Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][OH:20]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:6]([CH2:18][CH2:19][OH:20])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1CCO
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-1H-benzimidazole (3.50 g, 25.95 mmol) in DMF (70.0 mL), Cs2CO3 (12.08 g, 36.33 mmol) and 2-bromoethanol (2.5 mL, 34.15 mmol) was added. After stirring at 150° C. for 1 h, the reaction mixture was allowed to reach rt and was diluted with EtOAc. The org. layer was separated and the aq. layer was extracted with EtOAc (5×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 2-(2-methyl-1H-benzoimidazol-1-yl)ethanol which was used in the next step without further purification. LC-MS conditions B: tR=0.25 min, [M+H]+=177.17.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(C)=O
Yield: 99.2 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 17.0 g.), 2,4-dichlorobenzyl chloride (25 g.), potassium carbonate (22.0 g.), N,N-dimethylformamide (25 ml.) and ethyl acetate (25 ml.) were treated in a similar manner to that of Example A-(1) to give ethyl 2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 33.7 g.)
Reaction SMILES: [CH3:1][C:2]12[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:3]1[NH:4][CH2:5][CH2:6][CH2:7]2.[C:15](O)(=O)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH2:15]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]2([CH3:1])[CH2:14][C:13]3[C:8]([CH:3]12)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH3:16]
Reactant: CC(=O)O
Reactant: CC12CCCNC1c1ccccc1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCN1CCCC2(C)Cc3ccccc3C12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of (4aRS,9bRS)-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (140 mg) in 1,2-dichloroethane (3 ml) were added acetic acid (0.214 ml) and sodium triacetoxyborohydride (1.1 g), followed by heating and stirring at 70° C. for 3 hours. The reaction solution was basified by adding a 1 M aqueous sodium hydroxide solution, extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (4aRS,9bRS)-1-ethyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (105 mg) as an oily substance. This was made into a hydrochloride by a conventional method, washed with ethyl acetate, and collected by filtration to obtain (4aRS,9bRS)-1-ethyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine hydrochloride (108 mg) as a colorless powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[NH:11][N:10]=1.Cl[CH2:16][C:17](=[O:19])[CH3:18]>O1CCOCC1>[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[N:11]([CH2:16][C:17](=[O:19])[CH3:18])[N:10]=1
Reactant: CC(=O)CCl
Reactant: COc1n[nH]c(=O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1nn(CC(C)=O)c(=O)s1
Reaction time: 20 h

Procedure:
69 g of potassium carbonate are added to a solution of 33 g of 5-methoxy-3H-[1,3,4]thiadiazol-2-one in 400 ml of dioxane and the reaction mixture is heated to 60°. Then 21 g of chloroacetone are added dropwise within a short period of time and the reaction mixture is stirred at 70° for 20 hours and then, at 20°, is filtered over Celite. The filtrate is concentrated by evaporation. The residue is stirred with diisopropyl ether and filtered with suction. 45 g of crystals of the title compound having a melting point of 66-67° are thus obtained.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[CH:31]=1>>[CH3:39][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:38]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: Cc1cccc(C(=O)O)c1
Agent: Cl
Product: Cc1cccc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with m-toluic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3-methylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 484 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH:9]([F:11])[F:10])=[N:3]1.S(Cl)([Cl:15])(=O)=O>ClC1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([Cl:15])=[O:8])[C:4]([CH:9]([F:10])[F:11])=[N:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1cc(C=O)c(C(F)F)n1
Solvent: Clc1ccccc1
Product: Cn1cc(C(=O)Cl)c(C(F)F)n1
Yield: 96.6 %

Procedure:
The solution of 16 g (100 mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde, 13.5 g (100 mmol) of sulphuryl chloride and 0.2 g of 2,2-azoisobutyronitrile in 50 ml of chlorobenzene was stirred at 70-80° C. for 6 h. The reaction solution was concentrated. 18.8 g of the product (95% yield) was obtained as an oil with a purity (GC) of 98%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:19])([F:18])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:14]([F:19])([F:18])[F:13]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 155 °C
Reaction time: 20 h
Yield: 72.1 %

