Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>COCCO>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:29]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: Cc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCCC(=O)O)c(O)c2c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 1-cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.20 mmol), β-alanine (365 mg, 4.10 mmol) and NaOMe (166 mg, 3.07 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. After the mixture was cooled to r.t., solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 47 mg of the title compound. MS: (+) m/z 406.21 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:6](N)[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([O:23][C:24]([NH:26][C@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])(=O)[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:12][C:11]([O:10][C:8]([N:4]1[CH2:5][CH:6]([C:32](=[O:33])[C@H:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[NH:26][C:24]([O:23][CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[O:25])[CH:2]([OH:1])[CH2:3]1)=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)C[C@H](NC(=O)OC(=O)c1ccncc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Product: CC(C)C[C@H](NC(=O)OCc1ccncc1)C(=O)C1CN(C(=O)OC(C)(C)C)CC1O

Procedure:
3-hydroxy4-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester was coupled with iso-nicotinoyloxycarbonyl leucine in a similar manner as that described above to give 8.5 grams of the title compound: MS (ES+) 451 (MH+, 100%).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[C:18](#[N:20])[CH3:19]>>[C:8]1([C:6]2[C:5]3[C:4](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]=[C:18]([NH2:20])[CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC#N
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Nc1cc(-c2ccccc2)c2ccccc2n1
Temperature: 25 °C

Procedure:
Acetonitrile (150 mL) was heated to reflux for 30 minutes in the presence of potassium hydroxide (14.2 g, 254 mmol). 2-amino-benzophenone (10.0 g, 50.7 mmol) in acetonitrile (165 mL) was added to the reaction mixture. After heating to reflux overnight, the mixture was cooled to room temperature, and the resulting solid was filtered. HCl (1.0 M, 100 mL) was added to the solution, and the resulting solid was filtered. The solids were combined, dissolved in ethyl acetate, dried over magnesium sulfate, and filtered. The volatile components were removed with a rotary evaporator, and the solid was recrystallized from ethyl acetate and heptane.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][NH:37]2)=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][N:37]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: Fc1ccc2c(c1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc(F)cc21

Procedure:
0.10 g (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 35 mg (0.26 mmol) 6-fluoro-2,3-dihydro-1H-indole, 0.10 mL (0.72 mmol) TEA and 90 mg (0.28 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Yield: 59 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-methanone (100 mg, 0.26 mmol), hydroxylamine hydrochloride (55 mg, 0.79 mmol) and sodium carbonate (83 mg, 0.78 mmol) in ethanol (1 ml) was heated under reflux conditions for 17 h, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×75 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (ethyl acetate/heptane) to yield the title compound as white solid (61 mg, 59%).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:14]=[C:13]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[S:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:12]=[C:11]([Br:33])[C:4]=1[O:5][CH2:6][C:7](OC)=[O:8]>CO>[Br:2][C:3]1[CH:14]=[C:13]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[S:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:12]=[C:11]([Br:33])[C:4]=1[O:5][CH2:6][C:7]([NH2:1])=[O:8]
Reactant: N
Reactant: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Solvent: CO
Product: NC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methanol (10 mL) was purged with ammonia gas for 10 min at 0° C. [2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-acetic acid, methyl ester (0.50 g, 0.787 mmol) was added and the vessel was sealed, warmed to room temperature and stirred for two days. The reaction mixture was concentrated, diluted with ether and filtered. The solid was boiled in ethyl acetate (8 mL), hot filtered and washed with ethyl acteate and pentane and dried in vacou to provide the title compound as an off white solid (0.22 g, 45%): mp 263-265° C.: NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1 H), 8.09 (d, J=8 Hz, 1 H), 7.88 (s, 2 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.67-7.51 (m, 5 H), 7.30 (ddd, J=8, 7, 1 Hz, 1 H), 6.71 (d, J=8 Hz, 1H), 4.56 (s, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 617 (30%), 619 (90%) 621 (100%) 623 (40%); Anal. Calc. for C24H14Br3NO2S: C, 46.48, H, 2.28, N, 2.26. Found: C, 45.69, H, 2.02 , N, 2.14.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:14]=2.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][CH2:21]1)[CH:14]=2
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2cc(N3CCNCC3)ccc2cc1-c1nc2ccccc2s1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3cc(-c4nc5ccccc5s4)c(=O)oc3c2)CC1
Reaction time: 4 h
Yield: 47.3 %

