Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][O-:3].[Na+].[H-].[Na+].C(=O)(OCC)OCC.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH2:28][OH:29])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCO>[O:3]=[C:2]1[N:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23][C@H:24]2[CH2:28][O:29]1
Reactant: CC[O-]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC[C@@H]2C1
Temperature: 80 °C

Procedure:
A NaOEt solution, prepared from sodium hydride (60% dispersion in mineral oil) (0.990 g, 26 mmol) and 100 mL EtOH, diethyl carbonate (9.00 mL, 74 mmol) and (S)-4-N-BOC-2-hydroxymethyl-piperazine (2.17 g, 10 mmol) was heated at 80° C. The reaction was cooled to RT and filtered. The filtrate was concentrated to dryness to give an off-white amorphous solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=2[F:68])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:68][C:59]1[CH:60]=[CH:61][C:62]([C:64]([F:65])([F:67])[F:66])=[CH:63][C:58]=1[O:57][CH:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:23])[CH2:52][CH2:53]1
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2cc(C(F)(F)F)ccc2F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(C(F)(F)F)ccc2F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
DIPEA (110 mg, 0.85 mmol) was added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.24 mmol) in DMF (2 mL) followed by HOBt (33 mg, 0.24 mmol) and EDCI.HCl (49 mg, 0.25 mmol). After 2 minutes 2-amino-1-[4-(2-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue obtained was purified by recrystallisation using 25% EtOAc in hexane to afford 89 mg (80.9% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457, 90.38%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (bs, 1H), 7.9 (t, 1H), 7.1 (m, 7H), 4.61 (m, 1H), 4.4 (d, 2H), 3.7 (m, 2H), 3.3 (m, 2H), 1.9 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[C:23]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([N:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([S:44]([NH:47][C:14]([NH:13][C:4]4[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=4[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:46])=[O:45])=[CH:40][CH:39]=3)[CH2:33][CH2:34]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NS(=O)(=O)c1ccc(OCCN2CCN(c3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(OCCN2CCN(c3ccccc3)CC2)cc1

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-[2-(4-phenylpiperazin-1-yl)ethyloxy)benzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-{4-[2-(4-phenylpiperazin-1-yl)ethyloxy] benzenesulfonyl}-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and to obtain from 813 mg (1.39 mmol) of N-{4-(2-(4-phenylpiperazin-1-yl)ethyloxy] benzenesulfonyl}-N'-(2-carboxy-5-chlorophenyl)urea 115 mg of the above-identified compound (yield 15.3%). Properties: colorless crystal, Melting point: 177°-179° C., PMR (δppm, DMSO-d6):2.65 (4H,t), 2.80 (2H,t), 3.13 (4H,t), 4.26 (2H,t), 6.75 (1H,t), 6.90 (2H,d), 7.12 (1H,s), 7.17-7.22 (5H,m), 7.85 (1H,d), 8.10 (2H,d), 11.59 (1H,br).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([O:21][CH3:22])=[C:11](C(O)=O)[S:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:1]([S:8][C:9]1[C:10]([O:21][CH3:22])=[CH:11][S:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C(=O)O)sc(C(F)(F)F)c1SCc1ccccc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: COc1csc(C(F)(F)F)c1SCc1ccccc1
Temperature: 150 °C
Yield: 69.9 %

Procedure:
A mixture of 3.6 g of 4-benzylthio-3-methoxy-5-trifluoromethyl-2-thiophenecarboxylic acid and 0.85 g of copper powder in 50 mL of quinoline was heated to 150° C. for 15 min. The mixture was cooled and partitioned with ether and aqueous HCl. The organic phase was separated, dried over MgSO4, filtered, concentrated and purified by column chromatography to give 2.2 g (71%) of an amber oil. 1H NMR (300 MHz, CDCl3): δ 7.2 (m, 5H); 6.4 (s, 1H); 4.1 (s, 2H); 3.8 (s, 3H). Anal. Calc'd for C13H11F3OS2: C, 51.30; H, 3.64; S, 21.07. Found: C, 51.13; H, 3.54; S, 21.02.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:4][CH:3]=1.O.NN>CCO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncn1CCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cncn1CCCN
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-(3-(5-Methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (i.e. 8.92 mmol, 1 eq., which may be prepared as described in D3) and hydrazine monohydrate (17.84 mmol, 2 eq.) were dissolved in dry EtOH (50 mL). The mixture was kept under reflux over night, then mixture was concentrated down to a volume of 25 mL. Hydrochloric acid (conc., 55 mL) was then added and the mixture was heated to 50° C. and kept at this temperature for 30 min. The formed precipitate was then filtered. The filtrate was cooled to 0° C. and solid NaOH was added until a final pH-value of 10-12 was reached. The aqueous solution was extracted by means of CHCl3 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed. The product was purified by means of flash-chromatography using silica gel and a CHCl3/MeOH-gradient.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:10]([OH:14])[C:11]([OH:13])=[O:12].O>C(O)(=O)C>[Cl:4][C:15]1[CH:16]=[C:17]([OH:18])[C:7]([OH:6])=[CH:8][C:9]=1[CH:10]([OH:14])[C:11]([OH:13])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)C(O)c1ccc(O)c(O)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(O)c1cc(O)c(O)cc1Cl
Reaction time: 2 h

