Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([CH3:11])=[CH:4][CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:15])=[O:9])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(Cl)nc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-methylpyridine-2-carboxylic acid (3.69 g, 21.51 mmol) was taken up in THF (100 mL)/MeOH (25 mL). A solution of TMS-diazomethane (21.5 mL, 43.0 mmol) was added and the resulting solution stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (2-20% EtOAc/hexanes) to give the title compound as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20]C(=O)C(Cl)Cl)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=1)=[O:7].[NH2:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>CN(C)C=O.C[Si](CC(N)=O)(C)C.C(Cl)Cl>[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][OH:20])[C:16]([NH:26][CH:27]2[C:45](=[O:46])[N:29]3[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]4[N:40]([CH3:41])[N:39]=[N:38][N:37]=4)[CH2:32][S:33][C@H:28]23)=[O:18])[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: O=CNc1cccc(C(=NOC(=O)C(Cl)Cl)C(=O)O)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3cccc(NC=O)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A solution of phosphoryl chloride (2.14 g.) in N,N-dimethylformamide (14 ml.) was stirred at 37° to 40° C. for 30 minutes. To the solution were added methylene chloride (14 ml.) and 2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (syn isomer) (4.48 g.) at -20° to -25° C. and stirred at -10° to -15° C. for 30 minutes [solution A]. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.6 g.) was dissolved in a solution of trimethylsilylacetamide (14 g.) in methylene chloride (150 ml.) at 40° C., and cooled to -10° to -15° C. The solution was added to the above solution A at -10° to -15° C. and stirred at the same temperature for 30 minutes. After removing methylene chloride from the resultant solution under reduced pressure, ice water and ethyl acetate were added to the residue, and adjusted to pH 4 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether. The precipitates were collected by filtration; washed with diethyl ether and dired to give 7-[2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5.0 g.), mp. 110° to 115° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[CH:19]=[O:20].[CH:21]1([CH2:25][NH:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:25][N:26]([CH2:27][CH3:28])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH:19]=[O:20])[CH2:24][CH2:23][CH2:22]1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Reactant: CCNCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC1CCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Potassium carbonate (0.83 g, 6 mmol) was added to a solution of 6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (1.04 g, 5.0 mmol) and cyclobutylmethyl-ethyl-amine (0.8 g, 7.0 mmol) in anhydrous DMF (8 mL) under nitrogen. After stirring for 0.5 h at RT, the reaction mixture was heated for 14 h at 80° C. Thereafter, the reaction was cooled to RT, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was separated from the aqueous mixture. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography using silica gel (200-400 mesh) and eluted with 20-60% hexane:ethyl acetate to afford the title compound as a pale yellow liquid (1.23 g, yield: 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[CH3:13][C:14]1([CH3:28])[O:19][CH2:18][C:17]([CH3:27])([C:20](=[O:26])[CH2:21][C:22](OC)=[O:23])[CH2:16][O:15]1.C1(C)C=CC=C(C)C=1.CO>CCCCCCCC>[N+:10]([C:7]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[C:4]([NH:5][C:22](=[O:23])[CH2:21][C:20](=[O:26])[C:17]2([CH3:27])[CH2:16][O:15][C:14]([CH3:13])([CH3:28])[O:19][CH2:18]2)[CH:6]=1)([O-:12])=[O:11]
Reactant: COC(=O)CC(=O)C1(C)COC(C)(C)OC1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: CCCCCCCC
Solvent: Cc1cccc(C)c1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C1(C)COC(C)(C)OC1

Procedure:
2Methoxy-5-nitroaniline (63.06 g, 0.375 mol) and methyl 2,2,5-trimethyl-b-oxo-1,3-dioxane-5-propanoate (90.0 g, 0.391 mol) were dispersed in n-octane (500 mL) and m-xylene (100 mL) in a 2-liter three-necked flask. The mixture was heated at the boiling point while methanol was continuously removed by a very slow nitrogen sweep. After 2 hr of heating the solution was allowed to cool slowly with good stirring; the yellow-orange precipitate which formed was filtered and allowed to air dry. The crude precipitate was dissolved in ethyl ether and extracted with dilute hydrochloric acid, after which the ethereal solution was washed once with dilute sodium bicarbonate, once with water, the organic and aqueous layers separated, and the organic layer dried over magnesium sulfate. The mixture was filtered and the excess solvent removed in vacuo. The residue was recrystallized from ethyl alcohol, m.p. 113-5° C.; H-NMR was consistent. Elemental analysis calculated for C17H22N5O7: C, 55.73; H, 6.05; N, 7.65. Found: C, 55.64; H. 6.14; N, 7.53.
