Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([CH:18]=C(C#N)C#N)[CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)C.[NH2:24][C:25]1[NH:26][C:27](=[O:32])[CH:28]=[C:29]([NH2:31])[N:30]=1>C(O)(=O)C>[NH2:24][C:25]1[N:26]=[C:27]([OH:32])[C:28]2[CH:4]=[C:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=3)[CH:18]=[N:31][C:29]=2[N:30]=1
Reactant: CCOC=C(C=C(C#N)C#N)CCc1ccc(C(=O)OC)cc1
Reactant: Nc1cc(=O)[nH]c(N)n1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCc2cnc3nc(N)nc(O)c3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Two grams of methyl 4-(3-ethoxymethylene-5,5-dicyanopent-4-en-1-yl)benzoate, 0.93 g of 2,4-diamino-6(1H)-pyrimidone, and 30 mL of acetic acid are heated at reflux with stirring for 4 hours. The reaction mixture is allowed to cool to room temperature and the solid which forms is collected by filtration, washed with water and diethyl ether and dried to yield methyl 4-[2-(2-amino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoate, m.p.>300° C; IR (KBr) vmax 3220, 2950, 1720, 1657, 1626, 1610, 1455, 1280, 1251, 1148, 1109, and 834 cm-1 ; 1H NMR (dTFA, d6DMSO) delta 8.38 (s 1H (7)-H), 7.99 (s, 1H, (5)-H), 7.55 (d, J=8.0 Hz, 2H, Ar), 6.87 (s, 1H (3)-H), 6.82 (d, J=8.0 Hz, 2H, Ar), 3.56 (s, 3H, --CH3), 2.77-281 (m, 2H, (6)-CH2 --), 2.67-2.73 (m, 2H, benzyl).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[O:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(OCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
3.6 ml (46 mmol) of trifluoroacetic acid is added to a solution of 1.56 g (4.64 mmol) of tert-butyl 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetate (prepared according to J. Heterocycl. Chem. (1994) 31, 1439-1443) in 20 ml of dichloromethane. The reaction mixture is stirred for 1 hour, concentrated under vacuum and the residue is dissolved in
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2].[H-].[Na+].Cl.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Cl>CN(C)C=O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][N:8]1[C:9]2[C:4](=[C:3]([CH2:1][CH3:2])[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=2)[CH:5]=[CH:6][C:7]1=[O:15]
Reactant: CCc1cc(CC)c2ccc(=O)[nH]c2n1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(CC)c2ccc(=O)n(CCN(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5,7-diethyl-1,8-naphthyridin-2(1H)-one (4.04 g., 0.02 mole) in 25 ml. of dry dimethylformamide under nitrogen atmosphere is added a 57% suspension of sodium hydride in mineral oil (0.84 g., 0.02 mole). This mixture is stirred at room temperature for 0.5 hours. Then a mixture of 2-dimethylaminoethyl chloride hydrochloride (3.17 g., 0.022 mole) and a 57% suspension of sodium hydride in mineral oil (0.93 g., 0.022 mole) in 25 ml. of dry dimethylformamide is added to the above suspension. The mixture is stirred at steam bath temperature overnight (16 hours). After the mixture is cooled to room temperature it is filtered to remove salt (2.6 g., theory 2.45 g.). Removal of the solvent under reduced pressure gives a pale tan waxy solid (4.8 g.). Several recrystalizations from hexane gives 1-(2-dimethylaminoethyl)-5,7-diethyl-1,8-naphthyridin-2(1H)-one melting at 59.5°-61° C.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15](=[O:18])[CH2:16][Cl:17])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl.CO>[ClH:17].[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15](=[O:18])[CH2:16][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCc2ccc(C(=O)CCl)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2ccc(C(=O)CN3CCCCC3)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 10 ml of dichloromethane was dissolved 1.50 g of 1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-chloro-1-ethanone obtained in Reference Example 2. To the solution was added 1.7 ml of piperidine, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into an aqueous solution of potassium carbonate, which was subjected to extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, from which was distilled off the solvent to leave an oily residue. To the residue was dissolved in 5 ml of methanol, to which was added 1.7 ml of 4N methanolic hydrochloric acid. Then the solvent was distilled off to leave 1.50 g of the title compound as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:7]=1.[C:33](O)(=[O:35])[CH3:34].CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:33]([NH:12][S:9]([CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])(=[O:11])=[O:10])(=[O:35])[CH3:34]
