Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][CH:29]2[CH:34]3[CH2:35][CH:31]([CH:32]=[CH:33]3)[CH:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COCCN(C)C1CCc2ccc(N)c(OC)c2CC1
Product: COCCN(C)C1CCc2ccc(Nc3ncc(Cl)c(NC4C5C=CC(C5)C4C(N)=O)n3)c(OC)c2CC1
Yield: 41 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-Methoxy-N*7*-(2-methoxyethyl)-N*7*-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide were combined to yield 1S,2S,3R,4R)-3-(5-Chloro-2-{1-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (82.19 mg, 41% yield) as a beige foam. Purification separated the compound into its corresponding enantiomers. 1H-NMR (CDCl3) δ 8.17 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 6.94 (d, J=7.7 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.36 (m, 1H), 6.32 (m, 1H), 5.62 (br s, 1H), 5.36 (br s, 1H), 4.36 (m, 1H), 3.73 (s, 3H), 3.45 (m, 2H), 3.35 (m, 4H), 3.07 (br s, 1H), 2.94 (br s, 1H), 2.77 (m, 2H), 2.60 (m, 2H), 2.50 (d, J=8.16 Hz, 1H), 2.25 (m, 5H), 2.15 (m, 2H), 1.31 (m, 2H). LC/MS (ESI+)=541 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[CH:15]([F:17])[F:16]>[OH-].[Na+].C(O)(C)C.ClCCl.O>[F:16][CH:15]([F:17])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(O)ccc1C
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cc(OC(F)F)ccc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
A mixture of ethyl 5-hydroxy-2-methylbenzoate (3.29 g, 18.2 mmol) in aqueous 30% sodium hydroxide (20 mL) and isopropyl alcohol (20 mL) was charged with 20 psi of chlorodifluoromethane in a high pressure flask, and stirred at room temperature for 10 min. After this time, the resulting mixture was heated at 50° C. for 0.5 h. After this time, the reaction mixture was cooled to room temperature and diluted with dichloromethane (50 mL) and water (200 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, gradient 0-7%, hexanes/ethyl acetate) afforded 2.50 g (59%) of ethyl 5-(difluoromethoxy)-2-methylbenzoate as colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J=2.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.18-7.16 (m, 1H), 6.50 (t, J=73.6 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 2.57 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); ESI MS m/z 231 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22].CC[O-].[Na+]>C1C=CC=CC=1.O>[CH2:21]([O:23][C:24]([C:25]1[C:26](=[O:27])[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:5]2[C:6]([C:8]=1[CH3:9])=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:29])[CH3:22]
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(C)=O)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A solution of 2 (0.20 g, 1.18 mmol) in 3 mL of anhydrous benzene was treated with ethyl-3-chloro-3-oxopropionate (165 μL, 0.20 g, 1.30 mmol). The reaction mixture was heated to 80° C. for 1 h. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was dissolved in 3 mL of ethanol, treated with NaOEt (40.0 mg, 0.59 mmol). The suspension was heated to 80° C. for 10 min, allowed to cool to room temperature, and diluted with H2O. The resulting white precipitate was filtered to give 3 (0.38 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J=2.3 Hz, 1H), 7.39 (dd, J=2.3, 9 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.81 (d, j=8.6 Hz, 2H), 5.47 (br S, 2H), 4.46 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.46 (s, 3H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH3:24])[N:3]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[CH3:43][O:44][C:45](=[O:48])[CH2:46][NH2:47]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:47][CH2:46][C:45]([O:44][CH3:43])=[O:48])=[O:21])=[CH:22][CH:23]=3)[CH2:13][CH2:14]2)=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
A mixture of 3.9 g (0.012 mole) of 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid, 6.5 g (0.039 mole) of diethyl phosphorocyanidate and 6.6 ml (0.047 mole) of triethyl amine in 500 ml of N,N-dimethylformamide (dried over 4H molecular sieves overnight) was stirred at room temperature for five hours. A mixture of 1.8 g (0.014 mole) of glycine methyl ester, hydrochloride, 2 ml (0.014 mole) of triethylamine and 10 ml of N,N-dimethylformamide was added to the suspension and the mixture was stirred at room temperature for another two hours. The solvent was removed under high vacuum (0.1 mm, dry ice-2-propanol trap) at 48° C. The solid residue was dissolved in 200 ml of ice water and neutralized with saturated sodium carbonate solution to pH 8. The solid was collected and washed with 100 ml of water. Recrystallization from acetonitrile gave 2.6 g of the product as a pale yellow solid, mp 255° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([CH3:17])=[CH:19][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: C=Cc1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)cc2)C1
Yield: 9.8 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (100 mg, 0.4 mmol), 4-methylstyrene (1 mL, 7.6 mmol) and NaH (100 mg, 60% dispersion in oil, 2.5 mmol) in DMF (2 ml) at 180° C. for 24 h to obtain 13 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=NO)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].Cl>O.CO>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:2])[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: O=S(=O)([O-])S(=O)(=O)[O-]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphate (131 g) in water (300 ml) was added to 1-(4-carbomethoxyphenyl)propan-2-one oxime (37.5 g) in methanol (200 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (100 ml) added, the mixture extracted with chloroform and the combined chloroform extracts washed with water followed by sodium bicarbonate solution. The chloroform layer was dried (MgSO4) and evaporated to give the title compound as an oil (bp 126°-129°/0.7 mm) which crystallised on standing, (mp 40°-47°). τ (CDCl3) 7.88 (3H, s), 6.28 (2H, s), 6.14 (3H, s), 2.77 (2H, d, J=8 Hz), 2,04 (2H, d, J=8 Hz).
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[C:26]([C:32]([F:35])([F:34])[F:33])([OH:31])[C:27]([F:30])([F:29])[F:28])[NH2:14])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].OC([C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][C:52]=1[O:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1)[NH2:49])(C(F)(F)F)C(F)(F)F>>[F:4][C:3]([F:6])([F:5])[C:2]([C:7]([F:10])([F:9])[F:8])=[O:1].[OH:31][C:26]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:19]=1[O:18][C:17]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[C:2]([C:3]([F:4])([F:5])[F:6])([OH:1])[C:7]([F:8])([F:9])[F:10])[NH2:23])([C:27]([F:30])([F:29])[F:28])[C:32]([F:35])([F:34])[F:33].[O:53]([C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1)[C:52]1[CH:46]=[CH:47][C:48]([NH2:49])=[CH:50][CH:51]=1
Reactant: Nc1ccc(Oc2ccc(N)cc2C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Nc1ccc(Oc2ccc(N)cc2C(O)(C(F)(F)F)C(F)(F)F)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Product: Nc1ccc(Oc2ccc(N)cc2)cc1
Product: O=C(C(F)(F)F)C(F)(F)F

