Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[Br:13]Br.C(Cl)(Cl)Cl.C(OCC)(=O)C>O>[Br:13][CH2:2][C:1](=[O:3])[CH:4]([CH:10]([CH3:11])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)CBr)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-acetyl-3-methylbutanoate (5.10 g, 29.6 mmol) in water (10 mL) at 0° C. was added bromine (1.53 mL, 29.6 mmol) dropwise over 2 h. Chloroform (30 mL) was added and the resulting solution was stirred at rt for 16 h. Ethyl acetate (300 mL) was added to the reaction solution and the organic phase was dried over sodium sulfate and concentrated to give the title compound. 1HNMR (500 MHz, CDCl3), δ4.300-4.282 (m, 2H), 2.601-2.575 (m, 1H), 2.406 (s, 2H), 1.331-1.303 (t, J=7.1 Hz, 3H), 1.085-1.072 (d, J=6.5 Hz, 3H), 1.048-1.035 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH:11]=[O:12])[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][OH:12])[C:7]([C:13]([F:14])([F:16])[F:15])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 39.9 g (156.9 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 300 ml of methanol was cooled to 0° C. Thereto was gradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 37.7 g (yield: 93.6%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][Cl:37].O>CN(C)C=O>[Cl:37][CH2:36][CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (86 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (330 mg) and 1-bromo-2-chloroethane (1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give 1-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (75 mg, yield 74%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>O1CCCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CSc1nccc(I)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(C(=O)Cc2ccc(F)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
20 g (79 mmoles) of 4-iodo-2-methylthiopyrimidine in 165 mL of tetrahydrofuran under argon is cooled to −70° C. 45.5 mL of isopropylmagnesium chloride (2M in THF) is then slowly added to the reaction mixture, keeping the temperature at −70° C. After 30 min., a solution of 4-fluorophenyl acetyl chloride (13.7 g, 79 mmoles) in 65 mL tetrahydrofuran is added dropwise to the reaction mixture which is further stirred at −78° C. for 1 hour and allowed to reach 0° C. After 30 min. at 0° C., the reaction is poured into ice-water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the oily purified by chromatography on silica gel (ethyl acetate/hexane 4/1) affording 9.5 g of 2-(4-Fluoro-phenyl)-1-(2-methylthio-pyrimidin-4-yl)-ethanone as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.IC.[CH2:29](Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(NCc3ccccc3)c12
Reactant: ClCc1ccccc1
Solvent: CI
Product: O=c1c(-c2ccc(Cl)cc2)cn(Cc2ccccc2)c2ccnc(NCc3ccccc3)c12

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-benzylamino-1,6-naphthyridine and iodomethane was replaced with benzyl chloride. MS 462 (M+1)+.
Reaction SMILES: [CH2:1]([PH:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4].[CH2:10]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH:23]=[O:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C>[CH2:10]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH:23]([P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[O:6][CH2:7][CH3:8])[OH:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[PH](=O)OCC
Reactant: O=CCCNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCP(=O)(OCC)C(O)CCNC(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1.50 g of ethyl (n-butyl)phosphinate, 1.01 g triethylamine and 2.07 g 3-(N-benzyloxycarbonylamino)propionaldehyde is heated to 100° C. for 4 hours. After this time the mixture is cooled to 20° and the volatile components are removed in high vacuum. Chromatography of the residue on silica gel affords ethyl 3-(N-benzyloxycarbonylamino)-1-hydroxy-propyl(n-butyl)phosphinate as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][CH2:12][OH:13].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(C2OCCCO2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
A mixture containing 3-bromobenzaldehyde (135; 18.5 g, 100 mmol), propane-1,3-diol (9.1 g, 120 mmol) and TsOH (0.1 g) in toluene (200 mL) was stirred under reflux in a Dean-Stark water separator for 18 h. Upon cooling to room temperature, the mixture was washed with 5% aqueous Na2CO3 (200 mL), dried (Na2SO4) and concentrated under reduced pressure to afford essentially quantitative yield of crude 2-(3-bromophenyl)-1,3-dioxane 136 as a yellow oil (25 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH3:22])[C:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:10]2[N:9]([CH3:22])[C:8]3[CH:23]=[CH:24][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[CH:15][CH:16]=1)#[N:21]
Reactant: COC(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)ccc21

