Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].C(O)(=O)C.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[N:6]1[CH:7]=[CH:8][C:3]([C:1](=[NH:2])[O:18][CH:15]([CH3:17])[CH3:16])=[CH:4][CH:5]=1
Reactant: N#Cc1ccncc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)OC(=N)c1ccncc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in isopropanol (50 ml), and sodium hydride (0.23 g, 9.6 mmol) from which oily matters had been removed by washing with ether was added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was neutralized by adding acetic acid (0.64 g, 10.7 mmol) and concentrated under reduced pressure. To the residual concentrate was added diethyl ether (50 ml). Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. To this concentrate was added hexane (80 ml), and deposited unreacted 4-cyanopyridine was removed by filtration. The filtrate was concentrated under reduced pressure to give crude isopropyl 4-pyridinecarboximidate (11.0 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=O)[CH:11]=2.Cl.[O:31]([NH2:33])[CH3:32].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=[N:33][O:31][CH3:32])[CH:11]=2
Reactant: O=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1

Procedure:
Prepare the title compound from (R)-cyclopropanecarboxylic acid[9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Preparation 71) (3.10 g, 7.94 mmol), methoxylamine hydrochloride (1.99 g, 23.8 mmol), and sodium hydroxide (0.48 g, 11.9 mmol) by essentially following procedures as described in Example 204. Purify using silica gel chromatography eluting with 10% EtOAc/CH2Cl2 to provide 1.94 g (58%) of product. mp: 200-203° C.; MS (ES) m/z 420 (M+1).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:4].[N+:13]([CH3:16])([O-:15])=[O:14]>CO>[CH2:3]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:16]/[N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)[CH3:4]
Reactant: C[N+](=O)[O-]
Reactant: CCc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
An aq. 6M NaOH solution (1.05 eq) was added to a methonolic solution of 4-ethylbenzaldehyde (1 eq) and nitromethane (1 eq) stirred at 0° C. During the slow addition of base, maintain the temperature between 10-15° C. The reaction generates a thick white precipitate. To allow smooth stirring, an additional amount of MeOH was added. After stirring for an additional 15 min., the ice bath was removed. Upon reaching RT, water was added to the reaction, which subsequently turned clear. The clear solution was added to a flask containing a stirred 6M aq. HCl solution. A yellow crystalline precipitate formed. After 10 min., the crystalline product was filtered, washed thoroughly with water, suction dried and recrystallized from abs. EtOH. 4-ethyl trans-beta-nitrostyrene (2) was afforded as a yellow crystalline product in 52% yield and >99% purity (LC/MS m/z 178.2 MH.
Reaction SMILES: C([NH:4][C:5]1[C:13]([S:14](=[O:27])(=[O:26])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C(=O)C)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7](NC2C=CC=CC=2)[C:6]=1[NH:35][CH2:36][C:37]1[O:41][CH:40]=[CH:39][CH:38]=1)(=O)C.[OH-].[Na+]>C(O)(=O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([NH:4][C:5]2[C:13]([S:14](=[O:27])(=[O:26])[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH2:22])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=2[NH:35][CH2:36][C:37]2[O:41][CH:40]=[CH:39][CH:38]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)c(Nc2ccccc2)c(NCc2ccco2)c1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(Nc2c(NCc3ccco3)cc(C(=O)O)cc2S(=O)(=O)Nc2ccccc2N)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.8 g of 4-(4-acetamidophenylamino-3-furfurylamino-5-(2-acetamidophenylsulfamoyl)-benzoic acid and 18 ml of 2 N aqueous sodium hydroxide is refluxed for 6 hours under nitrogen. After cooling to room temperature it is acidified with glacial acetic acid to a pH of 4-5, the precipitate collected and recrystallized from 6 ml of 50% aqueous ethanol, to yield the 4-(4-aminophenylamino)-3-furfurylamino-5-(2-aminophenylsulfamoyl)-benzoic acid melting at 182° with decomposition.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2].C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Yield: 97.2 %

