Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[N:26]1([C:32]2[N:33]=[CH:34][C:35]([C:44]([OH:46])=O)=[N:36][C:37]=2[O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH3:47][O:48][C:49](=[O:56])[C@H:50]([CH2:52][CH:53]([CH3:55])[CH3:54])[NH2:51]>>[CH3:47][O:48][C:49](=[O:56])[C@@H:50]([NH:51][C:44]([C:35]1[CH:34]=[N:33][C:32]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[C:37]([O:38][CH2:39][C:40]([F:41])([F:42])[F:43])[N:36]=1)=[O:46])[CH2:52][CH:53]([CH3:55])[CH3:54]
Reactant: O=C(O)c1cnc(N2CCOCC2)c(OCC(F)(F)F)n1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cnc(N2CCOCC2)c(OCC(F)(F)F)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-morpholin-4-yl-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid and (S)-leucine methyl ester (commercially available). m/z (ES+): 435.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH:16]2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]3[O:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[C:37]=3[CH:47]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[K+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]3[O:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[C:37]=3[CH:47]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCc4ccccc4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(OCc4ccccc4)cc3)cc21
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
0.090 g of benzyl 4-(4-benzyloxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate is dissolved in 3 ml of dioxane. 3 ml each of methanol and 40% KOH are added and the reaction mixture is stirred in a sealed flask at 100° C. over 3.5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 10 ml of water and extracted with tert-butyl methyl ether (3×30 ml). The combined organic phases are washed with 10 ml of water, then 10 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC(=O)[NH:37][C:38]1([CH2:43][O:44][C:45]2[CH:50]=[CH:49][C:48]([CH:51]=O)=[CH:47][CH:46]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1)(C)(C)C>>[NH2:37][C:38]1([CH2:43][O:44][C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:47][CH:46]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1
Product: COc1cc(NCCCc2ccc(OCC3(N)CCCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 93.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl[1-(4-formylphenoxymethyl)cyclopentyl]carbamate (74 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.CO[C:21](C)(C)[CH3:22]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)[CH2:16][CH:17]=[CH:21][CH3:22]
Reactant: CO[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Reactant: COC(C)(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](OC)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.65 g of ethyltriphenylphosphonium bromide were suspended in 40 ml of tert.butyl methyl ether while gassing with argon. The suspension was treated at room temperature with 797 mg of potassium tert.butylate and stirred for 1 hour. The mixture was subsequently cooled to 0° C., treated dropwise within 3 minutes with a solution of 1.1 g of 3-[trans-4-(trans-4-methoxycyclohexyl)cyclohexyl]propionaldehyde in 15 ml of tert.butyl methyl ether and then left to warm slowly to room temperature while stirring. After 2 hours the pale yellow suspension was partitioned in diethyl ether/water. The aqueous phase was separated and washed three times diethyl ether. The organic phases were washed twice with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the yellow, solid crude product on silica gel with ethyl acetate/petroleum ether (vol. 3.97) gave 0.91 g of trans-4-(3-pentenyl)-1-(trans-4-methoxycyclohexyl)cyclohexane with a Z/E ratio of 86:11.
