Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1.C[O:20][C:21](=[O:43])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]3[O:35][CH:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:33][C:32]=3[CH:42]=2)=[CH:24][CH:23]=1>O1CCCC1>[CH2:17]([C:14]1[CH:13]=[N:12][C:11]([N:39]2[CH2:40][CH2:41][CH:36]([CH:34]3[CH2:33][C:32]4[CH:42]=[C:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([OH:43])=[O:20])=[CH:27][CH:26]=5)[CH:29]=[CH:30][C:31]=4[O:35]3)[CH2:37][CH2:38]2)=[N:16][CH:15]=1)[CH3:18]
Reactant: CCc1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(C(=O)O)cc5)ccc4O3)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyldiisopropylamine (1.38 mL) and 2-chloro-5-ethylpyrimidine (380 μL) are added to a solution of 4-(2-piperidin-4-yl-2,3-dihydro-benzofuran-5-yl)-benzoic acid methyl ester (0.90 g) in tetrahydrofuran (20 mL) and the reaction mixture is heated to reflux for 48 h. The solvent is evaporated after cooling to room temperature. Dichloromethane and water are added; the aqueous phase is separated and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and the solvent is evaporated. The residue is mixed with methanol (20 mL) and 1 M aqueous sodium hydroxide solution (6.67 mL). The reaction mixture is stirred at 55° C. for 12 h. The solvent is evaporated after cooling to room temperature. Dichloromethane and water are added; the organic phase is separated and extracted with water. The combined aqueous phases were adjusted to pH 2 with 1 M hydrochloric acid. The title compound is collected by filtration and dried at 50° C. in vacuo. LC (method 8): tR=1.56 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH2:11][CH2:10][NH:9]1.[OH-].[Na+]>CO>[CH3:3][O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH:12]([OH:16])[CH2:11][CH2:10][NH:9]1
Reactant: COc1ccccc1CC1NCCC(=O)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1CC1NCCC(O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (0.31 g) is added to 2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-one (2.00 g, prepared according to J. Med. Chem. 2002, 45, 3755-3765 from racemic starting material) dissolved in methanol (20 mL). The solution is stirred for 3 h at room temperature and then 1 M sodium hydroxide solution (40 mL) is added. After stirring for 10 min, the mixture is extracted with dichloromethane. The combined organic extracts are washed with water and dried (MgSO4). The solvent is evaporated to give the title product.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>FC(F)(F)C(O)=O>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]([C:16]([OH:18])=[O:17])[NH2:8])[N:12]=[CH:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1cscn1)C(=O)O
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (80 ml) was added to N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (42, 21.79 g, 80 mmol) which was synthesized in accordance with the method described in the literature (Synth. Commun., 20, 3507 (1990)) and the resulting mixture was stirred for 2 h under ice-cooling, Subsequently, to the mixture was added p-toluenesulfonic acid hydrate (15.22 g, 80 mmol) and the resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added water and methanol, and excess trifluoroacetic acid was removed by concentrating in vacuo. To the residue was added diethyl ether and the precipitation which appeared was filtered off to give 29.8 g (quantitative) of the compound (43).
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:7][CH:8]=2)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:7][CH:8]=2
Reactant: O=CC1c2cc(CCCC(=O)O)ccc2-c2c(C(=O)O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CCCc1ccc2c(c1)C(CO)c1cccc(C(=O)O)c1-2
Reaction time: 2 h

Procedure:
In an argon-purged flask, crude 9-formyl-7-(3-carboxy-propyl)-4-fluorenecarboxylic acid (4.0 g, 0.0123 mol) was dissolved in anhydrous methanol (50 mL). The flask was placed in a room temperature bath and sodium borohydride (2.3 g, 0.0615 mol) was carefully added to the reaction in portions (Caution! Flammable gas evolution.). The reaction was stirred for two hours and another portion of sodium borohydride was added (1.2 g, 0.031 mol). After another six hours the reaction was treated with a small amount of water. The organic solvent was partially removed at reduced pressure and the mixture was acidified with concentrated HCl. Brine was added and the product was twice extracted with ethyl acetate (300 mL and 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product (3.3 g, 83%) was purified by flash chromatography: silica gel 60 Å eluted with 50:50:2 ethyl acetate/chloroform/glacial acetic acid. The purified product was an orange solid (1.7 g, 43%). 1H-NMR (CD3OD): δ (ppm) 8.3 (d, 1H, Ar); 7.8 (m, 2H, Ar); 7.6 (s, 1H, Ar); 7.4 (t, 1H, Ar); 7.2 (m, 1H, Ar); 4.0 (m, 2H, CH2); 3.9 (m, 1H, CH); 2.8 (t, 2H, CH2); 2.4 (t, 2H, CH2); 2.0 (m, 2H, CH2).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][NH2:13]>C1COCC1>[CH3:12][NH:13][CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1nc2ccccc2s1
Reaction time: 8 h
Yield: 115.4 %

