Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:29])([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:21])([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:29])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2c(N)nc3c(c2n1CC(C)(C)OCCS(C)(=O)=O)CCCC3
Yield: 75.8 %

Procedure:
A mixture of 2-(ethoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 9, 1.70 g, 4.04 mmol) and platinum(IV) oxide (1.0 g) in trifluoroacetic acid (20 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 40 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (20 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a white solid. The solid was recrystallized from toluene to afford 1.3 g of 2-(ethoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white, fluffy powder, mp 150-153° C.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[CH3:18].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1>>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[C:3]([CH3:18])=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: Cc1c(Cl)sc2ncnc(NC3CCNCC3)c12
Reactant: Fc1cccc(CBr)c1
Product: Cc1c(Cl)sc2ncnc(NC3CCN(Cc4cccc(F)c4)CC3)c12

Procedure:
The title compound was prepared (119 mg, 91%) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95 mg, 0.336 m. mol) and 1-(bromomethyl)-3-fluorobenzene (70 mg, 0.37 m. mol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.95 (m, 1H), 5.30 (d, 1H), 4.05 (m, 1H), 3.55 (s, 2H), 2.95 (m, 2H), 2.50 (s, 3H), 2.25 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 390.91; Observed: 391.2 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[O:15])[CH:10]2C(OCC)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:10]2)[CH2:21][CH2:22]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)C(C)OC12CCN(C(=O)OCC)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)CC(=O)C(C)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 2.74 g ethyl 8-ethoxycarbonyl-2-meth-yl-3-oxo-1-oxa-8-azaspiro[4,5]decane-4-carboxylate in 10 ml N,N-dimethylformamide, were added 512 mg sodium chloride and 315 μl water, and the mixture was heated with stirring for two hours in an oil bath held at 140°-150° C. The reaction mixutre was poured into 30 ml ice water, the resulting mixture was extracted with chloroform, and the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent from the dried solution, the residue was purified by silica gel column chromatography using, as eluent, a mixed solvent of n-hexane/ethyl acetate (1:1 by volume), giving 1.54 g of 8-ethoxycarbonyl-2-methyl-1-oxa-8-azaspiro[4,5]-decan-3-one as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][C:47]=1[CH3:59].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:59][C:47]1[CH:48]=[C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])[CH:50]=[CH:51][C:46]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])c(C)c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-methyl-4-(2-propoxyethoxy)phenyl borate (165 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1) and recrystallized from ethanol to give 7-[2-methyl-4-(2-propoxyethoxy)phenyl]-N[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 121) (184 mg).
Reaction SMILES: [CH:1]1([N:7]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][NH:22][CH:23]([CH2:28][CH3:29])[C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([N:7]([CH2:32][CH:33]2[CH2:34][CH2:35]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]([CH2:28][CH3:29])[C:24]([OH:26])=[O:25])=[CH:30][CH:31]=3)=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-({4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]benzyl}amino)butanoate (Example 74, 50 mg; 0.10 mmol) in a mixture of MeOH (2 ml) and THF (2 ml) was treated with an aqueous solution (5 N) of sodium hydroxide (300μl; 1.5 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was acidified with HCl 1N until pH 4. The precipitate was filtered and dried under vacuum to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([NH2:45])(=[O:44])=[O:43]>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]([CH3:1])=[C:3]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]([C:25]([F:27])([F:26])[F:28])=[N:5]2)=[CH:12][CH:11]=1)=[O:24])(=[O:44])=[O:43]
Reactant: NS(=O)(=O)c1ccccc1F
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 2-fluoro-benzenesulfonamide: MS (ESI) m/z 547 [M+H]+, 545 [M−H]−, 1H-NMR (CDCl3) δ 7.86-7.81 (1H, m), 7.74-7.58 (1H, m), 7.48-7.24 (1H, m), 6.45 (1H, br.s) 3.54-3.49 (2H, m), 2.87 (2H, t, J=6.7 Hz), 2.23 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][C:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[O:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7]2.P([O-])(O)(O)=[O:34].[Na+].OO.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.C(#N)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][C:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:34])=[O:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCC=O)(c1ccccc1)C2
Reactant: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCC(=O)O)(c1ccccc1)C2
Reaction time: 0.5 h
Yield: 240.7 %