Reaction SMILES: NN.C=CN1C(=O)CCC1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](S(O)(=O)=O)=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[N+:27]([O-:29])=[O:28])([O-:13])=[O:12]>>[N+:11]([C:14]1[C:19]([N+:11]([O-:13])=[O:12])=[C:18]([N+:24]([O-:26])=[O:25])[C:17]([N+:27]([O-:29])=[O:28])=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[N+:27]([O-:29])=[O:28])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: C=CN1CCCC1=O
Agent: NN
Product: O=[N+]([O-])c1c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
FIG. 2 illustrates the decrease in concentration of hydrazine in solution over time at 50° C. after the addition of PVPP. FIG. 3 also illustrates the decrease in concentration of hydrazine in solution over time at 50° C. after the addition of PVPP. FIG. 4 illustrates the reaction between trinitrobenzene sulfonic acid and hydrazine to form hexanitrobenzene, used to detect the concentration of hydrazine in solution.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH:37]5[CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: NC1CC1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (40 mg, 17%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]1[NH:11][C:10](=[O:12])[CH:9]=[C:8]1[OH:13]>C(O)(=O)C>[Br:5][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]1[NH:11][C:10](=[O:12])[C:9](=[N:1][OH:3])[C:8]1=[O:13]
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=C(Br)c2ccccc2)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=C(Br)c2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(bromophenyl-methylene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H. -D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(bromophenylmethylene)-pyrrolidine-2,3,4-trione 3-oxime was 65%, with a melting point of 158° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[ClH:17].[N:18]1(C(=N)N)[CH:22]=[N:21]C=N1.CCOCC>CN(C)C=O>[ClH:17].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:22](=[NH:18])[NH2:21])[CH2:3]1
Reactant: CC1CCCNC1
Reactant: N=C(N)n1cncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1CCCN(C(=N)N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 3-methylpiperidine (2.347 ml, 20 mmol), diisopropylethylamine (3.49 ml, 20.00 mmol) and 1H-1,2,4-triazole-1-carboximidamide hydrochloride (2.444 g, 22.00 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. Ether (50 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The ether layer was separated and DMF layer was stirred with ether (50 ml) at 5° C. (ice water bath) for 10 minutes and the ether layer was separated from the residue. Ether (20 ml) was added to the residue and the mixture was stirred at 5° C. The resulting solid was triturated with ether, collected, washed with ether and dried to give the title compound as a colourless solid (2.95 g, 83%). LC/MS [M+H]+=142.
Reaction SMILES: [S:1]([CH2:12][CH2:13][NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)[S:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][Cl:10].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.C(#N)C>[Cl-:10].[Cl-:10].[S:1]([CH2:12][CH2:13][NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][N+:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[S:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][N+:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: O=C(CCCCl)NCCSSCCNC(=O)CCCCl
Reactant: Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: Cc1cccc[n+]1CCCC(=O)NCCSSCCNC(=O)CCC[n+]1ccccc1C
Product: [Cl-]
Temperature: 50 °C
Reaction time: 120 h