Procedure:
5.0 g of 2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid-methyl ester (15.7 mmol) are dissolved in 50 ml of methanol, treated with 20 ml of an aqueous sodium hydroxide solution(1 N) and boiled under reflux for 0.5 hours. It is then treated with 20 ml of an aqueous solution of hydrochloric acid (1 N) and diluted with water. The precipitated crystals are filtered off, and washed with water, acetone and ether. The raw product obtained is re-crystallized from dimethyl formamide. Yield: 4.5 g (94%); MPt.: >220° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:22])[N:18]([CH3:21])[CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[F:29][C:30]([F:42])([F:41])[C@@:31]([O:36][Si](C)(C)C)([CH3:35])[C:32](Cl)=[O:33].NC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:8]([F:9])=[C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:22])[N:18]([CH3:21])[CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32](=[O:33])[C@:31]([OH:36])([CH3:35])[C:30]([F:42])([F:41])[F:29]
Reactant: CCN(C)C(=O)c1ccc(Sc2ccc(N)c(Cl)c2F)cc1
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Nc1ccccc1
Product: CCN(C)C(=O)c1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2F)cc1
Reaction time: 4 h
Yield: 47.9 %

Procedure:
2-Chloro3-fluoro-4-[4-(N-methyl-N-ethylcarbamoyl)phenylsulphanyl]aniline (Method 83; 580 mg, 1.7 mmol) was dissolved in DCM (6 ml) and pyridine (0.28 ml) was added. (S)-3,3,3-Trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (508 mg) was dissolved in DCM (1 ml) and added to the aniline. The solution was stirred for 4 hours and then washed with HCl (2 M) to remove excess pyridine. The organic layer was evaporated to dryness, dissolved in MeOH (17 ml) and HCl (2M, 1.7 ml) was added. The solution was left to stir overnight at room temp. The MeOH was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, the organic layers were combined, washed with water, brine and dried by pouring down a Chem Elut column and eluting with EtOAc. The resulting solution was evaporated to dryness and purified by chromatography on a Bond Elut column, eluting with 5-65% EtOAc/hexane to yield the title compound (390 mg) as a white solid. NMR: 1.0 (s, 3H), 1.6 (3, 3H), 2.8 (s, 3H), 3.2 (d, 2H), 7.2 (d, 2H), 7.3 (d, 2H), 7.6 (t, 1H), 7.9 (s, 1H), 9.9 (s, 1H); m/z 477.
Reaction SMILES: [Cl-].ClC1N(C)CC[N+]=1C.[CH3:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH2:22]([C:27]12[CH2:34][CH2:33][C:30]([C:35]([NH:37][NH2:38])=O)([CH2:31][CH2:32]1)[CH2:29][CH2:28]2)[CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:12]([C:13]2[O:15][C:35]([C:30]34[CH2:31][CH2:32][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:34][CH2:33]3)[CH2:28][CH2:29]4)=[N:37][N:38]=2)=[C:11]([CH3:10])[CH:19]=1
Reactant: CCCCCC12CCC(C(=O)NN)(CC1)CC2
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: CN1CC[N+](C)=C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC12CCC(c3nnc(-c4ccc(OC)cc4C)o3)(CC1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride (5.07 g, 30.0 mmol) was added to a solution of 2-methyl-4-methoxybenzoic acid (2-D) (856 mg, 5.0 mmol) and 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide (2-C) (1.25 g, 5.25 mmol) in methylene chloride (60 mL) followed by triethylamine (8.36 mL, 60 mmol) and the mixture stirred at room temperature for 48 h. The mixture was diluted with methylene chloride and washed with water, 1N HCl, 10% NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate, 9:1) to give 2-(4-methoxy-2-methylphenyl)-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (2-E) Mass spectrum: 369 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 3H); 1.27 (m, 8H); 1.56 (m, 6H); 2.03 (m, 6H); 2.70 (s, 3H); 3.89 (s, 3H); 6.86 (m, 2H); 7.89 (d, 1H) ppm.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:5]1.C([Li])CCC.[Si:18]([O:35][CH2:36][CH2:37][CH:38]([C:47](=[O:52])NCOC)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.O>[Si:18]([O:35][CH2:36][CH2:37][CH:38]([C:47](=[O:52])[C:2]#[C:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:5]1)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])([C:31]([CH3:32])([CH3:34])[CH3:33])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)CC1CC(C=C(Br)Br)C1
Reactant: COCNC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Yield: 96.7 %

