Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9](C)C)(=[O:5])[C:2]([CH3:4])=C.Cl.Cl.[N:14]([C:22]([C:25](=[NH:27])N)(C)C)=N[C:16](C(=N)N)(C)C.[C:28]([OH:31])(=[O:30])[CH3:29]>[Cl-].C[N+](C)(CC=C)CC=C>[C:28]([OH:31])(=[O:30])[CH2:29][CH2:16][CH2:4][CH2:2][C:1]([OH:6])=[O:5].[NH2:9][CH2:8][CH2:7][NH:14][CH2:22][CH2:25][NH2:27]
Reactant: C=C(C)C(=O)OCCN(C)C
Reactant: CC(=O)O
Reactant: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: C=CC[N+](C)(C)CC=C
Agent: Cl
Agent: [Cl-]
Product: NCCNCCN
Product: O=C(O)CCCCC(=O)O
Reaction time: 2 h

Procedure:
122.5 g of methylglycol, 83.3 g of a 60% strength aqueous solution of dimethyldiallylammonium chloride and 50 g of dimethylaminoethyl methacrylate are initially placed in a 700 ml 4-necked flask, equipped with an anchor stirrer, a thermometer, a reflux condenser and a gas inlet tube, and the pH of the mixture is adjusted to a value of 8.5 with 3.8 g of glacial acetic acid. Nitrogen is then passed in, the mixture is heated to an internal temperature of 80° C. and 0.2 g of 2,2'-azobis-(2-amidinopropane) dihydrochloride is added at an internal temperature of 60° C. and copolymerization is carried out within the temperature range from 76° to 80° C. Stirring is then continued for a further 2 hours. 22 g of a condensation product formed from 1 mol of adipic acid and 1 mol of diethylenetriamine are then added, followed by 2.052 g of epichlorohydrin in the form of a 10% strength solution in ethanol. Crosslinking of the copolymers is complete after stirring for 10 to 20 minutes at 70° C. The pH of the solution is then adjusted to a value of 7.0 by adding 1.5 g of H2SO4 (diluted with water in the ratio 1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[C:5]([C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1)=[O:6].Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)Cl.C(Cl)Cl.[CH3:42][CH2:43]CCCC>>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[C:5]([C:7]1[C:20]2[C:21]3[C:10]4[C:9](=[CH:42][CH:43]=[C:31]5[C:11]=4[C:12]4[C:34](=[CH:35][CH:30]=[C:14]6[C:13]=4[C:22]=3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15]6)[CH:33]=[CH:32]5)[CH:8]=1)=[O:6]
Reactant: COc1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)c(OC)c1
Reactant: CCCCCC
Reactant: Clc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc3ccc4ccc5ccc6ccc7ccc2c2c7c6c5c4c32)c(OC)c1

Procedure:
The synthesis was carried out essentially as described for 2a, but chlorobenzene was used as a solvent instead of methylene chloride. Yield after column chromatography (methylene chloride/ hexane): 48%. Found: C, 85.52; H, 4.21; C33H20O3 (NM 464.51) requires C, 85.33; H, 4.34%. Mass-spectrum, MALDI-TOF: 464.22 (100), 300.1 (30). Calculated exact mass for C33H20O3:464.14125; found 464.14189 [1.4 ppm error].
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].CO.[OH-].[Na+]>C1COCC1.[OH-].[Na+]>[NH2:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][C:7]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: COC(=O)c1cc(-c2ccc(S(N)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 45 °C
Yield: 98.8 %

Procedure:
To a solution of 4-(4-(aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylic acid methyl ester (Example 1, Step 5) (0.210 g) in THF (2.0 mL) were added MeOH (1.0 mL), NaOH 1N (1.0 mL) and a few drops of NaOH 10N. The resulting mixture was heated at 45° C. for 2 h and the reaction was then partitioned between EtOAc and HCl (3N) to provide the title product as a white solid (0.200 g).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:18]1[CH2:24][CH:23]=[CH:22][CH2:21][NH:20][C:19]1=[S:25]>CC(C)=O>[BrH:1].[C:5]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]2([OH:17])[N:20]3[CH2:21][CH:22]=[CH:23][CH2:24][N:18]=[C:19]3[S:25][CH2:2]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: S=C1NCC=CCN1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: Br
Product: OC1(C(c2ccccc2)c2ccccc2)CSC2=NCC=CCN21
Reaction time: 3 h