Procedure:
The reaction liquid was found by gas chromatography (GC) analysis to contain 39.8% of the target compound, 3,3′-bis(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-4,4′-oxydianiline, 5.4% of 3-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-4,4′-oxydianiline, and 53.0% of the total of various imines produced by the reaction of hexafluoroacetone with the amine moiety of 4,4′-oxydianiline. After adding 50 ml of water to the reaction liquid, stirring was conducted. This mixed liquid was filtered, followed by washing with water and then vacuum drying, thereby obtaining 4.30 g of the target compound, 3,3′-bis(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-4,4′-oxydianiline (yield: 33%; purity: 80.7%).
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Br:29])=[C:7]([C:9](=[N:26][O:27][CH3:28])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]([CH3:20])[S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:30]>>[ClH:30].[NH2:3][C:4]1[S:5][C:6]([Br:29])=[C:7]([C:9](=[N:26][O:27][CH3:28])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]([CH3:20])[S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1nc(N)sc1Br

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer, 1.8 g.) was treated with conc. hydrochloric acid (0.89 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 1.8 g.).
Reaction SMILES: I.[CH3:2][S:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:21]([N:8]2[CH2:7][CH2:6][N:5]=[C:4]2[S:3][CH3:2])=[O:22])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CSC1=NCCN1
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCN=C2SC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide (1.22 g, 1.0 equiv) in CH2Cl2 (25 mL) under an atmosphere of argon at 0° C. was added triethylamine (1.5 mL, 2.2 equiv) and then 3-methoxybenzoyl chloride (0.78 mL, 1.1 equiv) dropwise. Thereaction mixture was allowed to warm to room temperature and stir for 24 hr. After concentration, the resulting residue was diluted with EtOAc (50 mL) and hexane (50 mL). The mixture was filtered and then the filtrate concentrated and dried under vacuum to give a quantitative yield of (3-methoxyphenyl)-(2-methylsulfanyl-4,5-dihydroimidazol-1-yl)-methanone which was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[OH:26]>[Pd]>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])=[CH:15][CH:16]=2)[CH:6]=[CH:5][C:4]=1[OH:26]
Reactant: CC(C)(O)CCCCCc1ccc(C=Cc2ccc(O)c(CO)c2)cc1
Agent: [Pd]
Product: CC(C)(O)CCCCCc1ccc(CCc2ccc(O)c(CO)c2)cc1

Procedure:
In a manner similar to Example 9(a), by reacting 150 mg (0.42 mmol) of 2-hydroxymethyl-4-{2-[4-(6-hydroxy-6-methylheptyl)phenyl]vinyl}phenol with 42 mg of 10% palladium/carbon, crystals (m=65 mg; Y=43%) are obtained. m.p.=110-1° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[CH3:18][S:19]([CH2:22][CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:21])=[O:20]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:23][CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:10]=1)=[O:8]
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCCS(C)(=O)=O)cc1
Product: CS(=O)(=O)CCn1cc(C(=O)Nc2nccs2)c2ccccc21

