Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][NH2:9].[OH-].[Na+].[S:12]([O-:16])([O-:15])(=[O:14])=[O:13].CS[C:19]([NH2:21])=[NH2+:20].CS[C:24]([NH2:26])=[NH2+:25]>C(OCC)(=O)C>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][NH:9][C:19]([NH2:21])=[NH:20].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][NH:9][C:24]([NH2:26])=[NH:25]
Reactant: CSC(N)=[NH2+]
Reactant: O=S(=O)([O-])[O-]
Reactant: NCCCc1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N=C(N)NCCCc1nccs1
Product: O=S(=O)(O)O

Procedure:
A mixture of 3-phthalimidothiobutyramide (15.0 g) and bromoacetaldehyde diethyl acetal (19.7 g) is heated at 100° C with frequent agitation for two hours. The solid mass is extracted with hot ethanol, and the extracts are treated with charcoal and filtered. On cooling, crystals are deposited. These are dissolved in water (50 ml) and the solution washed with ether (25 ml) and diluted with aqueous sodium acetate to pH 6. A yellowish-brown solid crystallizes out which is collected and washed with water yielding 3-(2-thiazolyl)propylphthalimide hydrobromide, m.p. 67°-70° C. The phthalimido derivative (5.0 g) is dissolved in ethanol (50 ml), hydrazine hydrate (2 ml) is added and the solution heated under reflux for two hours. The solvent is removed under reduced pressure and the residue is dissolved in concentrated hydrochloric acid (30 ml) and heated under reflux for one hour. After cooling, phthalhydrazide is removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from methanol-ether yielding 3-(2-thiazolyl) propylamine dihydrochloride, m.p. 160°-165° C. 3-(2-Thiazolyl)propylamine (2.7 g) (prepared from the amine dihydrochloride by reaction with aqueous sodium hydroxide and extraction with ethyl acetate) is mixed intimately with finely powdered S-methyl-thiouronium sulphate (5.3 g) and the mixture is heated at 140°-150° C for one hour. After cooling, the mass is extracted with hot ethanol several times, and the combined extracts are diluted with ether which causes the precipitation of a white solid. Recrystallization from aqueous ethanol yields 3-(2-thiazolyl)propylguanidine hemisulphate, m.p. 160°-163° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH:48]3[CH2:50][CH2:49]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH:48]3[CH2:49][CH2:50]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K36) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (347 mg, 71%).
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]1([CH3:21])[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.C1(SCl)CCCCC1.[CH2:30]([N:32](CC)CC)[CH3:31]>C1C=CC=CC=1.O>[CH2:5]([NH:13][C:30](=[N:32][CH2:20][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:14][CH3:21])[CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C
Reactant: CCCCCCCCN
Agent: ClSC1CCCCC1
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCCCCCCCN=C(C)NCCCCCCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In like manner a mixture comprising 120 grams (2.0 moles) of anhydrous acetic acid and 314 grams (4.3 mole) of n-octylamine along with 200 cc. of xylene is placed in a 1 liter flask equipped with a Dean-Stark water trap. The flask is then heated to reflux and maintained thereat for a period of 3 hours, the water of condensation which is formed during the reaction being continuously removed from the system. At the end of the 3-hour period, the temperature of the flask is increased until the xylene solvent has been distilled off. Upon recovery of the solvent, the reaction mixture is then allowed to cool to room temperature and transferred to a separate flask. The N,N'-dioctylacetamidine which is prepared thusly is then placed in a flask along with triethylamine and a benzene solvent following which the flask is then cooled to a temperature of 0° C. Upon reaching this reduced temperature, the mixture is treated by slowly adding dropwise an equimolar amount of cyclohexanesulfenyl chloride, the temperature of the solution being maintained in a range of from 0° to 10° C. Upon completion of the addition of the cyclohexanesulfenyl chloride which is accompanied by continuous stirring, the mixture is allowed to return to room temperature while maintaining the stirring thereof. At the end of a 1-hour period, the solid which is formed is washed with benzene and air dried for a period of 24 hours. The solution is then washed with water, dried over magnesium sulfate and the benzene solvent is removed by vacuum. Upon further standing, the desired product comprising N,N'-dioctyl-N-cyclohexylthioacetamidine will crystallize out and may be then recrystallized from an isopropyl-ethyl acetate solution.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9](Cl)=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].C(Cl)Cl.N[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([N:25](CC)CC)C>O>[CH2:1]([O:3][C:4]1[C:5]([C:9]([NH:25][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[OH:16])=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2]
Reactant: CCOc1cscc1C(=O)Cl
Reactant: NOc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOc1cscc1C(=O)Nc1ccccc1O
Reaction time: 8 h