Procedure:
1-(2,2-Dibromovinyl)-3-isobutylcyclobutane (40 g) and tetrahydrofuran (280 mL) were mixed. To the mixture was added n-butyllithium (2.66 M in hexane) (104 mL) dropwise at −78° C. The mixture was stirred at ice temperature and a solution of tert-butyl 5-(tert-butyldiphenylsilanyloxy)-3-methoxymethylcarbamoylvalerate (54 g) in tetrahydrofuran (100 mL) was added dropwise to the mixture. After stirring at ice temperature for 1 hr, saturated aqueous ammonium chloride (180 mL) and water (100 mL) were added to the reaction mixture. The mixture was extracted with ethyl acetate (600 mL), washed with saturated aqueous ammonium chloride (180 mL and 400 mL) and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (90 g) and ethyl acetate/hexane=1/20 (600 mL) into the resultant residue, the mixture was stirred at RT for 1 hr. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (60.09 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.Cl>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1c(Nc2cc(Cl)ccc2[N+](=O)[O-])sc2ccccc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Nc2cc(Cl)ccc2N)sc2ccccc12
Temperature: 30 °C
Yield: 88.3 %

Procedure:
Ethyl 2-(5-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (3.2 g) was suspended in ethanol (40 ml) and a solution obtained by dissolving tin(II) chloride dihydrate (7.7 g) in ethanol (50 ml) and 18% hydrochloric acid (50 ml) was added with stirring the mixture. The mixture was stirred at 60° C. for 2 hr and cooled to 30° C. Potassium carbonate was added until the reaction mixture was basified. After filtering through celite, the filtrate was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure to give ethyl 2-(2-amino-5-chloroanilino)benzo[b]thiophene-3-carboxylate (2.6 g).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:8]([C:10]1[C:11](=[O:22])[N:12]([CH3:21])[C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)[NH2:9].C(N(CC)CC)C>O1CCOCC1>[CH3:21][N:12]1[C:13]2[C:18](=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)[N:19]=[C:10]([NH:8][NH:9][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[C:11]1=[O:22]
Reactant: CCCCC(=O)Cl
Reactant: Cn1c(=O)c(NN)nc2cc(Cl)ccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCC(=O)NNc1nc2cc(Cl)ccc2n(C)c1=O

Procedure:
Pentanoyl chloride (52.6 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-chloro-1H-quinoxalin-2-one (43.8 mmol) and triethylamine (52.6 mmol) in 500 ml. of dioxane and stirred at room temperature for 2 hours. The dioxane is removed under vacuum and the residue washed with water and ether, filtered and dried under high vacuum at 65° for 3 hours to give crude product.
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:4]N(C)C)#[N:2].Cl.[NH2:15][C:16]([NH2:18])=[NH:17].C(=O)([O-])[O-].[K+].[K+].NC1N=CN=C(N)C=1C1C=CC=CC=1>CN(C)C=O>[NH2:17][C:16]1[N:18]=[C:1]([NH2:2])[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:15]=1
Reactant: CN(C)C=C(C#N)c1ccccc1
Reactant: N=C(N)N
Agent: Cl
Agent: Nc1ncnc(N)c1-c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccccc2)c(N)n1