Reaction SMILES: O.[OH-].[Li+].[CH:4]([C:7]1[S:8][C:9]([CH3:16])=[C:10]([C:12]([O:14]C)=[O:13])[N:11]=1)([CH3:6])[CH3:5]>O.CO>[CH:4]([C:7]1[S:8][C:9]([CH3:16])=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)c1nc(C(C)C)sc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc(C(C)C)nc1C(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of lithium hydroxide monohydrate (0.2 g) in water (3 mL) was added to a solution of methyl 2-isopropyl-5-methylthiazole-4-carboxylate (example 69, step a) (0.5 g) in methanol (7 mL) and the reaction mixture was stirred at 20° C. for 3 hours. The methanol was removed under reduced pressure and the remaining aqueous solution was washed with ethyl acetate. The aqueous layer was acidified by dropwise addition of concentrated aqueous HCl and this mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. The resultant gum crystallised on standing. Trituration with a mixture of isohexane (4 mL) and ether (1 mL) afforded the subtitled compound. Yield 0.160 g.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]2[N:7]=[CH:8][O:9][C:5]2=[CH:4][CH:3]=1.Cl[C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:16]([O:1][C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]3[N:7]=[CH:8][O:9][C:5]3=[CH:4][CH:3]=2)[N:17]=1
Reactant: COC(=O)c1c(O)ccc2ocnc12
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2ocnc12
Temperature: 115 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
A mixture comprising 0.6 g of methyl 5-hydroxybenzoxazol-4-carboxylate, 0.6 g of 2-chloro-4,6-dimethoxypyrimidine and 0.7 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 115° C. for two hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to obtain 0.4 g (yield: 39%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)on1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)on1
Yield: 95.3 %

Procedure:
A mixture of 2.8 g of methyl 2-[5-(4-chlorophenyl)-3-isoxazolyl]benzoate, 12 ml of concentrated HCl, and 14 ml of acetic acid was held at reflux for 4 hours, cooled, diluted with water, and filtered to give 2.55 g (95%) of white solid, mp 174°-176° C. Recrystallization of the solid gave 2.18 g of solid, mp 175.5°-177.5° C.
Reaction SMILES: N1(CCCCCCCCCCC(O)=O)C=CC=C1.[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH:22]([S:26]([OH:29])(=[O:28])=[O:27])[C:21]1=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[S:26]([C:22]1([S:26]([OH:29])(=[O:28])=[O:27])[CH2:23][C:24](=[O:25])[N:20]([OH:19])[C:21]1=[O:30])([OH:29])(=[O:27])=[O:28]
Reactant: O=C1CC(S(=O)(=O)O)C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CCCCCCCCCCn1cccc1
Solvent: CN(C)C=O
Product: O=C1CC(S(=O)(=O)O)(S(=O)(=O)O)C(=O)N1O
Reaction time: 8 h

Procedure:
The following are introduced into a 25 ml round-bottomed flask, in order: 11-(1-pyrrolyl)undecan-1-oic acid (2 mmol; 503 mg), of N-hydroxysulphosuccinimide (2 mmol; 434 mg) and dicyclohexylcarbodiimide (DCC) (2.4 mmol; 495 mg). 10 ml of dimethylformamide (DMF) are subsequently added. A cloudy mixture is obtained, which is subjected to magnetic stirring overnight.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:39][CH3:40])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:22]>C(O)C.N1CCCCC1>[CH2:39]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)amide as a yellow solid (72.6 mg, 54%).
