pyrazole-3-carboxylic acid methyl ester as a solid (679 mg, 63%).
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:24]2[O:29]CCCO2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.[C:30](=[O:32])=[O:31].Cl>C1COCC1.C(OCC)C>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([CH:24]=[O:29])[CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[C:30]([OH:32])=[O:31]
Reactant: O=C=O
Reactant: COc1cc(OC)cc(C2OCCCO2)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(OC)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous TMEDA (2.05 ml, 13.62 mmole) and 90 ml dry THF was cooled to -78° C. under an argon atmosphere. n-Butyllithium (11.35 ml of a 1.20M soln.) was added and after 15 minutes, 2-(3,5-dimethoxyphenyl)-1,3-dioxane (44) (FIG. 23) (3.05 g, 13.62 mmole) predissolved in 50 ml dry THF was added. The reaction was warmed to 0° C. and was stirred at that temperature for an additional 60 minutes (the solution turned from a blood red color to a dark brown color). The aryl lithium solution was then poured onto solid carbon dioxide covered with anhydrous diethyl ether. A white precipitate formed immediately. When the reaction warmed to room temperature, 15 ml of 10% HCl was added and the reaction was stirred overnight. The product was then extracted into chloroform. The organic layer was dried over MgSO4, and concentrated in vacuo to a white solid (1.311 g, 46%). The solid can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]1C(C(N)=O)=C(C)C=CN=1.[OH-].[Na+].BrBr>>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1C(N)=O
Reactant: Nc1cccnc1Cl
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccnc(Cl)c1N
Yield: 90 %

Procedure:
In a manner similar to that described for 2-chloro-3-aminopyridine in Example 14, the title compound was prepared in 90% yield (m.p. 63°-66° C., uncorrected) from 2.57 g of 2-chloro-4-methyl-3-pyridinecarboxamide, 2.28 g of NaOH, and 3.1 g of bromine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[C:6]#[N:7])([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Product: N#Cc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
4-chloro-benzonitrile was reacted with nitric acid to obtain 3-nitro-4-chloro-benzonitrile melting at 100°-101° C. which was reacted with N-hydroxy-phthalimide to obtain 0-(4-cyano-2-nitrophenoxy)-phthalimide melting at 233°-234° C. The latter was reacted to obtain 0-(4-cyano-2-nitro-phenyl)-hydroxylamine melting at 154°-155° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=P(Cl)(Cl)Cl.[CH3:17]O>>[C:1]([O:11][CH3:17])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1ccccc1
Temperature: 25 °C

Procedure:
To a round-bottomed flask, trans-cinnamic acid (7 g, 47.25 mmol) and MeOH(70 mL) were added. POCl3 (0.43 mL, 4.73 mmol) was added dropwise. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was cooled to room temperature, quenched with 1N NaOH solution. The mixture was extracted by EtOAc and washed with H2O. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under vacuum (7.1 g, 80˜95%)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([O:23][CH3:24])[C:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[C:16]3[Cl:36])([C:7]2[N:11]([CH3:12])[N:10]=[N:9][CH:8]=2)[OH:6])[CH2:2]1.C=O.[C:39](O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:36][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:5]([C:7]3[N:11]([CH3:12])[N:10]=[N:9][CH:8]=3)([CH:3]3[CH2:4][N:1]([CH3:39])[CH2:2]3)[OH:6])[CH:14]=2)[N:19]=[C:18]([O:23][CH3:24])[C:17]=1[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=1
Reactant: COc1nc2ccc(C(O)(c3cnnn3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CN(C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a flask containing azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (252 mg, 0.49 mmol, Example 124) was added MeOH (5 mL), formaldehyde (0.5 mL, 6.72 mmol), acetic acid (0.15 mL, 2.62 mmol) and sodium cyanoborohydride (1 M solution in THF, 1 mL, 1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours and then the contents were concentrated to dryness and the residue was dissolved in DCM. 1 N Aqueous NaOH was then added to adjust the pH of the solution to pH 10. The aqueous portion was extracted with DCM (3×25 mL) and CHCl3 (2×25 mL). The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by FCC (2% 2 M NH3-MeOH increasing to 10% 2 M NH3-MeOH) to provide the title compound as an off white solid. 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.48-7.52 7.50 (m, 3H), 7.44-7.32 (m, 3H), 4.35 (s, 2H), 4.06 (s, 3H), 3.75 (s, 3H), 3.56-3.47 (m, 1H), 3.46-3.36 (m, 1H), 3.31-3.17 (m, 1H), 3.12-3.01 (m, 1H), 3.00-2.90 (m, 1H), 2.31 (s, 3H); MS (ESI): mass calcd: Chemical Formula: C26H25ClF3N5O2, Exact Mass: 531.2. m/z found 532.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:18])[NH:16][NH2:17])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15]([NH:16][N:17]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccc(O)cc1