Reactant: CC(=O)O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide (0.05 g, 0.10 mmol) in dichloromethane (1 mL) was added acetic acid (0.007 g, 0.12 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide (0.030 g, 0.16 mmol), 4-dimethylaminopyridine (0.019 g, 0.16 mmol) and triethylamine (0.023 g, 0.23 mmol). The reaction was stirred at ambient temperature overnight. The reaction was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and the aqueous layer back extracted with dichloromethane (3×). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.039 g, LRMS: 526.20).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C([N:16](CC)CC)C.CS(Cl)(=O)=O.[OH-].[NH4+]>C(Cl)Cl.C(#N)C>[NH2:16][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccccc1C1CC1CO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccccc1C1CC1CN
Temperature: 25 °C
Yield: 13 %

Procedure:
A cold solution of 2-(2-(hydroxymethyl)cyclopropyl)benzonitrile (425 mg, 2.454 mmol) in methylene chloride (15 mL), and triethyl amine (1.368 mL, 9.81 mmol) was treated with methanesulfonyl chloride (0.287 mL, 3.68 mmol) dropwise with ice bath cooling. The cooling bath was removed, the reaction warmed to rt for 1 hr. The reaction was diluted with methylene chloride washed with water and brine, dried over magnesium sulfate, and concentrated to give a wax. A solution of the material in acetonitrile (15 mL) and ammonium hydroxide (2 mL, 51.4 mmol) was stirred for 16 h at rt. The reaction was concentrated to about ½ volume and diluted with ether. The suspension was extracted with 1N HCl. The acid extracts were made basic with 50% sodium hydroxide, then extracted with methylene chloride (4×). The organics were dried potassium carbonate and concentrated. The resulting dark wax (400 mg) was then purified on silica gel using 1-20% MeOH/methylene chloride to give an orange wax. The wax was triturated with acetone to give 2-(2-(aminomethyl)cyclopropyl)benzonitrile as a white solid (55 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ 7.91 (br. s., 2H), 7.80 (dd, J=7.8, 1.0 Hz, 1H), 7.65 (td, J=7.8, 1.3 Hz, 1H), 7.40 (td, J=7.6, 1.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 2.97 (t, J=6.9 Hz, 2H), 2.32-2.19 (m, 1H), 1.68-1.48 (m, 1H), 1.23 (dt, J=8.8, 5.2 Hz, 1H), 1.10 (dt, J=8.7, 5.2 Hz, 1H). LCMS: M+1=173.05.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:6]=1.[H][H]>CO.[Ni]>[NH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:8]=1)[C:4]([N:3]([O:2][CH3:1])[CH3:21])=[O:20]
Reactant: [H][H]
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: CON(C)C(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reaction time: 5 h
Yield: 45.2 %

Procedure:
N-Methoxy-N-methyl-5-nitro-3-pentafluorosulfanylbenzamide (4.2 g) was dissolved in methanol (120 ml), and Raney nickel (approx. 700 mg) was added. With a hydrogen balloon attached, hydrogenation was effected on a magnetic stirrer. After 5 h, the catalyst was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by means of preparative chromatography. The product-containing fractions were combined, freed of the acetonitrile, basified with sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.73 g of the desired compound were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH2:13]([O:15][CH2:16][CH2:17]O)[CH3:14]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:14][CH2:13][O:15][CH2:16][CH3:17])=[O:8])=[CH:3][C:2]=1[C:10]([O:12][CH2:17][CH2:16][O:15][CH2:13][CH3:14])=[O:11]
Reactant: CCOCCO
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Product: CCOCCOC(=O)c1ccnc(C(=O)OCCOCC)c1

Procedure:
As described in Example 26, 10 g of pyridine-2,4-dicarboxylic acid are reacted with ethylene glycol monoethyl ether via the acid chloride. The reaction mixture is worked up analogously to Example 26. The product is obtained as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:34]([S:36][C:37]1[N:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41](O)=[CH:42][CH:43]=2)[N:38]=1)[CH3:35]>C1COCC1>[CH2:34]([S:36][C:37]1[N:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41]([O:33][CH:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:26])[CH2:28][CH2:29]3)=[CH:42][CH:43]=2)[N:38]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCSc1ncc2ccc(O)cc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCSc1ncc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of triphenylphosphine (2 eq) in THF was added di-terbutylazodicarboxylate (2 eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that was added tert-butyl-4-hydroxypiperidine-1-carboxylate (5 eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 2-(ethylthio) quinazolin-7-ol (1 eq). The mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and purified by flash column chromatography (10% EtOAc/Hexane) to provide product as a white solid in 90% yield. ES/MS m/z 390.