Procedure:
To a solution of 1-bromo-2-methoxy-4-nitrobenzene (10.0 g, 43.0 mmol) in N,N-dimethylformamide (200 mL) were added potassium trifluoroacetate (13.0 g, 86.0 mmol), copper iodide(I) and toluene (40 mL), and the mixture was stirred at 155° C. for 20 hr while removing the produced water drops by a Dean-Stark trap. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), the insoluble material was filtered off, and the filtrate was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→88/12). The obtained solution was concentrated under reduced pressure to give the title compound (6.86 g, 72%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=O)[CH3:2].[CH2:13]([NH2:17])[CH2:14][CH2:15][NH2:16]>>[CH3:2][C:1]12[NH:17][CH2:13][CH2:14][CH2:15][N:16]1[C:6](=[O:8])[C:5]1[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: NCCCN
Product: CC12NCCCN1C(=O)c1ccccc12

Procedure:
16.4 Parts of o-acetyl-benzoic acid and 8 parts of 1,3-propanediamine are heated for 2 hours at 150°-160°. The reaction mixture is then distilled under high vacuum. The 10b-methyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol -6(2H)-one obtained of the formula ##STR35## boils at 120°-123°/0.1 Torr. After recrystallising from ethyl acetate/benzine, it melts at 64.5°. The following compounds are obtained in an analogous manner:
Reaction SMILES: O.[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[CH2:14][CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.N>CN(C=O)C>[CH2:19]1[O:20][CH:16]([CH2:15][CH2:14][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:17][CH2:18]1
Reactant: BrCCC1OCCO1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CCC2OCCO2)cc1
Temperature: 0 °C
Yield: 65.9 %

Procedure:
A mixture of sodium 4-toluenesulphinate monohydrate (37.2 g, 0.19 mole) and 2-(2-bromoethyl)-1,3-dioxolane (20 ml, 0.17 mole) in dry DMF (100 ml) was stirred at room temperature for 64h, resulting in a homogenous solution. This was poured into ice/water (1 liter) containing conc. ammonia solution (100 ml) and stirred vigorously until a white precipitate formed. The solid was filtered off, washed with water, dried and recrystallised from propan-2-ol/ether to give the title compound (D24) as a white solid (28.7 g, 66%) m.p. 78°-80° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.C1(O)C=CC=CC=1.C(O)(=O)CC.[BrH:51]>>[BrH:51].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][NH:19][CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(-c4c(F)cc5c(=O)c(C(=O)O)cn(C6CC6)c5c4C)cc3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Cc1c(-c2ccc3c(c2)CNC3)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In 5.3 ml of 47% hydrobromic acid was suspended 0.53 g of 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3 carboxylic acid, and 0.28 g of phenol and 3.2 ml of propionic acid were added to the suspension, after which the resulting mixture was heated under reflux for one hour under a nitrogen stream. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue obtained, after which the crystals formed were collected by filtration, to obtain 0.38 g of colorless, crystalline 1-cyclopropyl-6-fluoro-8-methyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrobromide. The hydrobromide obtained was suspended in 3.8 ml of ethanol and then dissolved in 7.6 ml of 0.5N aqueous sodium hydroxide solution, after which a carbon dioxide gas was blown into the solution. The crystals formed were collected by filtration, to obtain 0.27 g of colorless, crystalline 1-cyclopropyl-6-fluoro-8-methyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10](=[O:17])[CH2:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][CH:20](OC)OC>C(O)(=O)C>[CH:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10](=[O:17])[C:9]3=[CH:18][O:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1Cc2cc(C3CCCC3)ccc2C(=O)N1
Reactant: COC(OC)OC
Solvent: CC(=O)O
Product: COC=C1C(=O)NC(=O)c2ccc(C3CCCC3)cc21
Temperature: 90 °C

Procedure:
A mixture of 6-cyclopentyl-4H-isoquinoline-1,3-dione (222 mg, 0.97 mmole), 10 mL of acetic acid and trimethylorthoformate (212 mg, 2.0 mmole) is stirred and heated to 90° C. After 2 hours at that temperature the reaction mixture is cooled and the solvents were removed in-vacuo and the residue taken up in 4% methanol in dichloromethane, passed through a short pad of Florisil and eluted with 4% methanol in dichloromethane. The eluate is evaporated and the product is treated with 4:1 hexanes-ethyl acetate and collected by filtration to give a yellow solid, 165 mg, (62%), MS (ES+): m/z 272.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[CH:8]3[O:9][CH:7]3[CH2:6][C:5]=2[CH:4]=1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[OH:9][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:8]1[N:21]1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C@@H:16]1[CH3:15]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: FC(F)(F)c1ccc2c(c1)CC1OC21
Solvent: CCO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Temperature: 95 °C