Procedure:
A 1.31 g. portion of 4-ethoxy-3-thiophenecarbonyl chloride is dissolved in 10 ml. of dry methylene chloride and then added dropwise to a solution of 0.75 g. of O-aminophenol in 10 ml. of dry methylene chloride with stirring. A 1.0 ml. portion of triethylamine is added and the mixture is then stirred overnight. This mixture is poured into water, stirred for 30 minutes and extracted three times with methylene chloride. The extracts are filtered through diatomaceous earth and then diluted with petroleum ether giving a white solid. This solid is recrystallized from a mixture of 250 ml. of methylene chloride and 250 ml. of petroleum ether giving 4-ethoxy-2'-hydroxy-3-thiophenecarboxanilide as white crystals.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9](=[O:21])[CH2:10][C:11](=[O:20])[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl>[Br:1][C:12]1[C:11](=[O:20])[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:21][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Reaction time: 3 h

Procedure:
A solution of bromine (10.25 ml, 0.198 mol) in chloroform (50 ml) was added dropwise over 30 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (52.0 g) in chloroform (400 ml) at -10° to -20° C. The pale solution was stirred for a further 3 hours without cooling, washed with water and evaporated. The residual solid was recrystallised from ethanol-water to give ethyl 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 135° C.). This ester was hydrolysed as in Example 33 to give the title product (mp 247° C. with decomposition).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][CH:49]([N:52]6[CH2:57][CH2:56][O:55][CH2:54][CH2:53]6)[CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:58])=[C:37]([OH:59])[C:36]3=[O:60])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:47][CH2:48][CH:49]([N:52]6[CH2:53][CH2:54][O:55][CH2:56][CH2:57]6)[CH2:50][CH2:51]5)=[CH:42][CH:41]=4)[C:38]([CH3:58])=[C:37]([O:59][CH3:3])[C:36]3=[O:60])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(C2CCC(N3CCOCC3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: OCCO
Solvent: CCOCC
Product: COC1=C(C)C(c2ccc(C3CCC(N4CCOCC4)CC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-(4-morpholinocyclohexyl)phenyl)-1H-pyrrol-2(5H)-one (0.350 g, 0.74 mmol, 1 eq) and MeOH (10 ml); yield: 0.040 g (11%); MS m/z: 487.2 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 12.34 (s, 1H), 8.13 (d, 1H), 7.70 (d, 1H), 7.45 (d, 2H), 7.17 (d, 5H), 5.75 (s, 1H), 3.95 (s, 3H), 3.56 (d, 4H), 2.35 (d, 4H), 2.1 (d, 1H), 1.90 (d, 2H), 1.69 (d, 5H), 1.4 (d, 4H); HPLC (METHOD [A]): rt 7.84 min (98.72%)
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[F:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: COc1ccc(N)c(F)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c(F)c1
Yield: 85 %

Procedure:
Prepared from VII and 2-fluoro-4-methoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 85%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2844, 2226, 1731, 1649, 1613, 1583, 1507, 1493, 1460, 1445, 1379, 1356, 1305, 1263, 1212, 1168, 1153, 1129, 1090, 1027, 980, 947, 841, 830, 818; 19F NMR (282 MHz, DMSO-d6) δ −120.02; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.30 (s, 1H), 6.92 (m, 1H), 6.80 (d, 2H, J=9.0 Hz); HRMS calcd for C17H11N5OSF (M+H+): 352.0668, found 352.0658.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].C(N(CC)CC)C.[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)=[O:15]>C(Cl)(Cl)Cl.O>[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:21])=[CH:18][CH:17]=1)=[O:15]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(C(=O)NCC(F)(F)F)cc1
Yield: 85.7 %

Procedure:
In a suspension of 1.00 g of 4-formyl benzoic acid in 15 ml of benzene, 0.87 g of thionyl chloride and 2 drops of N,N-dimethylformamide were added, and stirred under reflux with heat for 2 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain 1.14 g of crude 4-formyl benzoic acid chloride as white crystal. In a solution of 0.66 g of 2,2,2-trifluoroethylamine and 0.81 g of triethylamine in 6 ml of chlororform, the solution of 1.14 g of the crude 4-formyl benzoic acid chloride in 6 ml of chloroform was added dropwise under cooling with ice and with stirring, after the completion of the addition dropwise, continued to stir at room temperature for further 18 hours. After the completion of the reaction, the reaction mixture was added in 30 ml of water, extracted with chloroform (20 ml×3). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residual solid was washed with hexane to obtain 1.32 g of the aimed product as white crystal.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[C:21]#[N:22])C1C=CC=CC=1.O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:22][C:21]1[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@@H:11]([NH2:10])[CH3:23])[N:20]=[C:26]([CH3:33])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[C@@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N

