Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:10][C:11]2[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O>C(O)C.O.C(OCC)(=O)C>[Cl:22][C:12]1[C:13](=[O:16])[CH2:14][CH2:15][C:11]=1[NH:10][C:9]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCC1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc(NC2=C(Cl)C(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
To a solution 0.49 g (1.69 mmole) of the 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one produced in Example 1(3) in 5 ml of an ethanol-water (9:1) solution was added 0.25 g (1.86 mmole) of N-chlorosuccinimide. The mixture was stirred at room temperature for 1.5 hours. After the reaction, the solvent was removed in vacuo. Next, the residue obtained was diluted with 100 ml of ethyl acetate and the solution was successively washed with a saturated sodium hydrogencarbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a crude product as a black oil. The crude product obtained here was purified by flash chromatography. The solvent was removed and the residue dried in vacuo to obtain the title compound 0.45 g (yield 82.5%) as a light pink solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15](SC)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[O:31][S:32]([O-:34])=O.[K+].[CH3:36]O>>[C:12]1([C:11]2[N:10]=[C:9]([C:20]([C:22]([F:24])([F:25])[F:23])([C:26]([F:27])([F:28])[F:29])[OH:21])[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][C:4]([S:32]([CH3:36])(=[O:34])=[O:31])=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2[nH]c(C(O)(C(F)(F)F)C(F)(F)F)nc2-c2ccccc2)cc1
Reactant: CO
Agent: [K+]
Product: CS(=O)(=O)c1ccc(-c2[nH]c(C(O)(C(F)(F)F)C(F)(F)F)nc2-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4.0 g (9.25 mmoles) of 4-phenyl-5-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)-1H-imidazole-2-methanol, 14.2 g (23.1 mmoles) of Oxone® and 115 ml of methanol were stirred overnight. The inorganic solid was filtered off, and the filtrate was concentrated to dryness. The residue was partitioned between ethyl acetate and water and the organic layer was separated. The organic layer was washed with brine and water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was recrystallized from a mixture of dichloroethane and butyl chloride affording 2.89 g (67%) of the title compound as a white solid, m.p. 223°-225°.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)C>O>[CH:34]1([N:33]([CH2:2][C:3]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=2)[CH3:32])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CNC1CCCCC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(CN(C)C2CCCCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 79.6 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g), N-methyl-N-cyclohexylamine (2.28 g) and ethanol (45 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave ethyl 2-(N-cyclohexyl-N-methylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (2.80 g, 80%). This compound was recrystallized from ethanol. Colorless prisms, mp. 172°-174° C.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]3[NH:31][C:30](=[O:32])[O:29][C:28]([CH3:34])([CH3:33])[C:27]=3[CH:35]=2)[CH:13]=[CH:14][C:15]=1[Cl:16].O>CO>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]3[NH:31][C:30](=[O:32])[O:29][C:28]([CH3:33])([CH3:34])[C:27]=3[CH:35]=2)=[O:7])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
One gram (0.0056 mol) of N-bromosuccinimide is gradually added to a solution of 2.13 gm (0.005 mol) of 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one in 50 ml of methanol, under stirring. After reaction for 24 hours, 500 ml of water at 80° C. is added, and the precipitate is subjected to suction filtration after stirring for two hours. By recrystallization from isopropanol/diisopropylether, crystals are obtained, melting point: 136°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[NH4+].[Br:17]N1C(=O)CCC1=O.CCOC(C)=O>C(#N)C>[Br:17][C:7]1[C:6]([CH3:8])=[CH:5][C:4]([N:9]([CH3:10])[CH3:11])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc(N(C)C)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)C)cc(F)c1Br