Reaction SMILES: Br[C:2]([CH3:13])([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1C)=[O:4].[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[OH:23].[C:24](=O)([O-])[O-].[K+].[K+].CO>CS(C)=O.O>[CH3:13][C:2]([O:23][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[CH3:14])([CH3:12])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:24])=[CH:9][CH:10]=1)=[O:4]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: Cc1ccccc1C(=O)C(C)(C)Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)C(C)(C)Oc2cc(C)cc(C)c2C)cc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
A solution of 2-bromo-2-methyl-1-(methylphenyl)-1-propanone (422 g) in dimethyl sulfoxide (DMSO, 681 mL) was added dropwise to a solution of 2,3,5-trimethylphenol (136.19 g) and potassium carbonate (276.4 g) in DMSO (681 mL), followed by stirring at 35° C. for 24 hours. To the mixture were added dropwise methanol (953 mL) warmed to 55° C. and then water (953 mL). The mixture was stirred at 55° C. for 30 minutes and then at 40° C. for 1 hour. Precipitated crystals were filtered and suspended in methanol (2043 mL). Water (681 mL) was added to the suspension and the mixture was stirred at 40° C. for 1 hour. Precipitated crystals were filtered to obtain the title compound (257.98 g, 87%).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[CH3:30][O:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:35]4[CH2:36][CH2:37][CH:32]([O:31][CH3:30])[CH2:33][CH2:34]4)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC1CCNCC1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCC(OC)CC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 4-methoxy-piperidine, the title compound was prepared as off-white solid. MS: m/e=438(M+H+).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=C(B(O)O)C=CC=1>>[Cl:21][C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1NCCc2c(-c3cccc(Cl)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 3-chlorophenylboronic acid (130 mg, 0.83 mmol) were coupled to yield 2-(3-chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 151 mg (67%), as a shiny pale-yellow solid. mp 147-149° C; 1H NMR (300 MHz, d6-DMSO) δ 3.06 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H, J=7.8 Hz), 7.46 (m, 1H), 7.58 (m, 4H), 7.70 (m, 2H), 7.64 (m, 1H), 8.11 (br t, 1H), 11.68 (br s, 1H); MS (FAB, MH+) 297; Anal. (C17H13N2OCl.0.9 H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>O1CCOCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: NCc1ccccn1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2ccccn2)nc(N2CCOCC2)n1
Yield: 50.2 %

Procedure:
A stirred mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (0.183 g, 0.5 mmol) and 2-aminomethylpyridine (0.135 g, 1.25 mmol) in 10 mL dioxane was heated gently until a clear solution was obtained. After cooling, the mixture was diluted with water to give an oily solid, which was recrystallized from aqueous MeOH to give 0.11 g (50% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyridinylmethyl)-1,3,5-triazin-2-amine: mp 192-193° C.; 1H NMR (CDCl3) (rotamers) δ8.65 (d, J=1.8 Hz, 1H), 8.57 (dd, J=4.7, 1.0 Hz, 1H), 8.40 and 8.25 (2d, J=7.5 and 5.5 Hz, 1H), 7.88 (m, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.62 (t, JHF=54.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.30 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 5.75 and 5.64 (2 m, exchangeable with D2O, 1H), 4.76 and 4.69 (2 d, J=5.7 and 5.8 Hz, 2H), 3.87 (m, 4H), 3.78 (m, 4H); Anal. Calcd. for C21H20F2N8O: C, 57.5; H, 4.6; N, 25.6. Found: C, 57.5; H, 4.5; N, 25.6%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[CH2:20][C:19]23[CH2:21][CH2:22][C@:12]1([OH:36])[CH:13]1[O:30][C:28]4=[C:29]5[C@@:14]12[CH2:15][CH2:16][N:17]([CH2:32][CH:33]1[CH2:35][CH2:34]1)[C@@H:18]3[CH2:23][C:24]5=[CH:25][CH:26]=[C:27]4[OH:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:38]1[N:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:41]=[N:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C@H:11]1[CH2:20][C:19]23[CH2:21][CH2:22][C@:12]1([OH:36])[CH:13]1[O:30][C:28]4=[C:29]5[C@@:14]12[CH2:15][CH2:16][N:17]([CH2:32][CH:33]1[CH2:34][CH2:35]1)[C@@H:18]3[CH2:23][C:24]5=[CH:25][CH:26]=[C:27]4[O:31][C:38]1[N:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:41]=[N:40][N:39]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: O=C(NCc1ccccc1)[C@H]1CC23CC[C@]1(O)C1Oc4c(O)ccc5c4[C@@]12CCN(CC1CC1)[C@@H]3C5
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)[C@H]1CC23CC[C@]1(O)C1Oc4c(Oc5nnnn5-c5ccccc5)ccc5c4[C@@]12CCN(CC1CC1)[C@@H]3C5
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Under an argon atmosphere, the compound 111 (2 g, 4.11 mmol) was dissolved in DMF (40 mL), the solution was added with 5-chloro-1-phenyl-1H-tetrazole (891 mg, 4.93 mmol), and potassium carbonate (1.42 g, 10.3 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The obtained crude product was purified by silica gel column chromatography to give the title compound 112 (2.5 g, 96%).
