Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31]>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30]([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:6]1[CH:7]=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:31]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCCNc1ccc(OC)c(-c2ccccc2)c1
Product: COc1ccc(Cl)cc1C(=O)N(CCCC(=O)O)c1ccc(OC)c(-c2ccccc2)c1
Yield: 70 %

Procedure:
Analogously to Example 59, reacting 7.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)aminobutyrate with 4.6 g of 5-chloro-2-methoxybenzoyl chloride, followed by saponification of the intermediate product, yields 7.1 g (70.1% of theory) of 4-[5-chloro-2-methoxy-N-(6-methoxybiphenyl-3-yl)benzamido]-butyric acid, MP 155° to 156°.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C-:20]#[N:21].[K+].O>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([C:20]#[N:21])[C:3]2=[O:19])=[CH:13][CH:14]=1
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Temperature: 140 °C
Yield: 65.1 %

Procedure:
A mixture of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (10.0 g) and potassium cyanide (2.5 g) in dry dimethylformamide (100 ml) was heated at 140° C. for 24 hours. The mixture was added to water and the product was extracted into chloroform. Evaporation of the solvent and crystallisation of the residue from ethanol gave the title compound (6.3 g) mp 232°-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[CH3:22][C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])([CH3:26])[C:24]#[CH:25].O1CCCC1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:23]([CH3:22])([CH3:26])[C:24]#[CH:25])[CH:28]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(C)=O)sc4c3)c2)c1
Yield: 22.3 %

Procedure:
Using N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (201 mg, 1.07 mmol), tetrahydrofuran (4 mL), N,N-dimethylformamide (10 μL), oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (4 mL), and in the same manner as in Example A40(xi), the title compound (56 mg, 22%) was obtained as a colorless solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)(=O)C.Cl>CO.O1CCCC1.[OH-].[Li+]>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:14]#[N:15]
Reactant: CC(=O)OCCOc1cccc(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-(3-Cyanophenoxy)ethyl acetate (3.01 g, 14.7 mmol) obtained in Step 1 was dissolved in a mixed solvent of methanol and tetrahydrofuran (1:1), and 2N lithium hydroxide solution (14.7 ml) was added under ice-cooling. The mixture was stirred at room temperature for 45 min, 3N hydrochloric acid (10 ml) was added under ice-cooling, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 85:15-55:45) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].[Cl-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[N:10]=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1c(Br)cnc2[nH]cnc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)c(Br)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
6-Bromo-7-chloro-3H-imidazo[4,5-b]pyridine (1.07 g, 4.60 mmol) in N,N-dimethylformamide (12 mL) was cooled to 0° C., mixed with sodium hydride (55 wt % dispersion in mineral oil, 300 mg, 6.88 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (12.0 mL, 6.78 mmol) and stirred at room temperature for 3 hours. After addition of saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1 (v/v)) to give the title compound as a yellow oil (640 mg, yield 38%).
Reaction SMILES: [CH2:1]([N:7]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:8](=[O:31])[CH2:9][C:10](=[O:30])[CH2:11][CH:12]([OH:29])[CH2:13][C:14]1([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[S:19][CH2:18][CH2:17][CH2:16][S:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:32]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:31])[CH2:9][CH:10]([OH:30])[CH2:11][CH:12]([OH:29])[CH2:13][C:14]1([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[S:15][CH2:16][CH2:17][CH2:18][S:19]1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCN(CCCCCC)C(=O)CC(=O)CC(O)CC1(CCc2ccc(O)cc2)SCCCS1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCN(CCCCCC)C(=O)CC(O)CC(O)CC1(CCc2ccc(O)cc2)SCCCS1
Reaction time: 3 h

Procedure:
A solution of the ketone 6e (242 mg, 0.44 mmol) in 6 mL of CH2Cl2 is added at 0° C. to a suspension of NaBH4 (50 mg, 1.32 mmol) in 9 mL of MeOH. After stiffing for 3 h at 0° C., the reaction medium is quenched by the addition of a saturated aqueous solution of NH4Cl. After dilution of the reaction medium in a CH2Cl2 and H2O mixture, it is extracted with CH2Cl2. The organic phases are then combined, dried over MgSO4, filtered and concentrated under vacuum. Purification is carried out on a silica column (cyclohexane/AcOEt 8:2) in order to produce the mixture of 4 non-separable diastereoisomers of the expected alcohol (173 mg, 0.03 mmol, 76%) in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:39])=[CH:33][CH:34]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: COC(=O)c1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 33A and methyl-4-bromobenzoate were processed as described in Example 52A to provide the title compound. MS (ESI+) m/z 519 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]=O>>[C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][CH:4]=1)[C:1](=[O:12])[O:11][CH2:13]2)([OH:8])=[O:7]
Reactant: C=O
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc2c(c1)COC2=O

