Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]5[O:34][CH:33]=[N:32][CH:31]=5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][C:41](Cl)=[O:42].C(O)C(N)(CO)CO>C1COCC1>[O:34]1[C:30]([C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]6[S:35][CH:39]=[CH:38][CH:37]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:31][N:32]=[CH:33]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
To a stirred solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-(1,3-oxazol-5-yl)phenyl]-2-pyrimidinamine (100 mg, 0.22 mmol) in 1 mL THF was added 2-thiopheneacetyl chloride (40 mg, 0.25 mmol). After 15 min. LC/MS indicated the reaction was complete and several equivalents of PS-trisamine were added and the mixture was stirred for 16 h followed by addition of 25 mg of TEA. The mixture was filtered and the resin washed well with THF. The filtrate was concentrated and the crude purified by HPLC (Agilent, 50-90% gradient over 15 min.) to give the title compound (45 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ 10.34 (s, 1H), 9.71 (s, 1H), 8.81 (d, J=6.8 Hz, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.18-8.37 (m, 3H), 7.87 (s, 1H), 7.67-7.72 (m, 2H), 7.54 (s, 1H), 7.24-7.42 (m, 6H), 7.09 (t, J=6.9 Hz, 1H), 6.93-6.95 (m, 2H), 6.49 (d, J=5.3 Hz, 1H), 3.84 (s, 2H) ppm. ES-LC/MS m/z=570 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:26](OC(OCC)OCC)C.Cl.[NH+]1C=CC=CC=1.C>C1(C)C=CC=CC=1.CO>[N:12]1([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:26]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2cnc3ccccc3c21
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65 mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 2 h. The reaction was then concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of CH2Cl2 and washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4 and concentrated to give a green oil. The green oil was dissolved in 200 mL of hot MeOH and treated with 10 g of activated charcoal. The hot solution was filtered and concentrated to give 5.25 g of tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light yellow syrup.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)([OH:3])=O.C(Cl)(=O)OCC(C)C.[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32])[CH3:25]>C(N(CC)CC)C>[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)=[O:3])[CH3:25]
Reactant: O=C(O)c1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: CCN1CCCC1CN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 49.9 %

Procedure:
5-Carboxyspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (2.04 g.), triethylamine (1.4 ml.), isobutyl chlorocarbonate (1.5 g.) and N-ethyl-2-aminomethylpyrrolidine (1.4 g.) were allowed to react in the same manner as Example 58. The product was converted to oxalate by a known procedure and recrystallization from ethanol gave colorless prisms of 5-(1-ethyl-2-pyrrolidinyl)methylcarbamoylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (1.567 g.).
Reaction SMILES: [C:1]([C:3]1[C:8](Cl)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[F-:10].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1[C:8]([F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: [F-]
Reactant: N#Cc1ncccc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ncccc1F
Yield: 50.1 %

Procedure:
A solution of 2-cyano-3-chloropyridine (1 g, 7.22 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was treated with potassium fluoride (1.26 g, 21.68 mmol) and heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 442 mg (50%) of 2-cyano-3-fluoropyridine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:22]
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(Cl)c1ccccc1F
Product: Cc1ccc(Cn2cnc(NC(=O)c3ccccc3F)c2C(N)=O)cc1
Yield: 60 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.25 g (5.43 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 87 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.15 g 4-(2-fluorobenzoylamino)-1-(4-methylbenzyl)-5-imidazolecarboxamide (yield 60%).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH2:22][CH3:23])[CH:20]=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].C[N:35](C)C1C=CC=CC=1>>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH2:22][CH3:23])[C:20]([NH2:35])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)c1ccccc1
Reactant: CCn1cnc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Agent: [NH2-]
Agent: [Na+]
Product: CCn1c(N)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 135 °C
Reaction time: 3 h