Procedure:
Dry THF (20 ml) was added to 0.4 g of 8-cyano-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 0.2 g of triethylamine and 0.27 g of ethyl bromoacetate. The resultant mixture was stirred at room temperature for 24 hours. After the completion of the reaction, THF was distilled off under reduced pressure, the residue was dissolved in chloroform, and the resultant solution was washed with water. The chloroform layer was dried over anhydrous Na2SO4 and then filtered. The chloroform was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (20:1), 0.5 g of 8-cyano-11-(1-ethoxycarbonylmethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 97%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18]C(=O)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1>O1CCOCC1>[ClH:16].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][C:31]1[CH:33]=[CH:34][CH:28]=[CH:29][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(CO)cccc12
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
A solution of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (3.68 g, 10 mmol) and 4-hydroxy-2-methylaniline (1.35 g, 11 mmol) in dioxan (50 ml) was heated at reflux for 2 hours, then the dioxan evaporated and the residue taken up in 1% methanolic sodium hydroxide (100 ml) and stirred 1.5 hours at room temperature. The methanol was evaporated, the residue taken up in water, adjusted to pH 7, and the solid filtered off. This was converted to the salt with ethanolic hydrogen chloride, then recrystallized from aqueous ethanol to give 3-isobutyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline hydrochloride (1.15 g, 30%), m.p. 225°-255° (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([C@@H:55]([NH2:59])[CH2:56][O:57][CH3:58])=[N:54][C:50]=2[CH:49]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:5]([NH:59][C@H:55]([C:53]1[NH:52][C:51]2[CH:60]=[CH:61][C:48]([Cl:47])=[CH:49][C:50]=2[N:54]=1)[CH2:56][O:57][CH3:58])=[O:7]
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CCCCC2=O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC[C@H](NC(=O)c1ccc(N2CCCCC2=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine in DMF and subsequent purification by chromatography on silica gel (eluting gradient: ethyl acetate/ethanol 95:5→90:10).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][CH:4]=1)[CH3:2].C(O[CH2:14][C:15]1[NH:16][C:17]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:18]([CH3:26])[C:19]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=O)C.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40](S(O)(=O)=O)=[CH:39][CH:38]=1>>[CH2:30]([O:29][C:27]([C:17]1[NH:16][C:15]([CH2:14][C:4]2[NH:5][C:6]([CH2:14][C:15]3[NH:16][C:17]([C:27]([O:29][CH2:47][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:28])=[C:18]([CH3:26])[C:19]=3[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:7]([CH2:8][CH3:9])[C:3]=2[CH2:1][CH3:2])=[C:19]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:18]=1[CH3:26])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c[nH]cc1CC
Reactant: COC(=O)CCc1c(COC(C)=O)[nH]c(C(=O)OCc2ccccc2)c1C
Product: CCc1c(Cc2[nH]c(C(=O)OCc3ccccc3)c(C)c2CCC(=O)OC)[nH]c(Cc2[nH]c(C(=O)OCc3ccccc3)c(C)c2CCC(=O)OC)c1CC
Temperature: 60 °C
Yield: 61 %

Procedure:
7C, FIG. 7. In a 500 mL round bottom flask was placed 250 mL of ethanol from an unopened bottle and this was then purged with dry nitrogen for ten minutes. 