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and toluene-4-sulfonic acid 2-methanesulfonyl-ethyl ester as R5X.
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][OH:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:20]([N:24]=[C:25]=[S:26])([CH3:23])([CH3:22])[CH3:21].[N-]=C=S.[CH2:30]([OH:32])[CH3:31]>>[CH2:10]([O:9][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[S:26])[C:18]([O:32][CH2:30][CH3:31])=[O:19])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Reactant: CCO
Reactant: CC(C)(C)N=C=S
Agent: [N-]=C=S
Product: CCOC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=S)NC(C)(C)C
Temperature: 80 °C

Procedure:
The process is performed as in Example 9, starting with 0.42 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate and 0.24 cm3 of tert-butyl isothiocyanate in 30 cm3 of ethanol at a temperature in the region of 20° C. for 3 days. The reaction is completed by addition of a further 0.48 cm3 of isothiocyanate followed by heating for 1 hour at a temperature in the region of 80° C. After an identical work-up, 0.6 g of ethyl (2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)-carbothioyl]amino}hexanoate is obtained in the form of a beige-colored oil with a tendency to crystallize. (Rf=0.62 in a 90/10 by volume mixture of dichloromethane/methanol, on a Merck 60F254R silica plate).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH:21]([C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[CH3:22])=[O:9])([CH3:6])[CH3:5].Cl>CO.[OH-].[Na+]>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH:21]([O:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:32])=[O:2])=[O:9])[CH3:22]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OC(C)c1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1c(C(=O)NC(C)(C)C(=O)O)ccc2ccccc12)c1nc2ccccc2s1
Yield: 33.6 %

Procedure:
135 mg 2-{[1-(1-Benzothiazol-2-yl-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 1 ml methanol and 1.5 ml 1M aqueous sodium hydroxide solution were heated to 100° C. for 2 min in a microwave reactor. The reaction mixture was then acidified using 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, filtrated and concentrated in vacuo. Precipitation with pentane yielded 44 mg of 2-{[1-(1-Benzothiazol-2-yl-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.5 %

Procedure:
To a solution of 4-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (65 mg, 54%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1>C(OCC)(=O)C>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:2]2[C:7]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Reactant: NCc1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1NCc1ccncc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A mixture of intermediate 1a (6.00 g, 20 mmol) and 4-pyridinemethanamine (30 mL) is stirred at 150° C. for 16 hours under an argon atmosphere. The cooled mixture is diluted with ethyl acetate (100 mL) and extracted with a saturated aqueous solution of sodium hydrogen carbonate (100 mL), followed by water (4×50 mL) and saturated aqueous sodium chloride (50 mL). The ethyl acetate solution is dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate and recrystallised from 2-propanol—diisopropylether to give the title compound as a colourless crystalline solid, m.p. 152-153° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([C:25]4[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=4)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CNCC2C1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CN(c3ccc(C#N)cn3)CC2C1
Temperature: 45 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (112.0 mg, 0.36 mmol) and 6-chloropyridine-3-carbonitrile (102.5 mg, 0.74 mmol) in a mixture of DCM (5 mL) and MeOH (5 mL) was added Et3N (200.7 mg, 1.98 mmol). The reaction mixture was stirred at 45° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) to give the title compound as a beige solid (0.12 g, 81%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[CH2:11]([O:13][C:14](=[O:33])[C:15]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27])([CH3:19])[CH3:18])[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:33])[C:15]([OH:32])([C:28]([F:29])([F:30])[F:31])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:9][CH:8]=[CH2:7])([CH3:19])[CH3:18])[CH3:12]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1O)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(F)cc1C(C)(C)CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Potassium carbonate (4.15 g, 30 mmol) and allyl bromide (2.16 ml, 25 mmol) are added to a solution of 4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (5.36 g, 15.84 mmol) in DMF (50 ml) while being cooled with ice. After 2 hours at 2° C. and after 2 hours at room temperature, the batch is poured into ice water and extracted with hexane-ether 2:1. The combined organic extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 5.7 g of the product.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1)[CH3:21]>CS(C)=O>[OH2:16].[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH2:20][CH3:21])[CH2:27]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: CCC1CNCCN1
Solvent: CS(C)=O
Product: CCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Product: O
Temperature: 140 °C
Yield: 58.3 %

Procedure:
A mixture of 2.8 g (0.01 mol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (II) and 3.4 g (0.03 mol) of 2-ethylpiperazine in 15 ml of dimethyl sulphoxide is heated at 140° C. for 2 hours. The solution is evaporated under high vacuum, the residue is heated with 30 ml of water to 90° C., the precipitate which has separated out is filtered off with suction, washed with water and methanol and isolated. 1.1 g (31% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-ethyl-1-piperazinyl)quinoline-3-carboxylic acid monohydrate, with a decomposition point of 255°-258° C., is obtained.