Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([NH2:9])[NH:6][N:5]=1)([CH3:3])[CH3:2].[NH:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19](=O)[CH2:20][C:21](OCC)=[O:22])=[CH:18][C:13]=2[N:12]=[N:11]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[NH:9][C:7]4[N:6]([N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[C:21](=[O:22])[CH:20]=3)=[CH:18][C:13]=2[N:12]=[N:11]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: CC(C)c1n[nH]c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CC(C)c1nc2[nH]c(-c3ccc4[nH]nnc4c3)cc(=O)n2n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 19.3 %

Procedure:
To a solution of 3-isopropyl-1H-1,2,4-triazol-5-amine (100 mg, 0.79 mmol) in n-BuOH (1 mL) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (275 mg, 1.18 mmol) and TsOH (7 mg, 0.04 mmol), and the resulting mixture was stirred for 5 h at 130° C. The solids were collected by filtration and washed with MeOH (3×1 mL) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-isopropyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (45 mg, 19%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.[CH3:11][C:12]1[CH:18]=[C:17]([C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([CH3:25])=[CH:15][C:13]=1[NH2:14]>C(Cl)Cl>[CH3:6][N:7]([CH3:10])[CH:8]=[N:14][C:13]1[CH:15]=[C:16]([CH3:25])[C:17]([C:19]#[C:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:18][C:12]=1[CH3:11]
Reactant: Cc1cc(C#CC(C)(C)C)c(C)cc1N
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(N=CN(C)C)c(C)cc1C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
Phosphorus oxychloride (182 mg) was added to a mixture of 5 ml of dichloromethane and 145 mg of N,N-dimethylformamide at 25° C. After the mixture was stirred at 25° C. for 1 hour, 1 ml of a methylene chloride solution containing 200 mg of the 2,5-dimethyl-4-(3,3-dimethyl-1-butynyl)aniline (Compound 4-25) produced in Production Example 2 was added dropwise thereto. The mixture was stirred at 25° C. for 2.5 hours, and the reaction solution was then poured into ice water. The pH was adjusted to 11 with an aqueous 1 N potassium hydroxide solution, and extraction was performed 3 times with dichloromethane. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby obtaining 30 mg of N,N-dimethyl-N′-[2,5-dimethyl-4-(3,3-dimethyl-1-butynyl)phenyl]formamidine (Compound 52).
Reaction SMILES: [CH2:1]([S-])[CH3:2].[Na+].Cl[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]1[N:24]([CH3:25])[C:14]2=[N:15][CH:16]=[C:17]([S:19][C:20]([F:23])([F:22])[F:21])[CH:18]=[C:13]2[N:12]=1.CN1C(=O)CCC1>O>[CH2:1]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]1[N:24]([CH3:25])[C:14]2=[N:15][CH:16]=[C:17]([S:19][C:20]([F:23])([F:22])[F:21])[CH:18]=[C:13]2[N:12]=1)[CH3:2]
Reactant: Cn1c(-c2sccc2Cl)nc2cc(SC(F)(F)F)cnc21
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccsc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
0.32 g of sodium ethanethiolate was added to a mixture of 0.71 g of 2-(3-chloro-thiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5-b]pyridine and 4 ml of NMP, under ice cooling, and the mixture was stirred at 70° C. for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and applied to a silica gel column chromatography to obtain 0.57 g of 2-(3-ethylthiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (3)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:14]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: O[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CC[C@H](O)C1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (50 mg, 0.25 mmol), (3S)-pyrrolidin-3-ol (24.4 mg, 0.28 mmol) and BOP (116.0 mg, 0.26 mmol) in 0.4 mL DMF was added hunig base (0.066 ml, 0.38 mmol). The mixture was stirred at room temperature overnight and directly purified by prep. HPLC to provide (3S)-1-((1-(4-chlorophenyl)cyclopropyl)carbonyl)pyrrolidin-3-ol (20 mg). LCMS: m/z 266.0 (M+H)+; 553.1 (2M+Na)+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:32]=[CH:31][CH:30]=[CH:29][C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:26](=[O:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[O:10])=[O:7]>O.[OH-].[Na+].C(O)C>[Cl:3][C:4]1[CH:32]=[CH:31][CH:30]=[CH:29][C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]([OH:28])[CH3:27])=[CH:16][CH:17]=1)=[O:10])=[O:7]
Reactant: CC(=O)C(Oc1ccc(NC(=O)NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O)C(Oc1ccc(NC(=O)NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of 0.1 g of sodiumborohydride in a mixture of 0.5 ml of water and 0.1 ml of 2 N sodium hydroxide solution was added to a suspension of 1.55 g of N-(2-chlorobenzoyl)-N'-[4-(α-acetylbenzyloxy)phenyl]urea obtained according to the method described in example 1, in 20 ml of ethanol. After stirring for another hour at room temperature the precipitate was sucked off, washed with ethanol and dried; 0.91 g of the desired product was obtained with a melting range of 142°-144° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])(=[O:17])=[O:16]
Reactant: CON(C)C(=O)c1ccnc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccnc(NS(C)(=O)=O)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
2-Amino-N-methoxy-N-methyl-isonicotinamide (575 mg, 3.16 mmol) was dissolved in pyridine (4 mL), followed by the addition of methanesulfonyl chloride (0.73 mL, 9.48 mmol). The reaction was subsequently warmed to 40° C. and stirred 5 h. The resultant mixture was quenched with 10% HCl, diluted with EtOAc, and the organic layer washed with 10% HCl and saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to produce the desired sulfonamide.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[N:21]=[C:15]2[NH:16][C:17](=[O:20])[CH2:18][CH:19]=[C:14]2[N:13]=1.[H][H].[ClH:25].O>CN(C)C=O.[Pd]>[ClH:25].[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[N:21]=[C:15]2[NH:16][C:17](=[O:20])[CH2:18][CH:19]=[C:14]2[N:13]=1
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C1=NC2=CCC(=O)NC2=N1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cc(N)ccc1C1=NC2=CCC(=O)NC2=N1