3,4-Diethylpyrrole 7B (1.29 g, 0.01 mol) and 2-acetoxymethyl-5-benzyloxycarbonyl-4-methyl-3-methoxycarbonylethylpyrrole 7A (7.83 g, 0.02 mol) were added and the mixture heated until all of the pyrroles dissolved. p-Toluenesulfonic acid (65 mg) was added and the reaction temperature maintained at 60° C. The reaction slowly changed color from a clear yellow to a dark red with the product precipitating out of the solution as the reaction progressed. After ten hours the reaction was cooled to room temperature, the volume reduced to one half on a rotary evaporator, and then placed in the freezer for several hours. The product was collected by filtration, washed with a small amount of cold ethanol to afford 4.61 g of an off white fine powder (61%): 1H NMR (CDCl3, 250 MHz): δ1.14 (6H, t, CH2CH3), 2.23 (6H, a, pyrrole-CH3), 2.31 (4H, t, CH2CH2CO2CH3), 2.50 (4H, q, CH2CH3), 2.64 (4H, t, CH2CH2CO2CH3), 3.60 (10H, br s, CH3CO2 -- and (pyrrole)2 --CH2), 4.44 (4H, br s, C6H5CH2), 6.99-7.02 (4H, m, aromatic), 7.22-7.26 (6H, m, aromatic), 8.72 (1H, s, NH), 10.88 (2H, br s, NH); 13C NMR (CDCl3, 250 MHz): δ10.97, 16.78, 17.71, 19.40, 22.07, 35.09, 51.46, 65.32, 117.37, 119.34, 122.14, 126.58, 126.79, 127.36, 128.19, 133.55, 136.62, 162.35, 173.49; CI MS (M+H)+ 750; HRMS 749.3676 (calc. for C44H51N3O8 : 749.3676).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:13][CH:10]2[CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ncc(Br)c(NC2CC2)n1

Procedure:
In analogy to compound 1.1, a solution of 1.0 g (4.39 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 15 ml of acetonitrile is reacted with 0.27 g (4.74 mmol) of cyclopropylamine in the presence of 0.74 ml (5.3 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.76 g (70% of theory) of the product.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:10]([NH:1][C@@H:2]([C:6]([OH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(O)[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(O)[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of (S)-2-amino-3-hydroxy-3-methylbutanoic acid (18.6 g, 140 mmol), aqueous NaOH solution (2 mol/L, 70 mL) and benzaldehyde (14.56 g, 137 mmol) was stirred at 25° C. for 1 hour and cooled to 0° C. Then to the mixture was added sodium borohydride (3 g, 80 mmol) portion wise with the temperature maintained below 10° C. Then the mixture was warmed to 25° C. and stirred for another 12 hours. The aqueous layer was washed with DCM (30 mL×3) and the organic layer was discarded. The aqueous layer was cooled to 5° C., and adjusted to pH 1-2 with con. HCl. The mixture was stirred at 5° C. for 4 hours, and filtered to give the title compound as a white solid (18.8 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH:21]=O)(=[O:14])=[O:13])=[C:7]([CH3:23])[CH:6]=1.[OH2:24].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH3:23])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2/[CH:21]=[CH:26]/[C:27]([O:28][CH2:29][CH3:25])=[O:24])(=[O:13])=[O:14])=[C:9]([CH3:11])[CH:10]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2C=O)c(C)c1
Reactant: C1CCOC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/C1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of triethyl phosphonoacetate (3.8 mmol, 1.2 eq) in THF (12 ml) was added dropwise to a suspension of NaH (3.8 mmol, 1.2 eq) in THF (12 ml) at 0° C. and the mixture was stirred for 30 min. 1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidine-2-carbaldehyde (3.2 mmol) in THF (6 ml) was then added and the mixture was stirred for a further 30 min. The reaction mixture was warmed to room temperature and stirred for 12 h. Hydrolysis was then carried out with water and the mixture was extracted with ethyl acetate. The organic phase was washed with water (20 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (5-20% ethyl acetate in hexane). Yield: 40%
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3]([O:5][NH:6][C@H:7]([C:26]([OH:28])=[O:27])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[N+:23]([O-])=O)=[O:4]>[Pd].CO>[NH2:23][C:11]1[C:12]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][CH2:8][C@@H:7]([C:26]([OH:28])=[O:27])[NH:6][O:5][C:3](=[O:4])[C:2]([CH3:29])([CH3:30])[CH3:1]
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1cccc(Oc2ccccc2)c1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)ON[C@@H](CSc1cccc(Oc2ccccc2)c1N)C(=O)O
Yield: 89 %

Procedure:
0.76 g of 58 (1.75 mmol), 76 mg of Pd/C (10%) and 34.5 mL of methanol are hydrogenated at 5 bar for 10 hours at 20° C. in an autoclave. After filtering off the catalyst through Celite, the solvent is evaporated off and 0.63 g of expected product 59 is obtained (brown oil), which product is used directly in the following step.