Procedure:
A mixture of 4.1 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-1H-benzimidazole, 1.2 parts of sodium amide and 20 parts of N,N-dimethylbenzenamine is stirred and heated slowly to 135° C. Stirring at 135° C. is continued for 3 hours. The reaction mixture is cooled and poured onto water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) and a small amount of ammonium hydroxide as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 1.5 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-1H-benzimidazol-2-amine; mp. 214.3° C.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[C:20]2[O:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[O:7])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH3:21][C:18]1([CH3:22])[CH2:17][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])[C:20]=2[O:19]1
Reactant: CCCCNC(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2O1

Procedure:
A suspension of 22 g of the N-(n-butylaminocarbonyl)-2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide prepared in Example 3, in 125 ml of xylene containing 0.3 g of DABCO was heated at 130°-135° C. while 5.3 ml of phosgene was added portionwise at a rate to maintain a reflux temperature of 130°-135° C. The mixture was refluxed for an additional 1.5 hours, cooled under nitrogen, and concentrated to dryness in vacuo. A sample of the crude oily product displayed a characteristic sulfonyl isocyanate band in the IR at 2200 cm-1.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH3:32][O:33][C:34](=[O:39])[C@H:35]([CH2:37][OH:38])[NH2:36]>C1COCC1>[CH3:32][O:33][C:34](=[O:39])[CH:35]([NH:36][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1([CH3:3])[O:5][CH2:6][CH2:7][O:8]1)[CH2:37][OH:38]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC1(CCCCC(=O)O)OCCO1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(CO)NC(=O)CCCCC1(C)OCCO1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoic acid (4.78 g, 25.40 mmol) in THF (165 mL) at −30° C. was treated sequentially with Et3N (7.50 mL, 53.33 mmol) followed by isobutyl chloroformate (3.81 mL, 27.94 mmol). After stirring for 1 h at −30° C., serine methylester hydrochloride (4.43 g, 37.94 mmol) was added and the reaction mixture was allowed to warm gradually to rt over 3 h and stirred for an additional 16 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (9:1:0→0:9:1 hept-EA-MeOH) gave the title compound as a colorless oil. TLC: rf (1000:50:4 CH2Cl2-MeOH—NH3)=0.1. LC-MS-conditions 02: tR=0.63 min [M+H]+=290.25.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:28](=[O:35])[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19]CC(OC(C)(C)C)=O)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.F[C:37](F)(F)[C:38]([OH:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+].[CH:49]1[C:61]2[CH:60]([CH2:62][O:63][C:64]([O:66]N3C(=O)CCC3=O)=O)[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]=2[CH:52]=[CH:51][CH:50]=1.Cl>C(Cl)Cl>[CH:58]1[C:59]2[CH:60]([CH2:62][O:63][C:64]([NH:8][C@H:9]([C:28](=[O:35])[N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:10][C:11]3[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:37][C:38]([OH:40])=[O:39])[CH:14]=[CH:15][CH:16]=3)=[O:66])[C:61]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:54]=2[CH:55]=[CH:56][CH:57]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCCCc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)c1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CCCCc1cccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 89.9 %