Procedure:
To a mixture of 8-(4,5,6,7-tetramethoxy-2-phenylindan-2-yl)octanal (985 mg), sodium dihydrogenphosphate (72.6 mg), 30% hydrogen peroxide (0.435 ml), acetonitrile (10 ml), and water (4 ml) was dropwise added a solution of sodium chlorite (80%, 355 mg) in water (14 ml) with cooling with ice in 30 min. After the reaction mixture was stirred for 30 min, aqueous sodium sulfite to the reaction mixture, which was then made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=1:2) to yield the entitled compound (665 mg) as an oil.
Reaction SMILES: [NH:1]([C:23]([O:25]CC1C=CC=CC=1)=O)[C@H:2]([C:10]([N:12]([CH3:22])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:33]([C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C@@H:34](C(O)=O)[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:51])[NH:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CO.[Pd]>[NH:33]([C:55]([O:57][CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:56])[C@@H:34]([C:23]([NH:1][C@H:2]([C:10]([N:12]([CH3:22])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:25])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:51])[NH:40][S:41]([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CN(CCC(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Temperature: -1 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Z-Phe-MeβAla-O-t-Bu (21.0 g, 47.6 mmol) was dissolved in methanol (200 ml), and added with 5% Pd-C (water content: 50%, 21 g) as catalyst, and catalytic reduction was carried out for four hours to remove the protective group. After the catalyst was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in dimethylformamide (100 ml). Z-D-Arg(Tos)-OH (20.0 g, 43.2 mmol) and 1-hydroxybenzotriazole (6.43 g, 47.6 mmol) were dissolved in the solution. The solution was cooled to −1° C., added with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (9.12 g, 47.6 mmol), and then stirred at −10° C. for one hour and further at room temperature for 18 hours. After the solvent was evaporated under reduced pressure, the reaction mixture was added with ethyl acetate (100 ml), and washed with 1N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate. The solvent was concentrated under reduced pressure to obtain 31.9 g of Z-D-Arg(Tos)-Phe-MeβAla-O-t-Bu as a colorless oily product.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].Cl.CCO.CN1C2C(N=C(N)NC=2NCC1CNC1C=[CH:32][C:31]([C:34]([NH:36][CH:37](C(O)=O)[CH2:38][CH2:39]C(O)=O)=O)=CC=1)=O>>[C:31]12([C:32]3[O:5][N:4]=[C:1]([CH3:2])[N:3]=3)[CH2:39][CH:38]1[CH2:37][NH:36][CH2:34]2
Reactant: CC(N)=NO
Reactant: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(C23CNCC2C3)n1
Yield: 82 %

Procedure:
The N-benzyl-2,5-dihydropyrrole ester was prepared, as described (Chem. Pharm. Bull. 1985, 33(7), 2762) by treating ethyl propiolate and N-(methoxymethyl)-N-(trimethylsilylmethyl)-N-benzylamine in DCM with 0.1M TFA in DCM, followed by aqueous work up and silica gel chromatography, in 44% yield. The cyclopropyl group was furnished by treatment with trimethylsulfoxonium Iodide and NaH in DMSO at room temperature, followed by aqueous work up and silica gel chromatography, in 43% yield as described in the literature (Korean J. of Med. Chem. 1994, 4(2), 119). The N-benzyl group was removed with palladium on carbon and ammonium formate in methanol. The Boc protecting group was directly installed with DMAP, TEA and Boc2O in DCM, followed by silica gel chromatography, in 60% yield for both steps. The oxadiazole ring was prepared as described above, by reaction with acetamide oxime and sodium methoxide in methyl THF. Aqueous work up and silica gel chromatography provided the intermediate in 54% yield. Standard deblocking with HCl-EtOH provided the desired product, as the HCl salt, in 82% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[N:5]2.[OH:21]O.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[C:6](=[O:21])[NH:5]2
Reactant: Brc1ccc2c(c1)ncc1nnc(-c3ccccc3)n12
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
7-Bromo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline (279 mg, 0.86 mmol) was dissolved in acetic acid (7.5 mL). Hydrogen peroxide (30%, 2.5 mL) was added, and the reaction was heated to 50° C. overnight. The reaction was poured into water (25 mL) and stirred at room temperature for 2 hours. The precipitate was filtered, washed with water, and dried to obtain the desired product, 5z.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1)=[CH:8][CH:9]=[C:10]2[OH:15])(=[O:3])[CH3:2].Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)=[CH:8][CH:9]=[C:10]2[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(O)ccc(Sc3cccc([N+](=O)[O-])c3)c12
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CC(=O)Nc1cccc2c(O)ccc(Sc3cccc(N)c3)c12
Yield: 60.1 %

Procedure:
5-Acetamido-4-(3-nitrophenylthio)-1-naphthol (1.0 g), iron pin dust (3.0 g), ethanol (25 ml) and concentrated hydrochloric acid (0.05 ml) were stirred and heated under reflux for 24 hours. Sodium carbonate (0.1 g) was heated to the hot mixture which was then filtered through keiselguhr. The filtrate was concentrated to dryness by rotary evaporation. The solid was stirred with a little ethanol and insoluble material was filtered off (0.2 g). The ethanol filtrate was diluted with water to give another 0.55 g of product. Total yield 0.75 g (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3Cl)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(S(C)(=O)=O)cc4Cl)c3)S2)CC1