Procedure:
This 1-bromo-3,3-diphenyl-2-propanone is dissolved in 50 ml. of acetone and added to a warm solution of 1.28 g. of 1,3,4,7-tetrahydro-2H-1,3-diazepin-2-thione in 100 ml. of acetone. The reaction mixture is warmed, with stirring, for 3 hours and then stirred for 72 hours. The mixture is cooled and the resulting solid is collected by filtration, giving the desired product.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@:11]1([C:25]([O:27]C(C)(C)C)=[O:26])[CH2:16][C:15](=[O:17])[C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20]C(C)(C)C)=[O:19])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.C(O)C>[C:3]([O:7][C:8]([NH:10][C@@:11]1([C:25]([OH:27])=[O:26])[CH2:16][C:15](=[O:17])[C@@H:14]2[C@@H:12]1[C@H:13]2[C:18]([OH:20])=[O:19])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@@H]21
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Add 2.5M sodium hydroxide (15.55 mL, 38.88 mmol) to a stirred solution of the ditert-butyl (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.0 g, 4.86 mmol) in tetrahydrofuran (24.3 mL) and ethanol (9.72 mL). Heat the reaction mixture to 60° C. and maintain stirring overnight. Continue heating for 4 hours then wash with ethyl acetate. Cool the aqueous phase in an ice bath and acidify to pH=2-3 with 1N hydrochloric acid solution. Extract with ethyl acetate (3 times), dry the organic on sodium sulfate, filter and concentrate to give the title compound as an orange solid (1.4 g, 96%). MS (m/z): 322 (M+23).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][O:39][C:40]([C:42]1[C:50]2[NH:49][C:48]([NH2:51])=[N:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]>>[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH:51][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1cccc2nc(N)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12
Yield: 75.5 %

Procedure:
2.6 g (75%) of the 2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from isoquinoline-3-carboxylic acid (1.7 g, 10 mmol), HBTU (4.6 g, 12 mmol), and the above synthesized 2-amino-3H-benzoimidazole-4-carboxylic acid methyl ester (1.9 g, 10 ml) as described in general procedure A. This ester was then hydrolyzed according to general procedure B to give 2.2 g (88%) of acid. LCMS: 333 (M+1)+.
Reaction SMILES: [CH3:1][SiH:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[Br:9]Br.Br>>[CH3:1][Si:2]([CH:6]([CH3:8])[CH3:7])([CH:3]([CH3:5])[CH3:4])[Br:9]
Reactant: BrBr
Reactant: CC(C)[SiH](C)C(C)C
Agent: Br
Product: CC(C)[Si](C)(Br)C(C)C
Reaction time: 1 h

Procedure:
20.8 g (0.16 mol) of the methyldiisopropylsilane prepared under Example 2, above, was placed in a 50 mL three-neck flask equipped with a reflux condenser, thermometer, and addition funnel. 25 g bromine (0.16 mol) was cautiously dripped in while cooling with ice and stirring with a magnetic stirring bar. A strong exothermic reaction developed, and hydrogen bromide was evolved. After addition of the entire quantity of bromine, the reaction was allowed to stand for 1 hour at room temperature and was then distilled in vacuo. 26.3 g (0.13 mol) of the target methyldiisopropylbromosilane (bp=92 degrees Centigrade/50 mmHg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22](C(O)=O)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.SCC(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Agent: O=C(O)CS
Solvent: O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 170 °C
Yield: 23.7 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (32) (102 mg, 0.22 mmol) and mercaptoacetic acid (2.2 mL) was heated to 170° C. for 1 h. At this time, the reaction mixture was cooled to room temperature and was diluted with water (120 mL) and was extracted with ethyl acetate (100 m/L). The organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (2×100 mL) and a saturated aqueous sodium chloride solution (100 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dissolved in methylene chloride and was purified by flash chromatography (Biotage 40S) using silica gel eluted with 100% ethyl acetate to elute the impurity followed by 0.2% glacial acetic acid in ethyl acetate to elute the desired product. The desired fractions were collected and concentrated under vacuum. The resulting solid was slurried in hot methanol (2 mL), filtered and rinsed with petroleum ether. The solids were dried in a vacuum oven at 80° C. to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (33) (21.4 mg, 23%) as a yellow solid; EI(+)-HRMS m/z calcd for C16H13Cl2N5O4 (M+) 410.0418, found 410.0419. Molecular Weight=410.2191; Exact Mass=409.0345
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]2=[O:23])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]2=[O:23]
Reactant: COC(=O)c1cc(OCc2ccccc2)c2c(c1)C(=O)N(CC(C)C)CC2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(O)c2c(c1)C(=O)N(CC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of methyl 5-(benzyloxy)-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (1 g, 2.72 mmol) in MeOH (10 mL) was added catalyst amount of 10% Pd on C. This mixture was stirred under H2 balloon at room temperature for 3 hr. The solids were filtered through a bed of Celite. Removal of the solvent gave the product (750 mg, 98%) as light yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, 6 H) 1.98-2.16 (m, 1 H) 3.05 (t, J=6.59 Hz, 2 H) 3.38-3.50 (m, 2 H) 3.57 (t, J=6.69 Hz, 2H) 3.82-3.93 (m, 3 H) 7.50 (s, 1 H) 7.74 (d, J=1.51 Hz, 1 H) 8.30 (d, J=1.32 Hz, 1 H); MS (ESI, pos): 278.
Reaction SMILES: CO[C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:28][NH:29][C:30]([NH2:32])=[O:31].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C:3]([NH:32][C:30]([NH:29][CH3:28])=[O:31])=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl ester (196.5 mg, 0.548 mmol) and methyl urea (121.8 mg, 1.64 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 3.1 mL, 2.19 mmol). The resulting reaction mixture was then heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate then 3/1 to 1/1 hexanes/ethyl acetate gradient elution) afforded 1-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionyl]-3-methyl urea (76.9 mg, 35%) as a white foam: mp 85-88° C.; EI-HRMS m/e calcd for C26H28N2O2 (M+) 400.2151, found 400.2150.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCCc1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(OCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (5.02 g, 36.3 mmol) and chloroethyl piperidine (7.36 g, 39.96 mmol) in 30 ml of DMF, 5 g of K2CO3 was added. The reaction was stirred at 80° C. overnight. After cooling the mixture was quenched with water then extracted in CHCl3. The organic layer was separated, dried over Na2SO4, filtered and concentrated. 2-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-ethanol (4.58 g, 18.4 mmol) was isolated as a brown oil; Yield 51%; MS: 250.3 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: Nc1cccnc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Temperature: 130 °C
Yield: 56.3 %