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of (3-Fluoro-5-methyl-phenyl)-dimethyl-amine (2.82 g, 18.4 mmol) in acetonitrile (28 mL) were sequentially added ammonium acetate (0.142 g, 1.84 mmol) and a solution of N-bromosuccinimide (3.27 g, 18.4 mmol) in acetonitrile (23 mL) drop-wise at 0° C. After 1 h., at r.t., the solvent was switched to EtOAc, and the solution was washed with saturated NaHCO3 (aq), dried (MgSO4), filtered, and concentrated in vacuo to give an orange, oily residue. Purification of this oil by flash chromatography (SiO2, 5% EtOAc/Hexanes) gave (4-Bromo-3-fluoro-5-methyl-phenyl)-dimethyl-amine as an ivory solid (3.96 g, 93%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[OH:21])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:22])[CH2:7][CH2:6]1)[CH3:2].N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:31].CC(C)=O>C(Cl)Cl>[CH2:1]([C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[O:21][C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:31])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:22])[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)CC[C@@H]3[C@@H]12
Reactant: CCCCCCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCCCCCCCCCOC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](CC)C[C@]12C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11β-Ethyl-17β-dodecyloxycarbonyloxyestr-4-en-3-one (9b, CDB-4722) was prepared as follows: Under nitrogen, a solution of 11β-ethylestr-4-en-17β-ol (7b, 0.1 g, 0.33 mmol) in dry CH2Cl2 (5 mL) was cooled to 0° C. in an ice bath. Pyridine (0.1 mL, 97.8 mg, 1.24 mmol) followed by dodecyl chloroformate (0.2 mL, 1.84 mg, 0.74 mmol) were added and the mixture stirred at 0° C. for 15 min and then allowed to warm to room temperature. The reaction was stirred at room temperature overnight, after which time, TLC (2% acetone in CH2Cl2) indicated a complete reaction. The mixture was diluted with additional CH2Cl2 (50 mL) and washed with water (1×), saturated sodium bicarbonate solution (1×), and water (1×). The organic fractions were filtered through anhydrous Na2SO4, combined and concentrated in vacuo to give 0.3 g residue as a clear oil. This crude material was purified by Flash chromatography (2% acetone in CH2Cl2) to give 0.16 g of a clear oil in 94% yield, which resisted crystallization.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH2:10][C:11](Br)=[O:12].C(N(CC)CC)C>ClCCl>[Br:9][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4-iodoaniline (14.5 mmol) in anhydrous dichloromethane at 0° C. was added a-bromo-acetylbromide (1.4 mL) and triethylamine (15 mmol). The mixture was warmed to room temperature, stirred for 1 h, the solvent removed, and residue dissolved in 5% hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the organic layer washed with brine, dried (Na2SO4), filtered, and evaporated. The solid residue was purified by recrystallization form ethyl acetate to afford the desired intermediate.
Reaction SMILES: FC1C(F)=CC(F)=C(F)C=1.[F:11][C:12]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:13]=1[C:14]#[N:15]>>[F:11][C:12]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:13]=1[CH2:14][NH2:15]
Reactant: N#Cc1c(F)c(F)cc(F)c1F
Agent: Fc1cc(F)c(F)cc1F
Product: NCc1c(F)c(F)cc(F)c1F

Procedure:
From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, and tetrafluoroterephthalaldehyde was obtained in an amount of only 42.2 mol %. The amount of 2,3,5,6-tetrafluorobenzene was 1.75 mol %, and the amount of 2,3,5,6-tetrafluorobenzonitrile was 1.40 mol %. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 28.1 mol % of 2,3,5,6-tetrafluorobenzylamine was confirmed. The results are set forth in Table 2.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C([O:37]C(=O)CC(C)=O)C>C(Cl)Cl>[OH:8][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:2]1[NH:1][C:29](=[O:37])[C:28]1[CH:31]=[CH:32][C:25]([C:24]([F:34])([F:33])[F:23])=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)C(NC(=O)c2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