Reaction SMILES: [Br:1]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C(=O)C.Br.[NH2:29][C:30]1[N:39]=[C:38]([NH2:40])[C:37]2[C:32](=[N:33][CH:34]=[C:35]([CH2:41]O)[N:36]=2)[N:31]=1.C1C=CC=CC=1>CCOCC>[Br:1][CH2:41][C:35]1[N:36]=[C:37]2[C:32](=[N:33][CH:34]=1)[N:31]=[C:30]([NH2:29])[N:39]=[C:38]2[NH2:40]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc(N)c2nc(CO)cnc2n1
Agent: Br
Solvent: c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Nc1nc(N)c2nc(CBr)cnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To the solution of dibromotriphenylphosphine (2.4337 g, 5.76 mmol) of 2 ml anhydrous N,N-dimethylacetamide was added (2,4-Diamino-Pteridin-6-yl)-methanol hydrobromide (335.8 mg, 1.747 mmol). The mixture is the stirred at RT for overnight. The solution was treated with benzene. The filtered solid was then successively treated with benzene and ether and evaporate the remaining solid. The residue was dissolved in minimum 48% HBr at RT which then was added MeCN to give a tan solid precipitate. Collect the solid in ice water bath and wash it with MeCN and ether. 352 mg product was obtained. Yield 60%; 1H NMR (500 MHz, DMSO-d6): δ 4.86021(s, 2H), 9.01 (s, 1H), 9.15 (s, 2H), 9.22 (s, 2H); ESI-MS: 255, 257(M++1)
Reaction SMILES: N(C1N=NC(C2C=CC=CC=2)=CC=1CCC)N.C(OCC)(=O)CC(OCC)=O.[C:29]1([C:35]2[CH:36]=[C:37]([CH2:50][CH2:51][CH3:52])[C:38]3[N:39]([C:41]([CH2:44][C:45]([O:47]CC)=[O:46])=[N:42][N:43]=3)[N:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([C:35]2[CH:36]=[C:37]([CH2:50][CH2:51][CH3:52])[C:38]3[N:39]([C:41]([CH2:44][C:45]([OH:47])=[O:46])=[N:42][N:43]=3)[N:40]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCc1cc(-c2ccccc2)nn2c(CC(=O)OCC)nnc12
Agent: CCCc1cc(-c2ccccc2)nnc1NN
Solvent: CCOC(=O)CC(=O)OCC
Product: CCCc1cc(-c2ccccc2)nn2c(CC(=O)O)nnc12

Procedure:
In a manner analogous to Example 1, by chlorinating 6-phenyl-4-propyl-3(2H)-pyridazinone [Chim. Ther. 6, 109 (1971)] there is obtained 3-chloro-6-phenyl-4-propylpyridazine, MS: 232 (M)+, which is converted by hydrazinolysis into 3-hydrazino-6-phenyl-4-propylpyridazine, MS: 228 (M)+. Subsequent ring condensation with diethyl malonate to ethyl 6-phenyl-8-propyl-s-triazolo[4,3-b]pyridazine-3-acetate, MS: 324 (M)+, followed by basic saponification gives the above acid as a solid, MS: 252 (M-CO2)+.
Reaction SMILES: C(S([NH:7][C:8]1([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][O:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CO.O1CCOCC1>[CH2:26]([O:25][C:23]([NH:7][C:8]1([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][O:10][CH2:11]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(C)C1(NC(=O)OCc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}propanoate (Preparation 34, 40 g, 140 mmol) in methanol (400 mL) at 0° C. was added a 4M solution of hydrogen chloride in 1,4-dioxane (72 mL). After 2 hours, a 4M aqueous solution of sodium hydroxide (400 mL) was added drop-wise until pH 7 was achieved whilst maintaining the temperature at 0° C. The methanol was removed in vacuo. The resulting solution was stirred with tetrahydrofuran (150 mL) and a 1M aqueous solution of sodium hydrogen carbonate (180 mL) at 0° C. Benzyl chloroformate (33.7 g, 187 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. The organics were removed in vacuo and the resulting solution extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to afford the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:36]=[CH:35][C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])=[CH:22][C:21]=1[N+:37]([O-:39])=[O:38].C(N(CC)CC)C>CN(C)C=O>[N+:37]([C:21]1[CH:22]=[C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])[CH:35]=[CH:36][C:20]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1)([O-:39])=[O:38]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (J.Med. Chem. 1998, 2157) (0.8 g), 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.9 g) and triethylamine (0.8 ml) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 72 h. The mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the organic layer was evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. The residue was triturated from methanol, yield 0.4 g as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH2:13][OH:14])[CH:12]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Si:29]([O:14][CH2:13][C:11]1[CH:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:8]=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of (5-morpholino-2-nitrophenyl)methanol (3.0 g, 12.6 mmol), triethylamine (2.54 g, 25.2 mmol) and 4-dimethylaminopyridine (0.2 g) in dichloromethane (100 mL) was added tert-butylchlorodimethylsilane (2.83 g, 18.9 mmol). After the addition was over, the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed by saturated sodium bicarbonate, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 4-(3-((tert-butyldimethylsilyloxy)methyl)-4-nitrophenyl)morpholine (4.0 g, yield 90.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 80 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (225 mg, 0.724 mmol) was reacted with tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (300 mg, 1.09 mmol) to afford the desired product (320 mg, 80%) as an orange solid: ESI MS m/z 552 [C27H30BrN5O3+H]+.