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH2:10]Br)=[C:6]([CH2:8]Br)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]([NH2:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:10][N:39]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:8]2)=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)cc(CBr)c1CBr
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
4.95 g of 5-bromo-1,2-bis(bromomethyl)-3-methoxybenzene (3-19) was dissolved in 150 ml of anhydrous DMF, to which 5.50 g of potassium carbonate and 4.30 g of tritylamine, and under an argon atmosphere, the resulting mixture was stirred at 90° C. for 8 hours. The reaction solution was poured into water, and extract with chloroform and the resulting organic layer was washed with saturated salt water, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and thereafter, the resulting residue was recrystallized with 2-propanol to obtain 3.35 g of 6-bromo-4-methoxy-2-tritylisoindoline (3-20).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Mg]Br)[CH3:11].[OH-].[Na+]>O1CCCC1>[CH2:7]([C:8]1([NH2:9])[CH2:11][CH2:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[Mg]Br
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
4.5 g (38 mmol) of phenylacetonitrile was dissolved in 50 mL of tetrahydrofuran, mixed with 12.4 mL (41.9 mmol) of tetraisopropyl propylorthotitanate and 78 mL (76 mmol) of 0.98M ethylmagnesium bromide in tetrahydrofuran and stirred at room temperature for 1 hour. After the stirring, 9.6 mL (78 mmol) of boron trifluoride ethyl ether complex was added, and the reaction solution was stirred at room temperature for another 1 hour. After completion of the reaction, 2 M aqueous sodium hydroxide was added, and the reaction solution was extracted with diethyl ether. After addition of 3 M hydrochloric acid, the organic layer was separated. The resulting aqueous layer was basified with 5 M aqueous sodium hydroxide and extracted with methylene chloride. The solvent was removed from the organic layer under reduced pressure to give 3.28 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]([F:23])([F:22])[F:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH:25]([CH2:28]Br)[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([C:20]([F:22])([F:21])[F:23])[N:9](/[CH:28]=[CH:25]/[C:26]#[N:27])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Reactant: N#CC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 41.1 %

Procedure:
From 4,5-bis(4-fluorophenyl)-2-trifluoromethyl-1H-imidazole (3.045 g), 2,3-dibromopropionitrile (5.33 g), anhydrous potassium carbonate (3.1 g) and triethylamine (5.2 ml) in dry DMF (19 ml) by the process as described for the preparation of Intermediate (3a) to afford a dark brown residue which was purified by FCC using gradient elution with System A (5-15% with 5% incremental increase of ethyl acetate per 500 ml eluant) to afford the title compound (1.449 g) as a white solid. νmax (CHBr3) 2229 cm-1 (C≡N).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O.O1CC[CH2:42][CH2:41]1>C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:41][CH3:42])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
1.3 mL (1.3 mmol) of aqueous 1 M sodium hydroxide solution are added to a solution of 0.44 g (0.86 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 10 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 6 hours. After cooling, the reaction is worked up by addition of 3 mL (3 mmol) of aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The product is recrystallized from a pentane/acetone mixture to give 0.33 g (78%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a cream-colored solid with a melting point of 103° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][CH:29]=[CH2:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1
Reactant: C=CCBr
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