Procedure:
tert-Butyl (S)-5-(3-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)pentanoate (Compound SP431) (4.70 g, 9.62 mmol) was dissolved in DCM (30.0 ml), trifluoroacetic acid (15.0 ml, 195 mmol) was added and the mixture was stirred for 50 minutes at room temperature, after which the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in dioxane (34 ml) and a 10% aqueous sodium carbonate solution (68 ml), N-(9-fluorenylmethoxycarbonyloxy)-succinimide (3.15 g, 9.33 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was made acidic by adding a 5 N aqueous HCl solution and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Na2SO4, and then filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-30:70) to afford the title compound (Compound SP432) (4.65 g, 87%).
Reaction SMILES: C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:5].[Mg+2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CO.ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:23])=[O:5])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CSc1ccc(F)cc1[N+](=O)[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
4-Fluoro-1-methylsulfinyl-2-nitrobenzene can be obtained in the following way: 4.7 g of magnesium monoperoxyphthalate are added portionwise to a solution, under argon, of 1.9 g of 4-fluoro-1-methylsulfanyl-2-nitrobenzene in 6 ml of methanol and 30 ml of dichloromethane. The reaction mixture is then stirred at a temperature in the region of 20° C. for 3 hours, and is then filtered through sintered glass and the solid is washed with dichloromethane. The filtrate is washed with an aqueous sodium hydrogencarbonate solution then with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a column of 125 g of silice (particle size 40-63 μm), eluting with pure dichloromethane. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.3 g of 4-fluoro-1-methylsulfinyl-2-nitrobenzene are thus obtained in the form of a yellow foam (Rf=0.23, silica gel thin layer chromatography, eluent: dichloromethane/ethyl acetate 90/10)).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[Se:9])[N:5]1[C:10](=[O:25])[CH:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([OH:16])[CH:13]=[CH:14][CH3:15])[CH3:3].[K+].[Br-]>>[CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[Se:9])[N:5]1[C:10](=[O:25])[CH:11]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:12]([OH:16])[CH2:13][CH2:14][CH3:15])[CH3:3]
Reactant: CC=CC(O)C(OCc1ccccc1)C(=O)N1C(=[Se])OC[C@@H]1C(C)C
Agent: [Br-]
Agent: [K+]
Product: CCCC(O)C(OCc1ccccc1)C(=O)N1C(=[Se])OC[C@@H]1C(C)C

Procedure:
(4S)-4-(1-methylethyl)-3-[3-hydroxyl-2-(phenylmethoxy)-1-oxo-4-hexen-1-yl]-2-oxazolidineselone, Yield: 85.0%. IR (KBr, cm−1) 3600, 3027.8, 2964.8, 2859.7, 1725.4, 1480.3, 1398.3, 1277.3, 1200.3, 1144.2, 1018.2, 829.1, 752.1, 703.1, 584.1; 1H NMR δ 7.40 (m, 4H), 6.63 (d, 1H, J=3.6 Hz), 5.80 (m, 2H), 4.71 (m, 4H), 4.40 (m, 2H), 2.58 (d, 1H, J=7.8 Hz), 2.27 (dhep, 1H, J=7.0 Hz, J=3.7 Hz), 1.75 (d, 3H, J=6.0 Hz), 0.94 (d, 3H, J=7.0 Hz), 0.88 (d, 3H, J=6.9 Hz); 13C NMR δ 188.92, 171.67, 136.98, 129.30, 128.72, 128.31, 128.16, 78.93, 73.88, 73.49, 69.81, 63.93, 28.65, 18.05, 17.82, 14.81; 77Se NMR δ 441.94 (d, J=4.9 Hz). HRMS (FAB) m/z 412.1039 (412.1028 calcd for C19H26NO4Se, M+H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][O:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Oc1ncccn1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)COc3ncccn3)C(=O)O)cc2)cc1

Procedure:
Example 56 is prepared from 2-hydroxypyrimidine and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:12](I)[CH3:13].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH2:12][CH3:13])[C:10]#[N:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCI
Reactant: COc1cccc(CC#N)c1
Product: CCC(C#N)(Cc1ccccc1)c1cccc(OC)c1
Yield: 20 %

Procedure:
The procedures described in the portion of Example 1 which is concerned with the preparation of starting materials were repeated except that 3-methoxyphenylacetonitrile was alkylated in turn with ethyl iodide and benzyl bromide. The 2-benzyl-2-(3-methoxyphenyl)butyronitrile so obtained was treated with boron tribromide to give the required starting material in an overall yield of 20% as a gum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6].[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)c2cccc(O)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2cccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution or 4-methoxybenzyl 3-hydroxybenzoate (7.7g, 29.8 mmole), 4-dimethylaminopyridine (0.73g, 6 mmole) and N-benzyloxycarbonyl-L-valine (8.3 g, 33 mmole) in 100 ml dichloromethane was added dicyclohexyl-carbodiimide (7.22 g, 35 mmole) and the mixture was stirred for 2 days at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated and ethyl acetate (250 ml) was added. The organic phase was washed twice with 5% acetic acid; 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 13.9 g=94%
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH2:29][O:30][CH3:31])[C:4]([C:6]1[CH:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9](=[O:21])[N:10]2[N:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[C:11]=12)=[O:5])[CH3:2].Cl.C(OCC)(=O)C>CO>[CH2:1]([N:3]([CH2:28][CH2:29][O:30][CH3:31])[C:4]([C:6]1[CH:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9](=[O:21])[N:10]2[NH:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[C:11]=12)=[O:5])[CH3:2]
Reactant: CCN(CCOC)C(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccc(Cl)cc3c12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CCOC)C(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CN2