Procedure:
1.13 g of N,N′-(disulfanediyldiethane-2,1-diyl)bis(4-chlorobutanamide) was dispersed in 0.5 mL of N-methylpyrrolidinone and 2.5 mL acetonitrile and heated at 50° C. 0.71 mL of picoline was added and the reaction mixture was stirred for 5 days at 50° C. A few milligrams of cesium carbonate and additional 0.35 mL of 2-picoline were added. After one day at 65° C., the reaction mixture was poured in 50 mL acetonitrile. The resulting gum was washed several times with ethyl acetate, solubilized in ethanol, filtered and dried under vacuum. 0.95 g of a beige solid were obtained.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4Cl)[CH:23]=[C:22]([CH3:34])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:42]CCl>>[Cl:42][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[C:22]([CH3:34])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: ClCCl
Reactant: Cc1cc(-c2ccc(Cl)cc2Cl)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(2,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (0.22 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as a white solid (0.024 g, 5%). MS (ISP) 477.1 [(M+H)+]; mp 267° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:15][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NC1CCCC1
Product: Clc1cc(Cl)nc(NC2CCCC2)n1
Yield: 35.2 %

Procedure:
The reaction of 2,4,6-trichloropyrimidine with cyclopentylamine carried out as described in Example 35 gives both compounds. The less polar 2-cyclopentylamino-4,6-dichloropyrimidine is obtained in a yield of 35.2%, m.p.: 48°-52° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][N:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].N1C=CC=CC=1.[CH3:18][C:19]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]3[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=3)[CH:27]=2)=[CH:23][N:22]=[C:21]([NH2:38])[CH:20]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:5][N:6]1[CH2:10][CH2:9][N:8]([C:7]([NH:38][C:21]2[CH:20]=[C:19]([CH3:18])[C:24]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[CH:27]=3)=[CH:23][N:22]=2)=[O:11])[C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CN1CCNC1=O
Reactant: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)N2CCN(C)C2=O)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A 0° C. solution of phosgene (15% in toluene, 2.82 mL, 4.00 mmol) in DCM (3 mL) was treated drop-wise with a solution of 1-methyl-2-imidazolidinone (0.107 g, 1.066 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (3 mL), warmed to RT, stirred for 0.5 h, then concentrated to dryness. The residue was dissolved in DCM (3 mL), cooled to 0° C., treated with a solution of 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.15 g, 0.533 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (3 mL), warmed to RT and stirred for 3 h. The mixture was treated with satd. NaHCO3, extracted with DCM (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN and the resulting solid was collected via filtration to afford 3-methyl-N-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (116 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.34 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.10 (s, 1 H), 8.01 (s, 1 H), 7.95 (s, 1 H), 7.16 (d, J=2.4 Hz, 1 H), 6.59 (dd, J=5.7, 2.5 Hz, 1 H), 3.84 (s, 3 H), 3.79-3.78 (m, 2 H), 3.45 (t, J=8.2 Hz, 2 H), 2.80 (s, 3 H), 2.14 (s, 3H); MS (ESI) m/z: 408.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH:6]=[CH:5]2
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reaction time: 0.5 h

Procedure:
28.18 g (125.8 mmol) 6-Bromo-2H-isoquinolin-1-one (6) were dissolved in 200 ml Dimethylacetamide and 7.55 g (188.7 mmol) sodium hydride (60%) were added at room temperature. After stirring for 30 minutes, 29.94 g (188.7 mmol) 4-Methoxy-benzylchloride were added and stirring was continued at room temperature until complete conversion was detected. The solvent was removed under reduced pressure, the residue taken up in saturated sodium hydrogen carbonate-solution and extracted three times with dichloromethane. The organic layers were dried over magnesium sulfate and evaporated. Final purification was achieved by silicagel chromatography. Rt=1.93 min (Method B). Detected mass: 344.1 (M+H+).
Reaction SMILES: [OH-:1].[Na+].Cl.ClCCN.[Cl:8]/[C:9](/[C:15](Cl)=[O:16])=[C:10](\[Cl:14])/[C:11](Cl)=[O:12].[OH2:18]>>[Cl:8]/[C:9](/[C:15]([OH:16])=[O:18])=[C:10](\[Cl:14])/[C:11]([OH:1])=[O:12]
Reactant: [OH-]
Reactant: O=C(Cl)/C(Cl)=C(/Cl)C(=O)Cl
Reactant: O
Agent: Cl
Agent: NCCCl
Agent: [Na+]
Product: O=C(O)/C(Cl)=C(/Cl)C(=O)O

Procedure:
160 g of 10% strength sodium hydroxide solution were added to 40.1 g (0.4 mol) of 2-chloroethylamine hydrochloride, dissolved in 150 ml of water, and 22.2 g (0.1 mol) of dichloromaleic acid dichloride were then introduced slowly at room temperature. The product which precipitated was filtered off and dried. 19.7 g of dichloromaleic acid bis-(2-(chloroethyl)-amide of melting point 107°-110° C. were obtained, that is to say 64% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](C=O)=[CH:5][CH:4]=1.OO.[OH:13]S(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([OH:13])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc(O)cc1