Procedure:
An amount of 1.7 gm of 2-(2-dimethylamino-4-nitro-phenyl)-4H-imidazo[4,5-b]pyridin-5-one is dissolved in 20 ml of dimethylformamide and mixed with 0.2 gm of 10% palladium/charcoal. The mixture is hydrogenated for three hours with hydrogen at ambient temperature under 5 bars of pressure. The mixture is filtered off from the catalyst, the mother liquor is mixed with 100 ml each of ether and of ethyl acetate, and finally 3 ml of etheral hydrochloric acid are added. The precipitate is recrystallized from methanol. After drying over phosphorus pentoxide and potassium hydroxide, a product is obtained which contains 1.5 mol of hydrochloric acid and 0.5 mol of water to 1 mol of base.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:10]2[CH:11]=[C:12]([C:15](=[CH2:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:23].[Br:24]N1C(=O)CCC1=O>O1CCCC1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:10]2[CH:11]=[C:12]([C:15](=[CH:22][Br:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:23]
Reactant: C=C(c1ccccc1)c1ccc2nc(N)n(C3=NCCS3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Nc1nc2ccc(C(=CBr)c3ccccc3)cc2n1C1=NCCS1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a stirred solution of 1.6 g. (5 mM) of 1-(thiazolin-2-yl)-2-amino-6-(α-methylenebenzyl)benzimidazole in 150 ml. of tetrahydrofuran were added in one portion 900 mg. (0.5 mM) of N-bromosuccinimide. The reaction mixture was stirred at room temperature for seventy-two hours, and then was concentrated to a volume of about 10 ml. by evaporation of the solvent under reduced pressure. The reaction mixture was diluted with 20 ml. of water, and the crystalline precipitate that formed was collected by filtration and identified as 600 mg. of 1-(thiazolin-2-yl)-2-amino-6-(α-bromomethylenebenzyl)benzimidazole. M.P. 197°-199° C. Yield 30%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][CH3:15])[CH:8]=[CH:7]2.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.O>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][CH3:15])[CH:8]=[CH:7]2
Reactant: BrCCCCCCCCBr
Reactant: COc1ccc2cc(O)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(OCCCCCCCCBr)ccc2n1
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 40 mg) was suspended in DMF (2 ml), and was cooled to 0° C. in ice water bath. 6-Hydroxy-2-methoxyquinoline (171 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. 1,8-Dibromooctane (0.37 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (225 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].[C:8](OC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.C(=O)([O-])[O-].[K+].[K+]>O>[OH:13][C:8]1[CH:9]=[C:10]([CH3:12])[N:5]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[N:4]=1
Reactant: COC(=O)CC(C)=O
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reaction time: 72 h
Yield: 46 %