Procedure:
To a stirred solution of 2-bromomethylbenzothiazole (0.4 g. 1.75 mmol) in THF (4 mL) was added 40% aqueous methylamine (0.30 g, 8.77 mmol). Stirring was continued overnight, then the mixture was concentrated. The residue was taken up in H2O, neutralized with 2.5 N NaOH, and extracted with CH2Cl2. The organic extracts were dried (MgSO4) and concentrated to give the title compound (0.36 g, 80%) as a brown oil: 1H NMR (250 MHz, DMSO-d6): δ 2.70 (s, 3H), 4.71 (s, 2H), 7.55 (m, 2H), 8.0 (d, J=7.9 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]3[N:18]=[CH:17][C:16]([S:19][CH2:20][CH2:21]C(OC)=O)=[C:15]([O:26][C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][CH:31]=[N:32]5)[CH:14]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].BrCC1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]3[N:18]=[CH:17][C:16]([S:19][CH2:20][CH:21]4[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH2:47][CH2:46]4)=[C:15]([O:26][C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][CH:31]=[N:32]5)[CH:14]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(-c3ccccc3)cs2)cc1Oc1cccc2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CSc2cnc(Nc3nc(-c4ccccc4)cs3)cc2Oc2cccc3ncccc23)CC1
Yield: 61.6 %

Procedure:
Following the procedure of Example 201, methyl 3-(6-(4-phenylthiazol-2-ylamino)-4-(quinolin-5-yloxy)pyridin-3-ylthio)propanoate (0.200 g, 0.389 mmol) (prepared as in Example 137), THF (10 mL), potassium 2-methylpropan-2-olate (1.36 ml, 1.36 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.108 g, 0.389 mmol) were combined to give tert-butyl 4-((6-(4-phenylthiazol-2-ylamino)-4-(quinolin-5-yloxy)pyridin-3-ylthio)methyl)piperidine-1-carboxylate (0.15 g, 61% yield) as yellow solid. 1H NMR (CDCl3) δ 8.94 (dd, 1H), 8.36 (s, 1H), 8.17 (d, 1H), 7.98 (dd, 1H), 7.55 (t, 1H), 7.49 (s, H), 7.47 (s, 1H), 7.35 (dd, 1H), 7.12 (m, 3H), 6.94 (d, 1H), 6.84 (s, 1H), 6.02 (s, 1H), 2.18 (d, 2H), 2.61 (t, 2H), 1.81 (m, 2H), 1.60 (m, 1H), 1.40 (s, 9H), 1.22 (t, 2H), 1.12 (m, 2H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:36][OH:37])[C:11]([NH:13][CH:14]2[C:34](=[O:35])[N:16]3[C:17]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=4)=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1>C(OCC)C.CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:36][O:37][CH3:3])[C:11]([NH:13][CH:14]2[C:34](=[O:35])[N:16]3[C:17]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=4)=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: C=[N+]=[N-]
Reactant: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Solvent: CO
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1

Procedure:
A solution of diazomethane in diethyl ether was added little by little to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.3 g.) in methanol (30 ml.) until the reaction terminated. The resultant solution was concentrated under reduced pressure, and the residue was pulverized with diethyl ether, collected by filtration and dried to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.26 g.) This product was identified with the authentic sample.
Reaction SMILES: C[C:2]1([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]1[C:14]([O:16]C)=[O:15].[CH3:23][Si](C)(C)[O-].[K+:28].C(OCC)C>O1CCCC1>[CH3:23][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[C:3]([C:14]([O-:16])=[O:15])[C:2]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[CH:7][N:6]=2)[CH:9]=[N:10][CH:11]=1.[K+:28]
Reactant: COC(=O)C1C=C(c2cccnc2)N=CC1(C)c1nccs1
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cncc(-c2cc(C(=O)[O-])c(-c3nccs3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate (7-3, 890 mg, 2.9 mmol, 1 equiv) in tetrahydrofuran (14.3 mL) was added potassium trimethylsilanolate (640 mg, 5.0 mmol, 1.75 equiv). The reaction mixture was stirred at room temperature for 1 hour. Ethyl ether (15 mL) was added and the precipitate was filtered to afford the title compound (7-4) as a white solid. ESI+MS[M+H]+C15H12N3O2S=298.1
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:31])[CH2:13][C@H:14]([N:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]([OH:17])=[O:16])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+]>CC(C)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:31])[CH2:13][C@H:14]([N:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]([OH:17])=[O:16])=[O:7])=[CH:32][CH:33]=1)=[N+:39]=[N-:40]
Reactant: Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a stiffed solution of 19 (0.115 g, 0.260 mmol) in acetone (6 mL) was added 5% HCl (6 mL) at 0° C. and the solution was stiffing for 5 min NaNO2 (0.020 g, 0.28 mmol) in 1 mL water was added dropwise to the above solution causing an immediate color change from colorless to orange. After 20 min of stirring at 0° C., NaN3 (0.034 g, 0.52 mmol) in 1 mL water was added dropwise to the reaction mixture causing an immediate color changed from orange to colorless to pale yellow. The reaction mixture was stiffed for additional 20 min and extracted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL). The final organic layer was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to obtain (S)-4-(2-(4-azidobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-4-oxobutanoic acid 20 (0.117 g, 96%) as an off white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a suspension of 4-phenylpiperidine (5.0 g) in acetonitrile (100 ml) was added triethylamine (8.64 ml) and then was added dropwise at 0° C. a solution of p-toluenesulfonyl chloride (6.50 g) in acetonitrile (30 ml). The mixture was stirred at 0° C. for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting crystals were collected by filtration, which were washed with hexane to give colorless crystals of 1-(4-methylphenylsulfonyl)-4-phenylpiperidine (8.93 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:4])[CH2:2][CH3:3].[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1C
Yield: 99.1 %