Procedure:
100 mg (0.28 mmol) 3-Benzothiazol-2-yl-7-piperazin-1-yl-chromen-2-one were dissolved in 15 mL DMF and treated under argon with 183 mg (2 eq.) cesium carbonate, cooled below 5° C. and treated with 1 eq (0.018 mL) Mel. After stirring for 4 h, the reaction mixture is diluted with 100 mL dichloromethane and washed twice with ice-water. The organic phase is evaporated and the residue column chromatographed (silica gel, dichloromethane/EtOH 9:1). Recrystallization from methanol/dichloromethane yields 50 mg (47%) desired product as an orange powder.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12](=O)[C:11]=3[C:21](O)=[O:22])=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:26])=O>O1CCCC1>[Cl:26][C:12]1[C:11]2[C:21](=[O:22])[C:6]3[C:5]([C:10]=2[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[CH:4][C:3]1[O:2][CH2:1][O:9][C:8]=1[CH:7]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1c(-c2ccc3c(c2)OCO3)c2ccccc2[nH]c1=O
Solvent: C1CCOC1
Product: O=C1c2cc3c(cc2-c2c1c(Cl)nc1ccccc21)OCO3
Temperature: 90 °C
Yield: 59.9 %

Procedure:
A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline carboxylic acid obtained in reference example 1 (10 g, 32.3 mmol) and phosphorous oxychloride (100 ml, 1.07 mol) was refluxed with heat for 4 hours. The reaction mixture was distilled to dryness and washed with n-hexane several times. To the residue obtained was added 50 g of polyphosphoric acid, and the mixture was heated at 90° C. for 2 hours. The reaction mixture was poured into ice water to filtrate a crystal precipitated. The crystal obtained was dissolved in tetrahydrofuran to filter off undissolved substances, and purified by silica gel column chromatography (eluent: chloroform) to give 6.0 g (yield 59.9%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]=1[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2)nc(-c2ccc([N+](=O)[O-])cc2)c1C(=O)O
Yield: 39.7 %

Procedure:
A suspension of ethyl 6-methyl-2-phenyl-4-(4-nitrophenyl)-5-pyrimidinecarboxylate (39 g) and aqueous sodium hydroxide (5.19 g in 10 ml H2O) in ethanol (390 ml) and water (195 ml) was refluxed for 10 hours. After evaporating the solvent, the residue was dissolved in a suspension of water (200 ml) and chloroform (200 ml) under stirring. The separated aqueous layer was adjusted to pH 3.0 with 10% aqueous HCl. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 6-methyl-2-phenyl-4-(4-nitrophenyl)-5-pyrimidinecarboxylic acid (14.3 g).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:25][C@@H:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)[N:19]=[N:20][C:21]=3[C:22]([NH2:24])=[O:23])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:31](O)(=[O:35])[C:32]#[C:33][CH3:34].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[C:31]([N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:18]2[N:19]=[N:20][C:21]([C:22]([NH2:24])=[O:23])=[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])=[CH:10][CH:11]=3)[N:17]=2)[CH2:27]1)(=[O:35])[C:32]#[C:33][CH3:34]
Reactant: CC#CC(=O)O
Reactant: NC(=O)c1nnc(N[C@@H]2CCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC#CC(=O)N1CC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(pyrrolidin-3-ylamino)-1,2,4-triazine-6-carboxamide (83) (90 mg, 0.22 mmol) in NMP (4 mL) were 2-butynoic acid (55 mg, 0.66 mmol), DIEA (380 μL, 2.2 mmol) and then PyBOP (230 mg, 0.44 mmol). The mixture was stirred at RT for 30 min, quenched with TFA (0.6 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC using 0.1% formic acid in water and neat MeCN to isolate the title compound, (R)-3-(1-but-2-ynoylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (505) as formic acid salt. LC-MS (ESI): m/z (M+1) 479.1. UV: λ=280 nm. Proton NMR (CD3OD): δ 7.87 (2H, m), 7.47 (2H, m), 4.56 (1H, m), 4.07 (1H, m), 3.88-3.77 (2H, m), 3.75-3.44 (9H, m), 2.37 (1H, m), 2.15 (1H, m), 2.05 (3H, s) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:7][CH:6]=1)#[N:4].Br[CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.O>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:23][CH:24]=1)#[N:4]
Reactant: C=CCOC(=O)C(Cc1ccc(C#N)cc1)C(=O)OCC=C
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.13 g (178.36 mmol) of sodium hydride are added in portions to a solution of 48.53 g (162.14 mmol) of diallyl 2-(4-cyanobenzyl)malonate in 180 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is then cooled to 0° C. again and, after addition of 55 g (194.6 mmol) of methyl 4-(2-bromoethyl)benzoate [CAS No. 136333-97-6] in 195 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture, which is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 10:1). 33.4 g (72.37 mol, 44% of theory) of a colorless solid are obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[NH2:19].C(Cl)(Cl)Cl.C([O:26]CC)C>ClCCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:26]
Reactant: Cc1ccc(N)c(CSc2nc3ccccc3[nH]2)c1
Reactant: CCOCC
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Cc1ccc(N)c(CS(=O)c2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared by the method of Example 3 using 2.63 g of the title product of Example 25 instead of the title product of Example 2 and using 1,2-dichloroethane as solvent instead of chloroform. Trituration with diethyl ether gave 3.0 g of the title compound. Analysis. Calc'd. for C15H15N3OS: C, 63.14; H, 5.30; N, 14.73; S, 11.23. Found: C, 61.44; H, 4.98; N, 14.35; S, 11.10.
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1>CO>[CH2:11]([N:21]1[CH2:26][CH2:25][N:24]([C:3]2[C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:23][CH2:22]1)[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: COc1cccccc1=O
Solvent: CO
Product: O=c1cccccc1N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-methoxytropone (1.36 g, 10.0 mmol) (Pietra, F. Chem Review, 1973, 73:293) and 1-piperonylpiperazine (6.61 g, 30.0 mmol) in methanol (50.0 mL) was refluxed for 16 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to column chromatography using ethyl acetate as the eluent. The title compound was obtained as a yellow oil (1.24 g, 38%). MS (FAB) 325 (M+ +1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[N:6]=[C:5]2Cl.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].O>O1CCCC1>[CH2:14]([O:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:7]([Cl:12])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nc(Cl)c2cc(Br)ccc2n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(OCc2ccccc2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a cooled solution of 6-bromo-2,4-dichloroquinazoline (1.39 g, 5 mmol) in tetrahydrofuran (50 mL) was added a solution of benzyl alcohol (0.52 mL, 5 mmol) and sodium hydride (210 mg, 5.25 mmol, 60% in mineral oil) in tetrahydrofuran (15 mL) dropwise at 0° C. After being stirred at room temperature for 2 hours, the reaction mixture was poured into cold water (10 mL) and then extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 1.73 g of the desired product as a yellow solid (yield was 99%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1ncc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 2-amino-5-bromopyrimidine (226 mg, 1.3 mmol) according to general procedure II. Obtained as a brown solid (60 mg, 14%). MS (ISP) 449.2 [(M+H)+]; mp 255-256° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[N+:9]([C:12]1[O:16][C:15]([CH:17]=[CH:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:23]2[CH:22]=[CH:21][N:20]=[C:19]2[CH:18]=[CH:17][C:15]2[O:16][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Reactant: ClCc1ccncc1
Product: O=[N+]([O-])c1ccc(C=Cc2nccn2Cc2ccncc2)o1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 4-picolyl chloride and 2-[2-(5-nitro-2-furyl)vinyl]imidazole. Recrystallization from ethanol-water gave an orange solid product melted 130°-131°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH2:21][CH3:22])[C@H:16]([C@@H:8]3[CH2:7][CH:6]([CH3:26])[C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14OCC[O:17]1.Cl>CO>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH2:21][CH3:22])[C@H:16]([C@@H:8]3[CH2:7][CH:6]([CH3:26])[C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]4=[O:17]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC21OCCO1
Agent: Cl
Solvent: CO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC2=O
Yield: 92.4 %