Procedure:
In the method of the invention, the terephthalic acid is condensed with paraformaldehyde liberating water, which reacts with the SO3. When the reaction is complete, 5-carboxyphthalide may be isolated as follows. The reaction mixture is hydrolysed with water. The condensed product, 5-carboxyphthalide inclusive possible diphthalide impurities may then be filtered off, and the 5-carboxyphthalide may be dissolved in aqueous medium by adjusting pH to about 6.7 to 7.3, leaving possible diphthalide impurities in the solid phase The diphthalide present may be filtered off whereupon 5-carboxyphthalide may be precipitated by acidification, filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[OH:10])=[O:6])[CH3:3].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CN(C)C=O>[CH3:15][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[O:10][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])=[O:6])[CH3:3]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-L-threonine (5.02 g., 22.9 mmol.) in dry dimethylformamide (10 ml.) was added dropwise over a period of 30 minutes to a cooled (0° C.) suspension of 60% sodium hydride (1.93 g., 48.25 mmol., 2.11 eq.) in dry dimethylformamide (40 ml.). The reaction was stirred at 0° C. until the frothing subsided (about 3.5 hours). The reaction mixture was treated dropwise with 1-fluoro-2-nitrobenzene (2.67 ml., 25.2 mmol., 1.1 eq.) over a period of 20 minutes and stirred at 0° C. under argon for 2 hours. The reaction mixture was then placed in the cold room (5° C.) and stirred overnight. The reaction mixture was poured into ice-water (500 ml.) and extracted with ethyl ether (2×200 ml.). The aqueous phase was brought to pH 1.0 with 6N hydrochloric acid (200 ml.) and extracted with ethyl acetate (3×300 ml.). The combined ethyl acetate extracts were washed with water (2×300 ml.), and brine (300 ml.), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude residue was loaded onto celite and purified by chromatography on a 10×20 cm. silica gel column. Elution with methylene chloride (3 l.), 99:1 methylene chloride:methanol (2 l.), 95:5 methylene chloride:methanol, and 100:5:0.5 methylene chloride:methanol:acetic acid (5 l.) gave 6.07 g. of title compound. TLC (methylene chloride:methanol:acetic acid, 100:5;0.5) Rf =0.16.
Reaction SMILES: [CH2:1]([CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:15][CH2:16][O:17][C:18](/[C:20](/Cl)=[N:21]\[OH:22])=[O:19]>C1(C)C=CC=CC=1>[O:14]=[C:11]1[N:10]2[CH:4]([CH2:1][CH:2]3[O:22][N:21]=[C:20]([C:18]([O:17][CH2:16][CH3:15])=[O:19])[CH2:3]3)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]2=[N:13][O:12]1
Reactant: C=CCC1CCCCc2noc(=O)n21
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=NOC(CC2CCCCc3noc(=O)n32)C1
Reaction time: 18 h
Yield: 74.6 %

Procedure:
To a solution of 0.5 g (2.6 mmol) of the product of Example 6 in 100 mL of toluene was added 0.8 g (5.2 mmol) of ethyl chlorooximidoacetate (Aldrich). This solution was brought to reflux and stirred for 18 hours. All solvent was removed in vacuo and the residue purified via C-18 chromatography (0-60% acetonitrile/water, 25 min.) with the product eluting at 54% acetonitrile. Concentration of the relevant fractions afforded 0.6 g (75% yield) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:11]([C:12]1[NH:8][C:4]2[C:5]([CH:14]=1)=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[CH3:10])=[O:15])[CH3:18]
Reactant: Cc1c(F)cccc1NN
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(F)c(C)c2[nH]1
Temperature: 0 °C
Reaction time: 15 h
Yield: 12.7 %

Procedure:
3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (6.9ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g,0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+)
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH3:19])=[C:12]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])([CH3:7])[CH3:6])C.[OH-].[K+]>CO.O>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:28])=[O:3])[CH:10]=2)[N:14]([CH3:18])[C:13]=1[CH3:19]
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1OC)c(C)n2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1c(C)n(C)c2ccc(OC(C)(C)C(=O)O)cc12