Procedure:
Analogously to Example 4a, 14 g (106 mmol) of 4-hydroxybenzaldehyde and 14 g (117 mmol) of tert-butylcarbazate in 125 ml of ethanol are reacted to form 4-hydroxybenzaldehyde-tert-butoxycarbonylhydrazone. (19.8 g, 80%). 9.73 g thereof are hydrogenated in 200 ml of THF in the presence of 0.6 g of 5% palladium on carbon at 1 atm hydrogen pressure to yield the title compound, which is crystallised from hot methanol. 1H-NMR (200 MHz, CD3OD): 7.18 (d, J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 3.80 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].C[N:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O.N1CCCC1>C(OCC)(=O)C>[I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(N6CCCC6)cc5ccc4n32)c1

Procedure:
A mixture of 141 g. of 10-(1,1-dimethylethyl)-3-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 725 ml. of N-methyl-2-pyrrolidinone and 75 ml. of pyrrolidine is stirred and heated at reflux for 1 hour, then cooled and diluted with 3.6 l. of ethyl acetate. The resulting precipitate of 10-(1,1-dimethylethyl)-3-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with water and dried; m.p. >360° C.
Reaction SMILES: C([O:8][C:9](=[O:38])[CH2:10][CH2:11][NH:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O)[CH:15]=1)C1C=CC=CC=1>C(O)=O.[Pd]>[NH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:38])=[O:8])=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)NCCCCCCC(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: O=CO
Product: NCCCCCCC(=O)Nc1cccc(C(=O)NCCC(=O)O)c1
Yield: 50.9 %

Procedure:
1.43 g of N-[m-[7-(1-t-butoxyformamido)heptanamido]benzoyl]-β-alanine benzyl ester and 476 mg of Pd/C are stirred in 28 ml of formic acid for 5 hours under hydrogen. The reaction mixture is filtered and the filtrate is evaporated in a vacuum. The residue is taken up in water and evaporated. 464 mg of N-[m-(7-aminoheptanamido)benzoyl]-β-alanine, m.p. 236° C., are obtained from methanol.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH:16][OH:17].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][N:16]([OH:17])[C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: ONCc1ccccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)N(O)Cc1ccccc1Cl
Yield: 29 %

Procedure:
This compound was prepared in the manner of Example 1, Step C, using 6.0 grams (0.05 mole) of trimethylacetyl chloride, 9.5 grams (0.06 mole) of N-(2-chlorophenylmethyl)hydroxylamine (prepared in Example I, Step A), and 14.2 grams (0.18 mole) of pyridine in 60 ml of methylene chloride. The crude product was recrystallized from hexane to give 3.5 grams of N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide; mp 100°-102°.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1sc(-c2ccccc2)nc1CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1sc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 92 %

Procedure:
Intermediate 62 was prepared as described above for the preparation of intermediate 52. From 3.27 g of N-(Boc)-L-Tyrosine methyl ester and 2.43 g of Intermediate 9C was prepared 5.07 g of BOC-protected intermediate methyl ester (92% yield; 1H NMR (CDCl3, 300 MHz) δ7.89-7.86 (m, 2H), 7.42-7.38 (m, 3H), 7.01 (d, 2H, J=6.3), 6.94 (d, 2H, J=6.3), 5.11 (s, 2H), 4.94 (d, 1H, J=6.0), 4.53-4.50 (m, 1H), 3.68 (s, 3H), 3.02-2.98 (m, 2H), 2.90 (q, 2H, J=5.7), 1.39 (s, 9H), 1.30 (t, 3H, J=5.7); From 5.05 g of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 62 as in example 52. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 4.28 g of intermediate 62; 1H NMR (DMSO-d6, 400 MHz) δ7.85-7.83 (m, 2H), 7.45-7.43 (m, 3H), 7.16-7.14 (m, 2H), 6.96-6.94 (m, 2H), 5.07 (s, 2H), 3.53 (s, 2H), 3.05-3.02 (m, 1H), 2.91-2.81(m, 4H), 1.21 (t, 3H, J=7.4); low resolution MS (ES+)m/e 382.94 (MH+); TLC Rf=0.33 (4/1, DCM/MeOH).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[C:17]([F:23])[C:16]=1[F:24]>CN(C=O)C.C(#N)C>[CH3:14][C:15]1[C:20]([F:21])=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:18]=[C:17]([F:23])[C:16]=1[F:24]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1c(F)c(F)nc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)nc(Oc2cccc(C(F)(F)F)c2)c1F
Temperature: 75 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 3-trifluoromethyl phenol (13.2 ml, 0.11 mol) in anhydrous DMF (200 ml) is added sodium hydride (4.8 g, 60%, 0.12 mol). After 30 min at ambient temperature the solution is added to another solution of 4-methyl-2,3,5,6-tetrafluoropyridine (16.5 g, 0.1 mol) in anhydrous acetonitrile (700 ml) at 50° C. during 3 hours. The resulting mixture is then stirred for 1 hour at 50° C. and 16 hours at 75° C. The solvents are removed in vacuo and to the residue is added ethyl acetate/pentane (1000 ml, 1/1 by volume). The mixture is washed twice with 2 M NaOH and 5 times with water. After drying and evaporation of the organic layer, the residue is purified by vacuum destillation. One obtains a colorless oil (23.3 g, 76 mmol, 76% yield, bp. 76° C. at 0.025 mbar) of 4-methyl-2,3,5-trifluoro-6-(3-trifluoromethylphenoxy)pyridine.