Procedure:
A mixture of 4-(trifluoromethyl)-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (1.2 g, 6.0 mmol) and tert-butyl (3S)-3-methylpiperazine-1-carboxylate (1.4 g, 7.2 mol) in ethanol (20 mL) was refluxed overnight. Another gram of tert-butyl (3S)-3-methylpiperazine-1-carboxylate was added. The mixture was transferred into a sealed flask and heated to 95° C. for 2 days. The solvent was concentrated and the residue was purified by flash chromatography eluting with 25% EtOAc/hexane, followed by 5% MeOH/EtOAc+0.5% concentrated NH4OH. Two isomers were isolated. Isomer 1 (fast moving isomer): 0.45 g; MS calculated for the C20H27F3N2O3 (M+H)+401; found 401.1. Isomer 2 (slow moving isomer): 0.38 g; MS found 401.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][C@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)CN
Solvent: CC#N
Product: CC(C)CNC[C@@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.5 mmol), 2-methylpropane-1-amine (1 ml) and ACN (2 ml) was heated under microwave radiation at 120° C. for 30 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (EtOAc/MeOH). Yield: 0.1 g, 77%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 213° C. MS m/z (rel. intensity, 70 eV) 299 (M+, 4), 256 (16), 207 (11), 86 (bp), 57 (8). [α]=+65° (MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7])[CH3:2].[C:13](O)(=O)[C:14]1C(=CC=C[CH:20]=1)N>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:7][CH:14]([CH3:20])[CH3:13])[CH3:2]
Reactant: CCOC(=O)c1ccccc1N
Reactant: Nc1ccccc1C(=O)O
Product: CCOC(=O)c1ccccc1NC(C)C

Procedure:
Following the reaction procedure of Example 8 but substituted a molar equivalent amount of anthranilic acid ethyl ester for the anthranilic acid, there is obtained N-isopropylanthranilic acid ethyl ester.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[C:8](Br)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])(=O)C.[K+].[Cl-]>CO>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[C:8]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc(Br)c2c1C(=O)c1c(O)cccc1C2=O
Reactant: NC1CCCCC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC(C)Nc1ccc(NC2CCCCC2)c2c1C(=O)c1c(O)cccc1C2=O

Procedure:
18 g of 1-isopropylamino-4-bromo-8-hydroxy-anthraquinone, 36 ml of cyclohexylamine, 6.5 of potassium acetate and catalytic amounts of copperI chloride are stirred at 80°-90° until only a little starting material is still detectable. The mixture is now diluted with 36 ml of methanol and the reaction product which has separated out is filtered off at 60°, washed with boiling hot methanol, finally stirring with dilute hydrochloric acid, filtered off, washed until neutral and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl.[OH-].[K+]>O>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:16]2[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]([NH2:11])[N:17]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cccc(Nc2cc(C)nc(N)n2)c1
Yield: 78.5 %

Procedure:
Compound No. 15: A suspension of m-aminoacetophenone (2.7 g) and 2-amino-4-chloro-6-methylpyrimidine (2.87 g) in 40 mL water was treated with 1.7 mL concentrated HCl and heated at reflux for 1 hour. Addition of 40 mL 1N KOH gave a light buff solid, which was filtered out and dried to give 3.8 g 4-(3-acetylphenyl)amino-2-amino-6-methylpyrimidine, mp 196°-98° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1cccc(C(F)(F)F)c1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 3-trifluoromethylbenzylamine, m.p. 102° C. MS [(+)ESI, m/z]: 614 [M+H]+ Anal. Calcd for C29H23BrF3N3O2S: C, 56.69; H, 3.77; N, 6.84. Found: C, 56.79; H, 3.66; N, 6.76.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[CH:7]([NH:20][C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2].Cl.[CH3:32]O>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[C@H:7]([NH:20][C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:32])=[O:28])=[CH:23][CH:22]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2C(Nc2ccc(C(=O)O)cn2)CC1C
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(N[C@@H]2C[C@H](C)N(C(C)=O)c3ccc(-n4cnc(C)c4)cc32)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of 6-{[1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarboxylic acid (for a preparation see example 143) (40 mg, 0.099 mmol) in dry methanol (2 mL) was treated at room temperature with HCl (4M in 1,4-dioxane, 200 μl, 0.800 mmol) and the resulting mixture was stirred at this temperature for one hour. Another portion of HCl (4M in 1,4-dioxane, 200 μl, 0.800 mmol) was added and the mixture was refluxed for 1 hour then cooled to room temperature and concentrated in vacuo. The residue was purified using MDAP (modifier: ammonium formate) to give methyl 6-{[(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarboxylate (12 mg, 0.029 mmol, 29%) as a white solid.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([OH:20])[C:17](O)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.Cl.[CH3:33][O:34][NH2:35]>>[OH:20][CH:16]([C:17]([NH:35][O:34][CH3:33])=[O:18])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:28]=[CH:29][CH:30]=[N:31][C:10]=1[N:2]1[CH:3]=[C:4]2[C:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:1]1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2c(n1)CCCC2
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCCC2