Procedure:
5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[CH:6]=[CH:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[Cl:14][C:15]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=1[C:17](=[O:20])[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH:7]=[CH:6]3)=[CH:11][C:2]=2[O:1][C:18]=1[C:17]([C:16]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:15]=1[Cl:14])=[O:20]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cc2c(cc1O)CCC=C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)C=CCC3
Temperature: 90 °C
Reaction time: 17 h
Yield: 19 %

Procedure:
To a solution of 3-hydroxy-5,6-dihydro-naphthalene-2-carbonitrile from step 1 (100 mg, 0.58 mmol) and 2,4-dichlorophenacyl chloride (144 mg, 0.64 mmol, 1.1 eq) in anhydrous N,N-dimethylformamide (2 mL) was added potassium carbonate (161 mg, 1.2 mmol, 2 eq). The reaction mixture was shaken at 90° C. for 17 h. The mixture was cooled to room temperature and poured into ethyl acetate and water. Separated the organic phase and extracted the aqueous layer with ethyl acetate twice. Combined the ethyl acetate extracts and the original organic layer and evaporated in vacuo. The crude product was purified by HPLC and gave 39.4 mg (14% for two steps) of (3-Amino-7,8-dihydro-naphtho[2,3-b]furan-2-yl)-(2,4-dichloro-phenyl)-methanone as a brown oil. 1H-NMR (acetone-d6) δ 7.63 to 7.61 (m, 2H), 7.59 (s, 1H), 7.52 to 7.54 (m, 1H), 7.13 (s, 1H), 7.04 (broad, s, 2H), 6.59 (tt, J=10 Hz, 1.2 Hz, 1H), 6.07 (m, 1H), 2.92 (t, J=8.0 Hz, 2H), 2.33 (m, 2H); MS LC-MS (MH+=358.1/360.1); Rf=0.51, 30% ethyl acetate-hexane.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[N:14][CH:15]=1)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[K+]>CCO>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:43])/[CH:42]=[CH:8]/[C:10]3[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=3)=[CH:37][CH:36]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1ccc(/C=C/C(=O)O)nc1
Reactant: CC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid trifluoroacetate (described in Example 45 STEP A, 206 mg, 0.71 mmol), 4-(4-acetyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (described in Preparation 12, 368 mg, 1.16 mmol) and 1.7 M KOH (2 ml) in EtOH (12 ml) was stirred at 4° C. overnight. The resulting precipitate was filtered and washed with AcOEt to give 250 mg of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-benzyl)-piperazine-1-carboxylic acid tert-butyl ester as its potassium salt.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[OH:7][CH2:8][C:9]1[N:10]=[C:11]2[C:20](=O)[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[N:12]2[C:26]=1[CH2:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1.C(N(CC)CC)C.O>ClCCl.CS(C)=O>[Cl:4][C:20]1[C:11]2[N:12]([C:26]([CH2:27][C:28]3[NH:29][CH:30]=[CH:31][N:32]=3)=[C:9]([CH:8]=[O:7])[N:10]=2)[C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n2c(Cc3ncc[nH]3)c(CO)nc12
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of dichloromethane (30 ml) and oxalyl chloride (1.5 ml, 16.5 mmol) is under stirring at -50° C. to -60° C. added dimethyl sulfoxide (2.8 ml, 36 mmol) diluted with dichloromethane (15 ml). The reaction mixture is stirred for 2 min. followed by addition within 10 min. of 2-hydroxymethyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 22) (1.65 g, 4.5 mmol) in dichloromethane (5 ml) and dimethylsulfoxide (10 ml). The stirring was continued for an additional 15 min. Triethylamine (12 ml, 86 mmol) was added and the reaction mixture was stirred for 5 min. and then allowed to warm up to room temperature. Water (300 ml) was added and the aqueous layer was reextracted with additional dichloromethane (4×100 ml). The organic layers were combined, washed with saturated sodium chloride solution (250 ml) and dried with anhydrous magnesium sulphate. The filtered solution was concentrated in vacuo to give crude 4-chloro-2-formyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxaline which was hydrolysed to the title compound in 10 min at 40° C. with glacial acetic acid (30 min.). The mixture was concentrated in vacuo and the residue diluted in water. Saturated sodium hydrogen carbonate was added and the aldehyde extracted with acetonitrile (6×250 ml) to give 830 mg (50%) of the title compound. M.p. >250° C.
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](CC(C)C)[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=CC=1)CCC.C[N:34](C=O)C.S(Cl)(Cl)=O>C1COCC1>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:32][C:19]=2[CH:20]=[C:21]([C:29]([NH2:34])=[O:30])[CH2:22][CH2:23]1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)C1=Cc2ccccc2NCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (16 ml) was added dropwise to a solution of N-methyl-N-[(1-propylimidazol-2-yl)methyl]-1,4-benzodiamine (0.38 g) and triethylamine (2.04 ml) in THF (7.6 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[methyl[(1-propylimidazol-2-yl)methyl]]amino]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 264) (0.92 g).