Procedure:
Suspend the foregoing dl-3-methoxy-17,17-ethylenedioxy-6-methyl-13-ethylgona-1,3,5(10)-triene (9.0 g) in methanol (200 cc) and concentrated hydrochloric acid (5.0 cc) and heat on the steam bath for 15 minutes. Remove the solvent under vacuum, partition the residue between ether and aqueous sodium bicarbonate and isolate the product. Recrystallize from methanol to obtain the dl-3-methoxy-6-methyl-13-ethylgona-1,3,5(10)-trien-17-one (7.29 g), m.p. 115°-123°C. Recrystallize a small portion to obtain an analytical sample, m.p. 123°-127°C, λ max. EtOH 280 mμ, λ max. KBr 5.75 μ.
Reaction SMILES: [C@@H:1]1([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[N:19]([O-])=[O:20].[Na+]>O.C(O)(=O)C>[C@@H:1]1([NH:12][C:13]([N:15]([N:19]=[O:20])[CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=N[O-]
Reactant: CCCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.1 %

Procedure:
1-(β-D-glucopyranosyl)-3-n-propylurea (1.50 g) was dissolved in a mixture of water (10 ml) and acetic acid (2 ml), and to the resulting solution was added 560 mg (1.5 mol. equivalents) of sodium nitrite at ambient temperature under stirring to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) for the removal of sodium ion and then concentrated to dryness below 35° C and under a reduced pressure. Crystallisation of the residue from n-propanol gave 1.35 g of the titled compound. Yield 80%. mp. 112° C (decomposition with foaming). [α]D21 -6° (c 1.0, H2O).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:16][C@@H:17]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[CH3:18]>>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[C@@H:17]([CH3:18])[CH2:16][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=2)=[N:11]1
Reactant: Cc1cc(-c2cc[nH]n2)ccc1C#N
Reactant: C[C@@H](CBr)N1C(=O)c2ccccc2C1=O
Product: Cc1cc(-c2ccn(C[C@H](C)N3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Yield: 25.4 %

Procedure:
2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.35 g, 12.2 mmol) was reacted with (S)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione (3.61 g, 13.5 mmol) using the method of Example 27(a). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to yield 1.15 g (25%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.59 (d, 3H), 2.47 (s, 3H), 4.41 (m, 1H), 4.83 (m, 2H), 6.46 (d, 1H), 7.39 (m, 2H), 7.47 (m, 2H), 7.69 (m, 2H), 7.78 (m, 2H).