Procedure:
One gram (2.6 m mole) of 2-[3-(2-methoxy-phenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid ethylester was dissolved in 18 ml of methanol and mixed with a solution of 0.35 g of potassium hydroxide in 2 ml of water. Within three to four hours 6 ml of water were added dropwise at room temperature so slowly that no ester precipitated. After stirring of the mixture for two to three hours, the methanol was distilled off at the rotation evaporator. Subsequently 20 ml of water were added and the alkaline solution was extracted twice with ether. After the aqueous phase was acidified with hydrochloric acid, the aqueous phase was extracted with ether. The ether extracts were dried over sodium sulfate. After the ether was distilled off, the residue obtained was treated with petroleum ether, whereby the crystalline acid was obtained.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](=[O:27])[NH:36][CH2:35][CH2:34][C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
18.9 g of N-(Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are added to a cooled solution of 20.04 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester, 14.9 g of 4-methoxyphenethylamine, 16.9 ml of diisopropylethylamine and 13.2 g of 1-hydroxy-benzotriazole in 250 ml of CH2Cl2. The reaction mixture obtained is stirred at rt for 16 hours, the reaction is quenched with aq. 2N HCl solution and the aq. phase obtained is extracted with CH2Cl2. The combined organic phases obtained are washed with aq. 2N HCl solution, brine and aq. saturated NaHCO3 solution, dried and solvent is evaporated. The residue obtained is purified by recrystallisation with EtOAc/hexane (1/3) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH3:14])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH2:14][Br:16])[CH3:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1CBr
Reaction time: 8 h

Procedure:
2-Methyl-4-nitro-benzoic acid ethyl ester (6.0 g, 28.7 mmol), N-bromosuccinimide (5.4 g, 30.3 mmol), and benzoyl peroxide (0.695 g, 2.87 mmol) were combined in CCl4 (250 mL). The reaction was heated to reflux and stirred under a halogen lamp overnight. After aqueous work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[Na].Cl>C(O)(C)C>[OH:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@@H:15]([OH:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: C[C@H](O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
To a stirred solution of 3α-acetoxy-5α-pregn-16-en 20-one (970 mg, 358.5 g/m, 2.7 mmol) in 130 mL of dry isopropanol was added sodium metal (8.0 g, 23 g/m, 348 mmol) slowly in small portions over 1 hr. After refluxing for 1 hour and additional amount of sodium (3.5 g) was added and reflux continued for 1 hour. The reaction mixture was acidified with 10% HCl and extracted with chloroform. The organic phase was dried over magnesium sulfate and concentrated to give the crude product. Recrystallization from acetone with cooling in the freezer gave 80 mg of a mixture (93:7) of 20α and 20β respectively. Additional recrystallization from methanol resulted in the pure titled product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.Cl.[NH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31].N1C=CC=CC=1>CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1
Reactant: NN1CCCC1=O
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(C)c1nnc2ccc(CC(=NN3CCCC3=O)c3ccc(F)cc3F)nn12
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.20 g, 0.63 mmol, Preparation #K.1), 1-aminopyrrolidin-2-one hydrochloride (0.13 g, 0.95 mmol, prepared according to WO02/094833 Preparation #38), pyridine (0.15 mL, 1.9 mmol), and HOAc (1.2 mL) was sonicated to give a solution in a sealed vial. After stirring for about 16 h, additional 1-aminopyrrolidin-2-one hydrochloride (0.086 g, 0.632 mmol) was added and the resulting solution was stirred at ambient temperature for about 2 d. The reaction was then concentrated under reduced pressure and purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give impure 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.16 g) as an oil that was carried on without further purification. A 10 mL round-bottomed flask equipped with reflux condenser and outfitted with a nitrogen inlet adapter was charged with 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.060 g, 0.15 mmol) in toluene (1.5 L) to give a yellow solution. Sodium ethoxide (0.020 g, 0.30 mmol) was added in one portion to give a yellow suspension. The reaction mixture was heated to reflux for about 5 h. The reaction mixture was allowed to cool to ambient temperature and continued stirring for about 2 d. The reaction mixture was diluted with water (5 mL) adjusted to about pH 2 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. The product-containing fractions were concentrated under reduced pressure and the resulting material was crystallized from EtOAc/heptane to give the title compound (0.031 g, 54%) as orange needles: LC/MS (Table 1, Method b) Rt=2.44 min; MS m/z: 381.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1>CN(C)C=O.CO>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])=[N:16]2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc2ccccc2n1
Temperature: 4 °C
Yield: 26.8 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 2-quinolinecarboxylic acid (10.4 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (7.2 g). After cooling at 4° C., the crystallized solid is separated by filtration, washed with distilled water (5×50 cc) and air-dried. The product obtained (7.4 g; m.p. 260° C.) is dissolved in a mixture of dimethylformamide (200 cc) and methanol (200 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with methanol (3×15 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)quinoline-2-carboxamide (3.6 g), m.p. 275° C., is obtained.