Procedure:
A mixture of 44.4 g (0.28 mole) trichloroacetamidine, 32.0 g (0.28 mole) methyl acetoacetate, 37.5 g (0.28 mole) potassium carbonate, and 450 ml water was stirred for 3 days. A trace of solid was removed by filtration and the filtrate was made acidic with hydrochloric acid. The product precipitated out to give 28.9 g (46% yield; (mp 173°-174° C.). The structure was confirmed via mp*, infrared and elemental analysis.
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][C@@H:15]([OH:28])[C@@H:16]2[NH:26][CH3:27])[CH2:8]1)(=O)C.O>C(O)C>[CH3:27][NH:26][C@H:16]1[C@H:15]([OH:28])[CH2:14][C@H:13]2[C@H:12]3[C@H:21]([CH2:20][CH2:19][C@:17]12[CH3:18])[C@:22]1([CH3:25])[C:9]([CH2:8][C@@H:7]([OH:6])[CH2:24][CH2:23]1)=[CH:10][CH2:11]3
Reactant: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
Sodium hydroxide solution (1.63 ml; 4 N) was added to a solution of 17β-methylamino-androst-5-ene-3β,16α-diol 3-acetate (1.63 g) in ethanol (32.6 ml) and the resultant solution was refluxed for 1 h. Water (350 ml) was added and the precipitated crude product was filtered off and washed with water. The product was dissolved in a mixture of dichloromethane-methanol (≈1:1) and treated with charcoal. After filtration through dicalite, the filtrates were evaporated to dryness and the resultant offwhite solid was crystallised from methanol-dichloromethane-ether to give pure 17β-methylamino-androst-5-ene-3β,16α-diol as needles (1.25 g; 86.8%), m.p. 241°-246° C. (decomp.), [α]D -100.2° (c 0.93 in pyridine).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([CH2:12][CH2:13][P:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:42]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([C:9](=[O:11])[NH:50][CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:43][CH:44]=1)[CH2:12][CH2:13][P:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(CCP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Reactant: NCCc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC(CCP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)NCCc1ccc(-c2ccccc2)cc1

Procedure:
A solution of the compound of Example 77 (770 mg, 1.67 mmol) in anhydrous DMF (2 mL) was treated with DIEA (1.5 mL), 4-biphenylethyl amine (672 mg, 3.34 mmol), and TBTU (775 mg, 2.34 mmol). The reaction mixture was stirred for 24 h at room temperature after which HCl (1M, excess) was added. The mixture was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed with 50% ethyl acetate in hexanes and the desired product was obtained as a white solid. 1H NMR (CDCl3, 400 MHz: 1.41(s, 9H); 1.61-1.87(m, 4H); 2.15, 2.59(2dd, J1=16.4 Hz. J2=4.2 Hz, 2H); 2.67(m, 1H); 2.80(m, 2H); 3.49(m, 2H); 4.96(m, 4H); 6.35(t, J=5.6 Hz); 7.32(m, 13H); 7.42(m, 2H); 7.55(m, 4H); 31P NMR(CDCl3, 400 MHz): 33.05.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>>[CH:5]([C:4]([CH:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])([CH3:7])[CH3:6]
Reactant: CC(C)C(=CCBr)C(C)C
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)C(=CCS(=O)(=O)c1ccccc1)C(C)C

Procedure:
Using the procedure of Example I, 1-bromo-3-isopropyl-4-methyl-2-pentene was reacted with sodium phenyl sulfinate to form (3-isopropyl-4-methyl-2-pentenyl)-phenyl sulfone having a melting point of 50° C. which was then reacted with ethyl β,β-dimethylacrylate to form ethyl dl-trans 3,3-dimethyl-2-(2'-isopropyl-3'-methyl-1'-butenyl)-cyclopropanecarboxylate. The said ethyl ester was hydrolyzed under alkaline conditions to form dl-trans 3,3-dimethyl-2-(2'-isopropyl-3'-methyl-1'-butenyl)-cyclopropane carboxylic acid having a melting point of 135° C. which was then reacted with thionyl chloride to form dl-trans 3,3-dimethyl-2-(2'-isopropyl-3'-methyl-1'-butenyl)-cyclopropanecarboxylic acid chloride having a boiling point of 78° to 80° C. at 0.1 mm Hg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCCO)C>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Solvent: CCOCCO
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 180 mg (0.96 mmol) of 4-phenoxyaniline in 5 mL of 2-ethoxyethanol is heated at reflux temperature for 3 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with saturated sodium bicarbonate, followed by brine, then dried over sodium sulfate and filtered through a pad of diatomaceous earth. Concentration in vacuo yields 115 mg (35%) of a beige solid, mp 175–179° C.
Reaction SMILES: [CH2:1]([O:3]C1N=C(C(O)=O)C=C(CC)N=1)C.C([O:17][C:18]([C:20]1[CH:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1)=[O:19])C.CC([O-])(C)C.[K+]>CO>[CH2:26]([C:24]1[N:23]=[C:22]([O:3][CH3:1])[N:21]=[C:20]([C:18]([OH:17])=[O:19])[CH:25]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CCOc1nc(CC)cc(C(=O)O)n1
Reactant: CCOC(=O)c1cc(CC(C)C)nc(S(C)(=O)=O)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COc1nc(CC(C)C)cc(C(=O)O)n1