Procedure:
3-Propanoyl-4-chloro-8-(3-methylthiopropoxy)quinoline (1.2 g, 3.71 mmol) and o-toluidine (0.795 g, 7.42 mmol) was refluxed in acetonitrile (18 ml) for 100 min. The solvent was evaporated and the residue was purified by column chromatography (methylene chloride: methanol 100:3). 1.45 g (99%) of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22]C)=[O:21])[C:12]1=[S:27].[OH-].[Na+]>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([OH:22])=[O:21])[C:12]1=[S:27]
Reactant: COC(=O)c1cccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)c1

Procedure:
substituting methyl 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl]benzoate and sodium hydroxide gave 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl]benzoic acid, m.p. 252°-254° C.;
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][N:4]=1)=O.Cl.[CH:24]([C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:26])[CH3:25].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:24]([C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:5][N:4]=2)[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)nc1
Reactant: CC(C)[C@H]1CC[C@H](N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)[C@H]1CC[C@H](NCc2ncc(Oc3ccc(C(N)=O)cn3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-(1-formylisoquinolin-4-yloxy)nicotinamide (Preparation 20) (150 mg, 0.51 mmol) and trans-4-isopropylcyclohexylamine hydrochloride (Preparation 9) (273 mg, 1.53 mmol) in 1,2-dichloroethane (10 mL) under argon was added acetic acid (30 μL, 0.51 mmol) followed by NaBH(OAc)3 (325 mg, 1.53 mmol). The mixture was stirred at rt for 16 h then the reaction solvent was removed in vacuo. The residue was partitioned between EtOAc (50 mL) and NaHCO3 (30 mL), and the organic phase washed with NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, NH4OH:MeOH:DCM 0.5:5:95) to give the title compound: RT=2.85 min; m/z (ES+)=419.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[N:22]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:32])[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:18]([O:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:32][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]4[C:26]=3[CH:25]=[CH:24][CH:23]=[N:22]4)[CH2:6][CH2:7]2)[CH:16]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1cc(N2CCN(C(=O)CCl)CC2)ncn1
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1cc(N2CCN(C(=O)COc3cccc4ncccc34)CC2)ncn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-1-(4-(6-isobutoxypyrimidin-4-yl)piperazin-1-yl)ethanone (20 mg, 0.064 mmol), quinolin-5-ol (10.2 mg, 0.070 mmol), and potassium carbonate (18 mg, 0.13 mmol) in DMF was (0.5 mL) was stirred at 90° C. for 3 h. After cooling to rt, the mixture was poured onto water, and the aqueous later was extracted with dichloromethane (three times). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 9.3 mg (34% yields) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH3:28]>>[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]3[CH:25]=[CH:26][C:13]([NH:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)=[O:37])=[CH:31][CH:30]=1)[CH3:28]
Reactant: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 23, 4-[4-[[7-(chloro)-4-quinolinyl]amino]benzoyl]piperazine is reacted with p-ethylphenyl isocyanate to give 1-[[(4-ethylphenyl)amino]carbonyl]-4-[4-[[(7-chloro)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11].Cl>N1C=CC=CC=1>[Cl:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
Valeryl chloride (12.06 g., 0.10 mole) is added dropwise to a cooled stirred solution of 2-chloro-4-nitroaniline (17.26 g., 0.10 mole) in pyridine (100 ml.). The mixture is warmed to ambient temperature, then heated (80°-100° C.) for 24 hours. The cooled solution is poured into cold 1 N hydrochloric acid (500 ml.) with stirring. The precipitated solid is collected, washed well with water and dried, 25.1 g., m.p. 80°-95° C. Recrystallization from cyclohexane yeilds material (19.75 g.) of m.p. 95°-97° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19](O)[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27](=[O:29])[CH3:28].CS(Cl)(=O)=O.Cl>CN(C)C=O.N1C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27](=[O:29])[CH3:28]
Reactant: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A solution of 21 -chloro-11β,17-dihydroxy-16α-(2-oxopropoxy)pregna-1,4-diene-3,20-dione (10 mmoles) in 40 ml of dimethylformamide and 20 ml of pyridine is stirred at 0°C for 75 minutes with 10 ml of methanesulfonyl chloride. The mixture is poured into cold, dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated to give the title compound.