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:3]([Cl:9])[C:4](OCC)=[O:5].[CH:16]([NH2:18])=O.C[O-].[Na+]>CO>[Cl:9][C:3]1[C:4]([OH:5])=[N:18][CH:16]=[N:1][C:2]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC=O
Reactant: CCOC(=O)C(Cl)=C(N)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(-c2ccccc2)c1Cl

Procedure:
45.73 g (0.20 mol) of ethyl 3-amino-2-chloro-3-phenyl-propenoate are reacted with 31.9 g (0.71 mol) of formamide and 93 ml of sodium methylate solution in 120 ml of methanol and worked up in analogy to Example 9 (reaction time 16 h). Yield: 32.9 g (79.7%)
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]=[CH2:13])(=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[H-].[Na+].Cl[CH2:17][C:18]1[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1>C1C=CC=CC=1>[C:18]1([CH2:17][C:2]([CH2:17][C:18]2[C:31]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=3)[CH:27]=[CH:26][CH:25]=[C:24]5[CH:23]=[CH:22][C:21]4=[CH:20][CH:19]=2)([C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])[C:1]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1
Reactant: ClCc1ccc2ccc3cccc4ccc1c2c34
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCOC(=O)C(Cc1ccc2ccc3cccc4ccc1c2c34)(Cc1ccc2ccc3cccc4ccc1c2c34)C(=O)OCC=C
Temperature: 25 °C

Procedure:
Diallyl malonate (0.36 g, 2.0 mmol) was added to a stirred suspension of NaH (2.5 mmol) in dry benzene (5 mL). After 30 minutes 1-chloromethylpyrene (0.5 g, 2.0 mmol) in benzene (20 mL) was added. The mixture was gently refluxed for 18 hours, cooled to room temperature and washed with saturated aqueous NaCl (2×5 mL). The organic layer was dried over MgSO4 and the solvent evaporated under reduced pressure to give the product, which was recrystallized from AcOEt/hexane to afford the desired product as white crystals, yield: 0.26 g, 42%, m.p. 178°-180° C. 1H NMR and 13C NMR were in accord with the desired product. Analysis (C43H32O4): calculated C:84.29, H:5.26; found: C:84.13, H:5.23.
Reaction SMILES: C(O[C:4]([C:6]1[N:18]=[C:17]([C:19]#[N:20])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[C:19]([C:17]1[C:16]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8]=2[C:7]([OH:27])=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:18]=1)#[N:20]
Reactant: CCOC(=O)c1nc(C#N)c2c3ccccc3n(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c1c1ccccc1n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 1(e) from 1-cyano-4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 385 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:32])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:14][CH:13]2[C:33]([O:35]C)=[O:34])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:32])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:14][CH:13]2[C:33]([OH:35])=[O:34])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COC(=O)C1CN(C(=O)c2cc(F)ccc2C)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cc(F)ccc3C)CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
To a mixture of 1.9 g (3.71 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate in 10 ml of tetrahydrofuran was added 5 ml (4.82 mmol) of 1 N NaOH. The mixture was stirred at room temperature for 1.5 hours and the solvent removed under vacuum. To the residue was added ethyl acetate and the mixture neutralized with 1 N HCl. The organic layer was separated, washed with brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.41 g of white solid. Anal. for C25H23FN2O6S: Calc'd: C, 60.2; H, 4.7; N, 5.6; Found: C, 60.2; H, 4.8; N, 5.4 S, 6.4; F, 3.6.