Procedure:
Prepared as in Example 2a from (S)-benzyl(1-(3-amino-2-cyanophenoxy)propan-2-yl)carbamate (Example 26c) and ethyl 3-oxobutanoate as brown solid. MS 304 (MH+).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9](I)[N:4]2[N:3]=1.[C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)#[N:12].C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([C:43]([F:46])([F:45])[F:44])[C:39]([NH2:42])=[N:40][CH:41]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:9]2[N:4]3[C:5]([S:6][C:2]([C:17]4[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=4)[C:11]#[N:12])=[N:3]3)=[N:7][CH:8]=2)=[CH:37][C:38]=1[C:43]([F:46])([F:44])[F:45]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C

Procedure:
To a mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.150 g, 0.455 mmol), 3-cyanophenylboronic acid (0.477 mmol) and PdCl2(Ph3P)2 (0.064 g) in dioxane (3 mL), an aq. solution of Na2CO3(2 M, 0.9 mL) was added. The reaction mixture was heated at 110° C. for 24 h in a sealed tube. The solvent was evaporated, the residue precipitated with water, and after drying the resulting gum was washed with Et2O. The residue was suspended in dioxane (3 mL), and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (1.05 eq), PdCl2(Ph3P)2 (0.2 eq) and a sat. aq. solution of K2CO3 (0.9 mL) were added. The reaction mixture was heated at 100° C. for 16 h and then concentrated to dryness. The residue was washed with water, followed by ethyl ether. The resulting solid was washed with DCM followed by MeOH. The DCM filtrate was evaporated and purified by HPLC to yield the desired product (0.10 g). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=5.15 min, [M+H]+ m/z 387.1; 1H NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.49 (s, 1H), 8.38-8.25 (m, 2H), 8.12 (d, J=7.9 Hz, 1H), 7.92-7.74 (m, 2H), 6.75 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O=[As](O[As](=O)=O)=O.O[CH2:21][CH:22]([CH2:24]O)O.S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:21]=[CH:22][CH:24]=[N:12]2)=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: OCC(O)CO
Reactant: COc1cc(N)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Solvent: O
Product: COc1cc2ncccc2cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a mixture of 3-methoxy-4-nitro-phenylamine (13.4 g, 80.0 mmol), arsenic pentoxide (11.0 g, 48.0 mmol) and glycerol (33 mL, 216.0 mmol) at 100° C., was added, dropwise, concentrated sulfuric acid (4.7 mL, 88.0 mmol). The reaction mixture was then heated at a temperature ranging between 150 and 160° C. for 2 hours and then was cooled. Water (200 mL) was added and the resulting mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc) to give 9.00 g (61% yield) of 7-methoxy-6-nitro-quinoline as an orange solid.
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:22]1[CH2:32][CH:23]1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(O)C.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl>[O:25]([CH2:24][CH:23]([OH:22])[CH2:32][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: OC(COc1ccccc1)CN1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1
Yield: 15 %