Procedure:
To a solution of 13.6 g 4-methoxybenzaldehyde and 1.1 equivalents 50 percent H2O2 in 55 ml methanol at about 20° C. is added 0.10 equivalent of 98 percent H2SO4. The mixture is refluxed for about 1.5 hours, then Na2SO3 is added to destroy excess H2O2. Then, NaHCO3 is added to neutralize any acid. The solvent is removed under reduced pressure. The resulting solid is taken up in about 50 ml CH2Cl2, is dried over Na2SO4, and is filtered. The sol-vent is removed under reduced pressure from the filtrate giving approximately a 94 mole percent yield of 4-methoxyphenol as is determined by nuclear magnetic resonance and gas chromatography.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#N)=[CH:15][CH:14]=3)=[CH:10][C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:32].[OH-:33].[K+]>C(O)C>[CH:1]1([N:7]2[C:11]([CH2:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]([OH:33])=[O:32])=[CH:15][CH:14]=3)=[CH:10][C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C2CCCCC2)cc1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C2CCCCC2)cc1

Procedure:
To a mixture of 0.395 g 4-({1-cyclohexyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}methyl)benzonitrile from Step A above in 9 mL ethanol and 3 mL water was added 0.80 g potassium hydroxide pellets. The resulting solution was refluxed under nitrogen over night. Ethanol was removed under reduced pressure. The product was precipitated by adding 14 mL 1 N HCl to the residue. The title compound was collected by filtrated, washed with water several times, and dried to give a off-white solid. 1H NMR (CD3OD, 600 MHz) δ 7.97 (d, J=8.2 Hz, 2H), 7.81˜7.84 (m, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 6.425 (s, 1H), 4.165 (s, 2H), 4.01 (tt, J=3.9 & 11.8 Hz, 1H), 1.86˜1.93 (m, 2H), 1.78˜1.83 (m, 2H), 1.64˜1.68 (m, 3H), 1.20˜1.35 (m, 3H). LC-MS: 2.49 min. (M+H=445.2).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CBr)n1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1ccccc1)CO2
Product: Cc1cccc(COc2ccc3c(c2)[C@@H](O)[C@H](Cc2ccccc2)CO3)n1

Procedure:
By the method of Example 5, 500 mg (1.96 mmol) of trans-3-benzyl-4,6-chromandiol and 401 mg of 2-(bromomethyl)-6-methyl pyridine were converted to present title product, purified by flash chromatography on silica gel using 1:1 ethyl acetate:hexane as eluant to yield 0.38 g (53%) of present title product as white crystals, m.p. 87°-90° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[N+:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:18])=[CH:10][CH:9]=1)([O-:7])=[O:6].[ClH:19]>O.CC(O)=O>[ClH:19].[NH:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NNc1ccc([N+](=O)[O-])c2ccccc12
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.9 g of sodium nitrite in 10 ml of water is added to a suspension, cooled to -5° C., of 5.2 g of 4-nitro-1-naphthylamine in 150 ml of concentrated HCl, 100 ml of 1N HCl and 150 ml of AcOH. The mixture is left stirring for 1 hour 15 minutes at a temperature of between -5° C. and 0° C. It is cooled to -15° C., and a solution of 12.5 g of stannous chloride dihydrate in 30 ml of concentrated HCl is added very slowly. The temperature is allowed to rise to RT and the reaction mixture is kept stirring for 2 hours 30 minutes. It is filtered, the solid is then taken up with water and the mixture is filtered again. 5.9 g of the expected product are obtained.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1)[CH3:25]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH2:24][CH3:25])[CH:27]=3)[C:33]2=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCc1cccc(N=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: CCc1cccc(-n2c(=O)c3cnc4c(OC)cccc4c3n(C3CCCC3)c2=O)c1
Yield: 66.9 %

Procedure:
1-Cyclopentyl-3-(3-ethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (89 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-ethyl-3-isocyanato-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:8]2)=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Yield: 44.5 %

Procedure:
A solution of 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acid methyl ester (312) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg, 1.02 mmol) in Pyridine (0.13 ml, 1.53 mmol)-CH2Cl2 (3.7 ml) was stirred at room temperature for 12 hr. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 181 (237 mg, 41%, in 3 steps).