Procedure:
The title compound is obtained as a yellow oil (82 mg) in analogy to 2-ethoxy-6-ethyl-pyrimidine-4-carboxylic acid starting from 6-isobutyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester, KOtBu and methanol; LC-MS: tR=0.77 min, [M+H]+=210.96.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[N:10]([CH2:20][CH3:21])[CH2:11][CH2:12][NH:13]C(=O)C(F)(F)F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH2:1]([O:8][C:9](=[O:22])[N:10]([CH2:11][CH2:12][NH2:13])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.7 %

Procedure:
To a solution of compound N (24.9 g, 78.2 mmol) in MeOH (300 ml) was added a solution of LiOH (3.8 g, 156 mmol) in water (30 ml). The reaction mixture was stirred at room temperature for 5 h. Next the solvents were evaporated to ¾ of initial volume followed by the dilution with water (200 ml). The solution was extracted with EtOAc (200 ml×2) and the organic layer was washed with brine (100 ml), dried over MgSO4 and evaporated in vacuo. Residue was dissolved in ether (200 ml) and treated with 2 N HCl/ether (200 ml). The formed precipitate was filtered, washed with ether and dried in vacuum to provide hydrochloride salt of compound O (12.1 g, 46.7 mmol) as white solid. LC-MS [M+H] 222.9 (C12H18N2O2+H, calc: 223.2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=O)=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([Cl:15])[CH:11]2[CH2:13][CH2:12]2)=[CH:4][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(F)nc1)C1CC1
Solvent: ClCCl
Product: Fc1ccc(N=C(Cl)C2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
N-(2-fluoro-5-pyridyl)-cyclopropane carboxamide (2.0 g, 0.011 mol) was added portionwise to a stirred solution of phosphorus pentachloride (2.31 g, 0.011 mol) in dichloromethane (20 ml) under a nitrogen atmosphere at room temperature. After complete addition the mixture was stirred at room temperature for one hour and then heated at reflux for a further one hour. The reaction mixture was then evaporated under vacuum to gave N-(2-fluoro-5-pyridyl)-cyclopropylmethanimidoyl chloride (2.1 g, 96%) which was used in Stage 3 without further purification or characterisation.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28]([C:24]4[O:23][CH:27]=[CH:26][CH:25]=4)=[O:29])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccco4)cc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and furan-2-carbonyl chloride (0.39 g, 3.00 mmol) in CH2Cl2 (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 18 h, the product was isolated by filtration, washed with CH2Cl2 (10 mL) and dried in vacuo to give furan-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.86 g, 75% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.11 min (96.16%); mp: 180-182° C.; 1H NMR (DMSO-d6) δ 1.94-2.17 (m, 1H, CHH), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.59 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 6.65 (dd, J=1.8, 3.5 Hz, 1H, Ar), 7.15 (d, J=3.6 Hz, 1H, Ar), 7.74-7.85 (m, 2H, Ar), 7.85-7.97 (m, 2H, Ar), 9.12 (t, J=6.1 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 41.87, 48.99, 111.93, 113.86, 121.97, 123.54, 129.81, 131.59, 133.44, 145.28, 147.39, 147.52, 157.93, 166.97, 167.10, 169.80, 172.72; LCMS: MH=382; Anal Calcd for C19H15N3O6+0.1H2O: C, 59.56; H, 4.00; N, 10.97. Found: C, 59.26; H, 3.45; N, 10.80.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:29][CH2:30]2)[CH:24]=1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: CC(C)Oc1ccc(Cl)cc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)Oc1ccc(Cl)cc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.206 g, 0.887 mmol, 1 eq) and 1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.328 g, 0.977 mmol, 1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.535 g, 2.524 mmol, 2.84 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with Ethyl Acetate and quenched with saturated NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.164 g, 39%). MS: APCI: M+1: 471.2 (Exact Mass: 470.21).