Procedure:
The reaction was carried out in analogy to reaction step 3.1 by reacting 3-[2-(4,5,6,7-tetrahydro-2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid and O-methylhydroxylamine hydrochloride.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:13][C:14]([CH3:18])=[C:15]=[CH:16]Br.O>C(O)C>[CH3:13][C:14]([CH3:18])([C:15]#[CH:16])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=C=CBr
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C#CC(C)(C)C(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl malonate (34.8 g.) was added to a solution of sodium (5.0 g.) in ethanol (500 ml.) and the mixture stirred for a few minutes. 3,3-Dimethyl-1-bromoallene (32.0 g.) was then added dropwise at the ambient temperature after which the mixture was refluxed for 3 hours. The ethanolic solution obtained was poured into an excess of water and the mixture extracted with chloroform (3×200 ml.). The extracts were combined, dried with anhydrous sodium sulphate and evaporated and the residual oil distilled under reduced pressure to yield ethyl 3,3-dimethyl-2-ethoxycarbonylpent-4-ynoate, as an oil b.p. 56°-60°/0.1 mm. Hg.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.OS(O)(=O)=O.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[CH:28]4)=[CH:22][C:17]=2[O:16][CH2:15]1>C1COCC1.CCOC(C)=O>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[C:28]4[Br:1])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1OCc2c1cc1c(Br)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.8 %

Procedure:
N-bromosuccinimide (10.7 mg, 0.06 mmol) and concentrated H2SO4 (5 μL) were added to a solution of 2 (15.4 mg, 0.044 mmol) in THF (1 mL). The solution was stirred at room temperature for 20 h, and then diluted with EtOAc (30 μL). The same workup and purification procedure as described for the isolation of 37 gave 38 (12 mg, 64%) as a pale yellow powder. mp 256° C. (decomp.); 1H NMR (CDCl3) δ 8.89 (s, 1H, H4), 7.65 (s, 1H, H6), 6.76-6.91 (m, 3H, H2′+H5′+H6′), 6.08 (AB, 2H, 3′,4′-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.97 (AB, 2H, 7,8-OCH2O—, Δδ=7.8 Hz, J=1.5 Hz), 5.22 (q, 2H, lactone-CH2—, J=8.4 Hz); MS (EI) m/z 428 [M+2]+, 426 [M]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[C:16]1([C:22]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[C:8]([C:5]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:7][C:2]([N:25]2[CH2:24][CH2:23][C:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]2)=[CH:3][CH2:4]1)#[N:9]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: N#CC1(c2ccccn2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1(c2ccccc2)CCN(C2=CCC(C#N)(c3ccccn3)CC2)CC1
Yield: 45 %

Procedure:
A mixture of 4.5 parts of 4-oxo-1-(2-pyridinyl)cyclohexanecarbonitrile, 5.2 parts of ethyl 4-phenyl-4-piperidinecarboxylate, 1 part of 4-methylbenzenesulfonic acid and 225 parts of methylbenzene is stirred and refluxed overnight using a water-separator. The reaction mixture is evaporated and the residue is crystallized from 2-propanol, yielding 4.5 parts (45%) of ethyl 1-[4-cyano-4-(2-pyridinyl)-1-cyclohexeneyl]-4-phenyl-4-piperidinecarboxylate; mp. 160° C.