0.50 g (2.3 mmol) of t-butyl 3-amino-4-hydroxypiperidin-1-carboxylate (product of PREPARATION 83) and 0.32 mL, (2.3 mmol) of triethylamine was dissolved in 30 mL of methylene chloride, and 0.34 mL, (2.3 mmol) of 4-trifluoromethyl benzylchloride was dropwise added thereto while stirring at 0° C. for 1 hour, followed by addition of 100 mL of ethylacetoacetate and then washing with water. An organic layer dried over anhydrous magnesium sulfate. The reaction solution was filtered off and distilled off under reduced pressure, then the residue was purified by column chromatography to give 0.48 g (1.2 mmol) of the title compound in a total yield of 54%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].[N-:12]=[N+:13]=[N-:14].[Na+]>O1CCOCC1.O>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)(=[O:3])[CH3:2]
Reactant: CSC(=S)NCCNC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCn1nnnc1S
Yield: 43.2 %

Procedure:
To a solution of methyl N-(2-acetamidoethyl)dithiocarbamate (12.6 g.) in dioxane (40 ml.) was added a solution of sodium azide (6.4 g.) in water (40 ml.), and the mixture was heated under reflux for 4 hours. After dioxane was removed from the resultant mixture under reduced pressure, the residue was washed with ether (350 ml.) and adjusted to pH 1 with 10% hydrochloric acid. After the resultant solution was extracted with ethyl acetate (1.5 l.), the extract was dried over magnesium sulfate and the solvent was evaporated to dryness to give 1-(2-acetamidoethyl)-1H-tetrazole-5-thiol (5.3 g.) having m.p. 137.5° to 139.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([O:25]C)=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:6]=1[CH3:38])=[O:4].CO.[OH-].[Li+].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[C:6]=1[CH3:38])=[O:4]
Reactant: COC(=O)Cn1nc2n(c1=O)[C@H](c1ccc(C#N)cc1)C(C(=O)OC)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
To a solution of Intermediate 25 (240 mg, 0.46 mmol) in THF (3 mL), was added MeOH (3 mL) followed by lithium hydroxide (3M in water, 200 μL, 0.6 mmol). The reaction mixture was stirred at RT for 2 hours, and then the volatiles were removed in vacuo. The resultant residue was dissolved in water, and the solution thus obtained was made acidic by addition of 6 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield the title compound as a colourless oil (250 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:16][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: COc1cc(C2CCNCC2)ccc1N
Reactant: C=CS(C)(=O)=O
Solvent: ClCCl
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To 2-(methyloxy)-4-(4-piperidinyl)aniline (0.50 g, 2.4 mmol) in DCM (5 mL) was added methyl vinyl sulfone (0.25 g, 2.4 mmol). The mixture was stirred in a sealed tube overnight. Silica gel was added, the solvent was removed under vacuum, and the material was purified by silica gel chromatography. The desired fractions were combined and rotovaped to give the title compound of step B (0.45 g, 1.4 mmol, 58%) as an oil. 1H NMR (400 MHz, CDCl3) 6 1H NMR (400 MHz, d6-DMSO) δ 6.63-6.57 (m, 3H), 3.79 (s, 3H), 3.71 (br s, 2H), 3.13 (t, J=6.6 Hz, 2H), 3.01 (s, 3H), 2.97 (d, J=11.4 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H), 2.42-2.32 (m, 1H), 2.15-2.04 (m, 2H), 1.80 (d, J=12.1 Hz, 2H), 1.69-1.57 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH2:29]([NH2:32])[CH2:30][CH3:31].Cl>O.CO>[CH2:29]([N:32]1[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][C:11](=[O:18])[C:12]([C:13]([OH:15])=[O:14])=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:30][CH3:31]
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Reactant: CCCN
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1
Yield: 36 %

Procedure:
4.0 gms of 2,6-diphenyl-3-ethoxycarbonyl-pyr-4-one, 50 mls of glacial acetic acid were mixed. 8.1 gms of n-propylamine and 6 mls of water was added slowly at room temperature. After 3 hours an additional 14 mls of water, 12 mls of 6% HCl and enough methanol to bring everything into solution, was added. The next day this acidic reaction mixture was poured into water and extracted with methylene chloride (2×100 mls). Evaporation of the organic extracts yield 4.4 gms of crude nicotinate ester which was suspended in 50 mls of 5% aqueous NaOH and heated at 85° for 4 hours. The resulting solution was acidified with HCl and extracted with methylene chloride (2×50 mls). Evaporation of the solvent yielded a solid mass. recrystallization from ether provided 1.5 gms of 1-propyl-2,6-diphenyl-4-oxonicotinic acid. mp=166°-167°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C.O>ClCCl>[C:18]([O:1][CH2:2][C:3]1[C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[N:7][CH:6]=[C:5]([C:15](=[O:17])[CH3:16])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(CO)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCc1cc(C(C)=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.8 %