First, 400 mg (1.2 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (intermediate 1) was dissolved in 2.0 ml of N,N-dimethylformamide, to which 257 mg (1.86 mmol) of potassium carbonate and 165 mg (1.36 mmol) of allyl bromide were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography, which afforded 405 mg (1.1 mmol) of 2-{4-chloro-2-fluoro-5-(2-propenyloxy)phenyl}-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (hereinafter referred to as intermediate 2), m.p. 79.8° C.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].NC1C=CC=CC=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(CBr)c1
Reactant: Nc1ccccc1N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc(CNc2ccccc2N2CCCCC2)c1
Yield: 87 %

Procedure:
To 1 g of 2-piperidinoaniline in 10 mL of DMF are added 795 μL of 3-methoxybenzyl bromide (1 equivalent) and 1.57 g of potassium carbonate (2 equivalents). The whole is heated to 100° C. for 2-3 hrs, until disappearance of the starting aniline. The medium is poured onto ice and then extracted with ethyl acetate. The organic phase washed with water is dried on magnesium sulfate, filtered and evaporated under reduced pressure. By silica gel chromatography of the residue (cyclohexane/ethyl acetate: 99/1) 1.46 g of the desired product may be isolated.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])[CH3:6].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:6][C:5]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of sodium ethoxide (6.81 g) in absolute ethanol (200 mL). was slowly added 2-acetylfuran (5.01 mL) at 0° C. The resulting solution was stirred at 0° C. for 2 hours, and diethyl oxalate (9.30 mL) was slowly added to the solution. The resulting solution was stirred for 18 hours, and the reaction was quenched with 1N hydrochloric acid solution. The resulting mixture was concentrated under reduced pressure, and residue was then extracted with methylene chloride. An organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give 10.0 g of 4-furan-2-yl-2,4-dioxo-butyric acid ethyl ester. This concentrate was used in the next steps without further purification.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[K+]>C(O)C.CO>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CN(C)C(=N)NC(=N)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen protection, to a 500 mL flask were added 16.6 g (0.1 eq.) metformin hydrochloride solid and 100 mL ethanol solvent, and the reaction was stirred under mild heating until the solid was completely dissolved, then was cooled to ambient temperature. To the reaction was added 105 mL (0.105 eq.) 1N potassium hydroxide in methanol, and stirred while the reaction temperature was controlled at no more than 40° C. After 1 hr, about 150 mL solvent was removed under reduced pressure prior to slowly cool to about 10° C., then precipitation was initiated. The reaction was suction filtered, the precipitate was washed 2× by fresh ethanol, and the filtrates were combined to give the free base of metformin in ethanol.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14](Cl)[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=3.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=3
Reactant: NCCCO
Reactant: FC(F)(F)Oc1ccc2c(c1)nc(Cl)c1ncc(Br)n12
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(Br)cnc12
Yield: 87.6 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-7-trifluoromethoxy-imidazo[1,2-a]quinoxaline (6.5 g, 17.7 mmol, 1 eq) in dioxane (87 mL) is added 3-aminopropan-1-ol (3.4 mL; 44.3 mmol; 2.5 eq). The resulting solution is then heated at reflux for 16 hours until completion of the reaction. The mixture is diluted with ethyl acetate (100 mL) and washed with a 1M aqueous solution of sodium hydroxide (50 mL). The organic layer is separated, dried over sodium sulphate and concentrated in vacuo to afford a beige solid. This powder is washed with diethyl ether to afford after filtration the title compound (6.3 g; 15.5 mmol; 87%) with a 99% HPLC purity.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:14])(=[O:13])[CH3:12].C(N(CC)CC)C>CC(O)CC>[C:11]([O:14][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCC(C)O
Product: CCOC(=O)CC(=O)COC(C)=O

Procedure:
71 ml of ethyl 4-chloro-3-oxobutyrate are reacted with 57 ml of acetic acid and 132 ml of triethylamine in 1 l of 2-butanol by the procedure described in Example 1.