Procedure:
A mixture of 2.6 g (0.0093 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47), 1.4 g (0.0093 moles) of 2,3-epoxypropoxybenzene and 25.0 ml of 2-propanol was heated at reflux for 5 hours. The reaction mixture was evaporated in vacuo and gave a solid. The solid was dissolved in dichloromethane and passed through a pad of magnesium silicate. The effluent was evaporated to a solid. The solid was recrystallized from ethanol/ether/hexane, filtered, and washed with ether and gave 600 mg of the product of the Example as yellow crystals, mp 143°-145° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1(C#N)[CH2:14][CH2:13][CH2:12]1.C[Mg]I.IC.[Mg].CC[O:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:26](=[O:25])[CH3:27])[CH2:14][CH2:13][CH2:12]1
Reactant: N#CC1(c2ccc3ccccc3c2)CCC1
Reactant: CCOCC
Agent: C[Mg]I
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CI
Product: CC(=O)C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(2-naphthyl)cyclobutanecarbonitrile (48.2 g) in toluene (100 ml) was added dropwise under nitrogen to a stirred solution of methylmagnesium iodide [prepared in the usual manner from iodomethane (22 ml) and magnesium (8.16 g)] in ether (60 ml), then the mixture was stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed with ether (50 ml), and added in portions to a mixture of concentrated hydrochloric acid (125 ml) and water (200 ml). The mixture was heated at 100° C. with occasional stirring for 10 minutes, then it was cooled to ambient temperature. The product was extracted into toluene (3×200 ml), then the extracts were washed with water (200 ml), and the solvent was removed in vacua. The residue was triturated with petroleum ether (b.p. 40-60° C.) (100 ml), and the resulting solid was collected by filtration and dried in vacuo to give 1-[1-(2-naphthyl)cyclobutyl]ethanone as a yellow solid (35 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:17]=[C:18]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][NH:23][CH2:24]2>COC(O)C>[NH:17]=[C:18]([N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][N:23]([C:2]1[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=1)[CH2:24]2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: N=C(c1cccc2c1CCNC2)N1CCOCC1
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(cccc4C(=N)N4CCOCC4)C3)[nH]c(=O)c2cc1OC
Temperature: 95 °C
Reaction time: 18 h
Yield: 17.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b(0.159 g, 0.62 mmol) and 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline 28a (0.179 g, 0.69 mmol) in methoxyethanol (10 mL) was heated to 95° C. with stirring for 18 h. the volatiles were evaporated and the residue was purified by flash column eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide to yield 50 mg of 2-[5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinolin-2-yl]-6,7-dimethoxy-3H-quinazolin-4-one 901. The product was converted to the hydrochloric acid salt, mp. 249–251° C., [M+H]+=450.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][S:10]SC>CCOCC.C([Li])CCC>[CH3:9][S:10][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1
Reactant: CSSC
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1ccc(Br)nc1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 2,5-dibromopyridine (23.4 g, 0.099 mol) in ether (500 mL), was added dropwise n-butyl lithium (n-BuLi) (1.52 M in n-hexane, 68 mL, 0.10 mmol) at −78° C. and the mixture was stirred for 1 hour at the temperature. Dimethyldisulfide (9.8 mL, 0.11 mol) was added slowly at −78° C. and the mixture was stirred for 1 hour at that temperature and further 1 hour at 0° C. The mixture was quenched with aqueous 1N hydrochloric acid (200 mL) and extracted with ether (100 mL×2), dried over MgSO4, and concentrated in vacuo to yield the title compound (18.9 g, 94%).
Reaction SMILES: C[Al](C)C.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][S:11][CH2:12][CH2:13][C:14]([O:16]C)=O.[NH2:18][CH2:19][C:20]([N:22]1[CH2:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][C:24]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:23]1=2)=[O:21].CO>C1(C)C=CC=CC=1>[Cl:37][C:35]1[CH:34]=[CH:33][C:24]2[O:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[CH2:28][N:22]([C:20](=[O:21])[CH2:19][NH:18][C:14](=[O:16])[CH2:13][CH2:12][S:11][CH2:10][C:6]3[O:5][CH:9]=[CH:8][CH:7]=3)[C:23]=2[CH:36]=1
Reactant: COC(=O)CCSCc1ccco1
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(CCSCc1ccco1)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 5 h

Procedure:
Trimethylaluminum (2.0M in toluene; 4.6 mL) was added dropwise via syringe to a stirred solution of methyl 3-[(2-furanylmethyl)thio]propanoate (0.75 gram) and 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (1.00 gram) in toluene (30 mL) at room temperature under nitrogen, and the reaction was stirred for 5 hours. Methanol (14 mL) was then added, and the reaction was stirred at room temperature overnight. The reaction was evaporated in vacuo, and the resulting orange residue was partitioned between chloroform (50 mL) and 1N NaOH (50 mL). The layers were separated and the aqueous layer was extracted with chloroform (50 mL). The combined chloroform extracts were washed with 1N NaOH (50 mL), 1N HCl (2×50 mL), and brine (50 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 3:1 chloroform:ethyl acetate followed by recrystallization from cyclohexane/ethyl acetate. The yield of the title compound was 0.63 gram (40%) in the form of a tan solid. Analysis calculated for C23H21ClN2O4S: C, 60.46; H, 4.63; N, 6.13; Cl, 7.67; S, 7.02. Found: C, 60.16; H, 4.62; N, 6.05; Cl, 8.06; S, 7.02. DSC: 90°-95° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+:21].[Na]>O1CCCC1>[OH2:15].[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+:21]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccccc1
Product: O
Reaction time: 3 h

Procedure:
A stirred solution of 111 g. of 2-amino-3-benzoylphenylacetic acid in 777 ml. of tetrahydrofuran was treated with 31.3 g. of 50% sodium hydroxide solution. The sodium salt began to separate after 15 minutes. After 3 hours stirring using an ice bath, the sodium salt was collected and dried (64.0 g., m.p. 245°-252° C.). The salt was recrystallized by adding 1 gm. of salt to 10 ml. of refluxing 95% ethanol followed by the addition of 5 ml. of hot isopropyl ether. After several hours cooling the salt is collected and air dried. The recrystallized salt (90% recovery) melted at 254°-255.5° C.