Procedure:
from N-ethyl-10-chloro-N-(2-methoxyethyl)-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxamide in methanol/glacial acetic acid (10:1), but without the addition of saturated methanolic hydrochloric acid, there is obtained N-ethyl-10-chloro-6,7-dihydro-N-(2-methoxyethyl)-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxamide of m.p. 184°-185° (ethyl acetate);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[C:14]([NH:16][C:17]([NH:22][CH3:23])=[N:18][CH2:19][CH2:20][SH:21])#[N:15]>C(O)C>[C:14]([NH:16][C:17]([NH:22][CH3:23])=[N:18][CH2:19][CH2:20][S:21][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])#[N:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CNC(=NCCS)NC#N
Solvent: CCO
Product: CNC(=NCCSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])NC#N

Procedure:
In order to characterise this product a solution of 2,4-dinitrochlorobenzene (7.7 g) in 95% ethanol (50 ml) was added to a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.0 g) in 95% ethanol. The mixture was refluxed for one hour and cooled. The resulting crystalline solid (7.73 g) was collected and was triturated with a large volume of ether and was recrystallised from acetonitrile to afford N-cyano-N'-methyl-N"-[S-(2,4-dinitrophenyl)-2-mercaptoethyl]-guanidine, m.p. 210°-211° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.NC(N)=[S:13].[OH-].[K+].Cl>C(O)C.O>[SH:13][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1
Reactant: NC(N)=S
Reactant: FC(F)(F)c1nnc(Br)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1nnc(S)s1
Yield: 59.1 %

Procedure:
699 g (3 moles) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole and 248 g (3.3 moles) of thiourea in a mixture of 600 ml of ethanol and 75 ml of water were heated for 2 hours under reflux. A solution of 223 g of potassium hydroxide in 2 liters of water was rapidly added dropwise to the reaction solution while it was still hot, and the mixture was once more heated under reflux, for 5 minutes. The cooled solution was adjusted to pH 5 with dilute hydrochloric acid and extracted repeatedly with methylene chloride. After drying and concentrating, the residue was recrystallized from a litte petroleum ether. The mother liquor yielded further product. 330 g (59% of theory) of 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole of melting point 73° C were obtained. ##STR85##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][N:18]2[CH2:17][CH2:16][N:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:10][CH:11]=3)[CH2:20][CH2:19]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(OCCCCBr)cc1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: Fc1ccc(Cc2ccc(N3CCN(CCCCOc4ccc(F)cc4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (10) synthesized in Example 3 and 4-(4-fluorophenyl)oxybutyl bromide to produce the above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24])([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:16])([F:15])[F:17])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Yield: 60.9 %

Procedure:
A solution of 109 mg of N-(6-nitro-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 3 ml of ethanol and 3 ml of acetic acid is hydrogenated in the presence of 30 mg of 10% palladium on carbon. After disappearance of the starting material followed by TLC the reaction mixture is diluted with ethanol and acetic acid and slightly warmed up. The catalyst is filtered off and the filtrate concentrated to dryness. Trituration of the residue with ethyl acetate gives 61 mg (61%) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide as a yellow powder, m.p. 240° C. (decomp.). 1H-NMR (DMSO-d6, 400 MHz): 3.12 (s, 3H); 5.66 (s, 2H); 7.24 (s, 1H); 7.46 (s, 1H); 10.3 (br s, 1H); 11.4 (br s, 1H).