Procedure:
This compound was prepared in a manner analogous to that of Example 2, Step E, using 4.9 grams (0.031 mole) of 1-cyano-1-phenyl-2-(N,N-dimethylamino)ethene, 11.8 grams (0.124 mole) of guanidine hydrochloride, and 21.4 grams (0.1 56 mole) of potassium carbonate in N,N-dimethylformamide. The yield of 2,4.-diamino-5-phenylpyrimidine was 0.7 gram; mp 162°-164° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=[O:16])[CH2:14][CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.C(O)(=O)C.[BrH:21].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=[O:16])[CH:14]([Br:21])[CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: Br
Reactant: CCOC(=O)c1nc(NC)sc1C(=O)CC
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc(NC)sc1C(=O)C(C)Br

Procedure:
To a solution of ethyl 2-methylamino-5-propionyl-4-thiazolecarboxylate (7.4 g) and 30% hydrogen bromide acetic acid (10 ml) in acetic acid (50 ml) was added pyridinium hydrobromide perbromide (13.0 g) at ambient temperature and the mixture was stirred for an hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give ethyl 2-methylamino-5-(2-bromopropionyl)-4-thiazolecarboxylate (7.4 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:7][CH:8]1[C:17]2[CH:16]=[C:15]([OH:18])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH:9]1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.Br[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O>CCCCCC.CC(N(C)C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:7][CH:8]1[C:17]2[CH:16]=[C:15]([O:18][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH:9]1[N:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Oc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Reaction time: 48 h
Yield: 96.5 %

Procedure:
NaH in paraffin (0.278 g, 6.38 mmol, 55% in paraffin) was washed with n-hexane and suspended in DMA (30 ml). 8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (1.2 g, 3.19 mmol) in DMA (20 ml) was added. After stirring for 1 h at room temperature tert-butyl 2-bromoethylcarbamate (2.14 g, 6.38 mmol) was added in portions and the mixture was stirred for 48 h. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl2 3:97). The product (1.6 g, 97%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)=[O:4].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([S:33]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:19][CH:20]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)c1ccc(CCCNCc2ccc(-c3nccs3)cc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1

Procedure:
The title compound of Step B was prepared from 5-[3-(4-thiazol-2-yl-benzylamino)-propyl]-thiophene-2-carboxylic acid methyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. MS 514 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH2:7]1[O:15][C:14]2[C:9](=[CH:10][C:11]([N+]([O-])=O)=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=2)[O:8]1.C(N(CC)CC)C.C(O)C>C(O)(=O)C.O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:11]1[CH:10]=[C:9]2[O:8][CH2:7][O:15][C:14]2=[CH:13][C:12]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: NCC(O)CO
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc2c(cc1NCC(O)CO)OCO2

Procedure:
0.6 mol (56.3g) of 3-amino-1,2-propanediol is added dropwise to a mixture, brought to reflux, prepared by adding 0.3 mol (63.6 g) of 4,5-methylenedioxy-1,2-dinitrobenzene and 46 ml of triethylamine to 90 ml of 96° strength ethanol. The reaction mixture is heated for 3 hours under reflux. After dilution with 600 ml of icecold water and neutralization with acetic acid, the expected product is drained. After recrystallization from acetonitrile, it melts at 120°-121° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][CH2:18][C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][CH2:18][C:19]3[S:23][C:22]([C:24](=[NH:44])[NH2:25])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)s1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)s1)n2C)c1ccccn1
Yield: 53 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(2-cyanothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 53% of theory, C26H28N6O3S (504.6) Rf value: 0.22 (silica gel; dichloromethane/methanol=5:1) ##EQU34##