Procedure:
To a solution of 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 4 mL of dioxane are added 53 mg of 3-aminopyridine. The reaction mixture is heated by microwave at 130° C. for 20 minutes and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 129 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-pyridin-3-ylurea, the characteristics of which are as follows:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[CH:9]=[N:8][CH:7]=[CH:6]2.C1OCCOCCOCCOCCOCCOC1.[C-:32]#[N:33].[K+].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.O>[C:35]([N:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:12]([Cl:13])=[C:3]([Cl:2])[CH:4]=2)[CH:9]1[C:32]#[N:33])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Clc1cc2ccncc2cc1Cl
Reactant: [C-]#N
Reactant: O=C(Cl)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CC1c2cc(Cl)c(Cl)cc2C=CN1C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 1.7 g (8.6 mmole) of 6,7-dichloroisoquinoline hydrochloride in 12 ml of methylene chloride was added 0.11 g (0.43 mmole) of 18-crown-6 followed by a solution of 1.67 g (26 mmole) of potassium cyanide in 12 ml of water. The mixture was stirred vigorously under nitrogen for 30 minutes and then a solution of 2.4 g (17.2 mmole) of benzoyl chloride in 10 ml of methylene chloride was added dropwise. After the reaction mixture was stirred at ambient temperature, under nitrogen for 3 hours, an additional 50 ml of methylene chloride and 50 ml of water was added. The organic phase was separated, washed successively with water, 5% aqueous sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulfate and concentrated. The resulting oil was triturated with methanol at 0° C. to give 2-benzoyl-6,7-dichloro-1-cyano-1,2-dihydroisoquinoline, m.p. 194°-196° C.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[C:10]1([C:12](=[CH:14][CH:15]=[CH:16]C=1)[OH:13])[OH:11].OO>CC(C)=O>[CH:9]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[C:10](=[O:11])[C:7]=2[C:5]([OH:6])=[C:3]([OH:4])[C:1]=1[OH:2]
Reactant: Oc1cccc(O)c1O
Reactant: Oc1ccccc1O
Agent: OO
Solvent: CC(C)=O
Product: O=c1c(O)cccc2cc(O)c(O)c(O)c12
Yield: 17.2 %