Procedure:
A mixture of 1-(5-(hydroxymethyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.16 g, 0.64 mmol, Step-6), acetic anhydride (0.18 mL, 1.91 mmol) and triethylamine (0.44 mL, 3.19) in dichloromethane (4 mL) is stirred at room temperature for 3 days. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo to give 0.16 g (86% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-8) without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([OH:19])=O)=[CH:11]2)=[O:5])[CH3:2].CC[N:22]=C=NCCCN(C)C.Cl.Cl.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[O:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]1[O:56][NH:57][C:58](=[O:66])[CH:59](N)[CH2:60][CH2:61][CH2:62][CH2:63][CH3:64].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17](=[O:19])[NH:22][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][C:58](=[O:66])[NH:57][O:56][CH:51]1[CH2:52][CH2:53][CH2:54][CH2:55][O:50]1)=[CH:11]2)[CH3:2]
Reactant: CCCCCC(N)C(=O)NOC1CCCCO1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)/C=C/c1ccc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc2[nH]c(C(=O)NCCCCCCC(=O)NOC3CCCCO3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
5-((E)-2-Ethoxycarbonyl-vinyl)-1H-indole-2-carboxylic acid (0.427 g, 1.6 mmol) was dissolved in anhydrous DMF (20 ml). EDCl.HCl (0.38 g, 2 mmol), Et3N (0.59 ml, 4.3 mmol), HOBt (0.27 g, 2 mmol) and 7 amino heptanoic acid (tetrahydropyran-2-yloxy) amide * (0.4 g, 1.6 mmol in anhydrous DMF 20 ml) were added and the reaction stirred at room temperature for 16 h under nitrogen. Water was added, the reaction mixture acidified to pH=6-7 (10% citric acid) and extracted with DCM. The organic layer was washed with 10% citric acid and saturated sodium hydrogen carbonate (×2). The solvent was removed in vacuo to give crude product which was purified by chromatography (EtOAc:hexane 1:2→EtOAc) to give the required product as a yellow solid (550 mg, 69% yield). LCMS purity 93%, m/z 488 [M++H]+
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.[F:16][C:17]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:18]=1[CH2:19][O:20][C:21]1[C:22]2[N:23]([C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.ClCCl>[F:16][C:17]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:18]=1[CH2:19][O:20][C:21]1[C:22]2[N:23]([C:28]([C:32]([NH:1][CH2:2][C@@H:3]3[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]3)=[O:33])=[C:29]([CH3:31])[N:30]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@@H]3CCCCN3)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At RT, 53 mg (0.25 mmol, 1.1 equivalents) of tert-butyl (2S)-2-(aminomethyl)piperidin-1-carboxylate were added to 75 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]-pyridine-3-carboxylic acid (Example 21A, 0.23 mmol, 1 equivalent), 90 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.24 mmol, 1.05 equivalents) and 88 mg of N,N-diisopropylethylamine (0.12 ml, 0.68 mmol, 3 equivalents) in 1.4 ml of DMF, and the mixture was stirred at RT overnight. After the reaction had ended, the mixture was purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions obtained were dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 66 mg (64% of theory; purity 95%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([NH:17][NH2:18])(=[O:16])[CH3:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=C[C:27]=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:18][NH:17][C:14](=[O:16])[CH2:15][CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(=O)NN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(=O)NNC(=O)CCNC(=O)OC(C)(C)C

Procedure:
25.00 g (132 mmol) 3-tert-butoxycarbonylamino-propionic acid, 11.45 g (130 mmol) ethanoic hydrazide, 50.91 g (159 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 50 ml diisopropylethylamine are stirred in 500 ml of tetrahydrofuran/dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is extracted with ethyl acetate and 10% potassium hydrogen carbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallised from isopropylether.