Procedure:
Pyrogallol (1 g) and catechol (1.5 g) were dissolved in a mixture of acetone-pH 5.0 phosphate citrate buffer (1:10, v/v, 50 mL), which contained 2 mg horseradish peroxidase. While being stirred, 2.0 mL of 3.13% H2O2 was added four times during 45 minutes. The reaction mixture was extracted by ethyl acetate (50 mL×3). After concentration, the residue was subjected to Sephadex LH 20 column eluted with acetone-water solvent system (45%). 300 mg Purpurogallin was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[C:4]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:3]=1[N+:34]([O-])=O.[Cl-].[NH4+]>C(OCC)(=O)C.CO.ClCCl.[Zn]>[NH2:34][C:3]1[C:4]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4OCC4CC4)cn(C)c(=O)c32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4OCC4CC4)cn(C)c(=O)c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-[4-amino-2-(cyclopropylmethoxy)-3-nitrophenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.119 g, 0.234 mmol) in ethyl acetate (1.2 mL) and methanol (1.2 mL) was treated with saturated aqueous ammonium chloride solution (0.274 mL, 4.09 mmol). The mixture was cooled to 0° C., treated with zinc (0.122 g, 1.87 mmol) in two portions over 5 min, stirred at RT for 30 min and heated at 55° C. for 1 h. The reaction mixture was diluted with dichloromethane, filtered through a Celite pad, and the solids were washed with dichloromethane. The filtrate was concentrated to give a residue. The residue was dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (20 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product that was used without further purification. LCMS calculated for C25H27N4O4S (M+H)+: m/z=479.2. found: 479.1.
Reaction SMILES: NC1(C2N[C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18]C)C(=O)N(CCC)[C:9]=3[N:8]=2)CCCC1.C(C(C(Cl)=O)C(Cl)=[O:28])C>O1CCCC1.N1C=CC=CC=1>[CH2:17]([NH:12][C:13](=[O:16])[CH2:14][C:9]([NH2:8])=[O:28])[CH3:18]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCCn1c(=O)c2[nH]c(C3(N)CCCC3)nc2n(CCC)c1=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNC(=O)CC(N)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.5 g di 8-(1-aminocyclopentyl)-1,3-dipropylxanthine in 45 ml of anhydrous tetrahydrofurane, 1.4 ml of pyridine are added and, after cooling to 5° C., 2.26 ml of ethyl malonyl chloride are dropwise added. The mixture is stirred at room temperature for 2 hours, followed by concentration under vacuum, addition of 1N HCl and extraction with ethyl acetate. The organic phase is washed with water, dried and evaporated, thereby obtaining 6.5 g of raw product which is purified by column chromatography (SiO2). 2.6 g of mono malonamide mono ethyl ester are obtained, which is finally saponified by treatment with tetrahydrofurane (26 ml) and NaOH 1N (30 ml) at room temperature for 1 hour.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([N:15]=[C:16](S)[N:17](C(OCC1C=CC=CC=1)=O)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])C.[C:39]([O:42][CH2:43][CH3:44])(=[O:41])C>O1CCCC1>[CH2:43]([O:42][C:39]([N:15]=[C:16]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:41])[C:44]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: CCN=C(S)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cc1c(N)ccc2cccnc12
Solvent: C1CCOC1
Product: Cc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pale yellow solution of 500 mg of 7-amino-8-methylquinoline in 20 mL of tetrahydrofuran are added 1.18 g of ethyl N,N-bis(benzyloxy-carbonyl)pseudothiourea and 1.01 g of mercuric acetate and the mixture is stirred at room temperature for 1 hour. The suspension is diluted with ethyl acetate and the organic layer is washed with water followed by brine. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate/hexanes and recrystallization from hexanes/methylene chloride to provide 1.257 g of 7-[N2,N3-bis(benzyloxycarbonyl)guanidino]-8-methylquinoline as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([S:35]([NH:38][C:2]2([C:26]#[N:27])[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [C-]#N
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(NS(=O)(=O)c4ccccc4)CC3)c(F)c2)C(=O)O1

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and phenylsulfonamide the compound was obtained in % yield.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].Cl.NO>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[O:6][N:2]=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Clc1ccc(-c2oncc2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (22.80 g, 79.7 mmol), hydroxylamine hydrochloride (18.01 g, 0.26 mole), and 150 mL ethanol was heated to reflux for 30 minutes. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1N hydrochloric acid and then treated with an aqueous saturated solution of sodium bicarbonate. The precipitates were collected by filtration, washed with water and ethanol, and dried to yield 5-(4-chlorophenyl)-4-(pyridin-4-yl)isoxazole (20.50 g, 93%). m.p. 120.8-120.9° C. 1H NMR (CDCl3/CD3OD/300 MHz) δ8.53 (d, 2H), 8.46(s, 1H), 7.51(d, 2H), 7.41-7.34 (m, 4H). ESLRMS m/z 257 (M+H). ESHRMS m/z 257.0457 (M+H, C14H9N2OCl requires 257.0482).