Procedure:
Sulphuryl chloride (0.8 ml) was added to a solution of 3,4-dihydroxymandelic acid (1.84 g, 10 mmol) in warm acetic acid (20 ml). The mixture was stirred for two hours then poured into water and extracted with ethyl acetate (6×40 ml). The extracts were washed with saturated brine (50 ml), dried and evaporated to a crystalline mass (2.36 g) which was recrystallised from ethyl acetate-cyclohexane, 0.97 g, 44%, mp 177°, δ[(CD3)2SO] 5.15(1H, s, CH), 6.71 and 6.85(2H, 2×s, Ar), 8.4-9.8(3H, m, 2×OH, CO2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1
Reactant: COC(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)O)cc3)c(C)c2c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of methyl 4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}benzoate (1.01 g) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (915 mg, 94%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][CH:35]([OH:38])[CH2:36][NH2:37])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:37][CH2:36][CH:35]([OH:38])[CH2:34][NH:33][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:39])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 300 mg (0.82 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 202 mg (1.06 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate in 6 ml of dimethylformamide with the addition of 204 mg (1.06 mmol) of EDC and 33 mg (0.25 mmol) of HOBt.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[S:13][C:14]([CH3:16])=[CH:15][C:8]=2[C:7]1=[O:17].[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:18][C:15]1[C:8]2[C:7](=[O:17])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH2:12][CH2:11][CH2:10][C:9]=2[S:13][C:14]=1[CH3:16]
Reactant: Cc1cc2c(s1)CCCN(CCCCCl)C2=O
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1sc2c(c1Br)C(=O)N(CCCCCl)CCC2
Reaction time: 0.33 h

Procedure:
To a solution of 5.0 g of 5-(4-chlorobutyl)-5,6,7,8-tetrahydro-2-methyl-4H-thieno[3,2-c]azepin-4-one in 60 ml of acetic acid was added 1.9 ml of bromine at 60° C. and stirred for 20 minutes. After cooling, to the mixture was added an aqueous saturated sodium thiosulfate solution and the mixture was neutralized with potassium carbonate, and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The resulting crude crystals were recrystallized from a mixed solvent of isopropyl alcohol and hexane to give 2.3 g of 3-bromo-5-(4-chlorobutyl)-5,6,7,8-tetrahydro-2-methyl-4H-thieno[3,2-c]azepin-4-one as pale yellow crystals, melting at 78°-80° C.
Reaction SMILES: CCOCC.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[OH:16][NH:17][C:18](=N)[CH3:19].Cl>CCOC(C)=O.CCO.[Cl-].[Cl-].[Zn+2]>[CH3:19][C:18]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]2)[O:16][N:17]=1
Reactant: N#CN1CCC(CO)CC1
Reactant: CC(=N)NO
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: Cc1noc(N2CCC(CO)CC2)n1
Yield: 12.9 %

Procedure:
[1-(3-Methyl-1,2,4-oxadiazol-5-yl)-4-piperidinyl]methanol (143 mg, 13%) was prepared from a solution of 1N ZnCl2 in Et2O (6.8 mL, 6.8 mmol), 4-(hydroxymethyl)-1-piperidinecarbonitrile (prepared as in Example 20, Step 1, 0.79 g, 5.6 mmol) and N-hydroxyacetamidine (0.5 g, 6.8 mmol) in EtOAc (10 mL) followed by concentrated HCl (2 mL) in EtOH (2 mL) in a manner similar to Example 20, Step 3. 1H NMR (400 MHz, CDCl3): δ 4.22-4.10 (m, 2H), 3.54 (d, 2H, J=6.4 Hz), 3.11-3.01 (m, 2 H), 2.21 (s, 3H), 1.89-1.79 (m, 2H), 1.78-1.69 (m, 1H), 1.41-1.20 (m, 2H); LRMS (ESI), m/z 198 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH3:23][O:24][N:25]=[C:26]([C:30]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[CH2:31][Br:32])[C:27](O)=[O:28].P(Cl)(Cl)(Cl)=O>C(Cl)Cl.CN(C)C=O>[CH3:23][O:24][N:25]=[C:26]([C:30]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[CH2:31][Br:32])[C:27]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)O
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 44.2 %

Procedure:
7-Amino-3-hydroxycepham-4-carboxylic acid (1.09 g., purity 84.8%), trimethylsilylacetamide (5.3 g.), 2-methoxyimino-3,3-diethoxy-4-bromobutyric acid (syn isomer, 1.8 g.), phosphorus oxychloride (0.68 ml.), N,N-dimethylformamide (0.55 ml.) and methylene chloride (25 ml.) were treated in a similar manner to that of Example 25 (1) to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])(=[O:3])[NH2:2].C1C(=O)N([Br:26])C(=O)C1>CC(O)=O.O>[Br:26][C:7]1[S:6][C:5]([NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13])=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sccc1C(N)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(C)(C)C(=O)Nc1sc(Br)cc1C(N)=O
Temperature: 25 °C

Procedure:
Intermediate 10 (46.5 g, 172 mmol) is dissolved in AcOH (700 mL). To the resulting suspension, NBS (32.2 g, 181 mmol) is added. The mixture is stirred at room temperature, after which it is evaporated to give a slurry. This slurry is taken up in water to give a suspension that is filtered. Resulting precipitate is dried in the vacuum oven and used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Li+].CC([N-]C(C)C)C.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([N:40]=2)=[CH:38][C:37]([CH:41]=[O:42])=[CH:36][CH:35]=3)[CH2:27][CH2:26]1>C1COCC1>[F:1][C:2]1[C:7]([CH:41]([OH:42])[C:37]2[CH:38]=[C:39]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][C:31]([N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[N:40]3)=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(F)cc1F
Reactant: O=Cc1ccc2ncc(N3CCOCC3)nc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(F)c(F)c(C(O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of N-(2,4,5-trifluorophenyl)pivalamide (550 mg, 2.4 mmol, 1.2 eq.) in THF (30 mL) cooled at −78° C. was added LDA (4.1 mL, 4.8 mmol, 2.4 eq.) dropwise. The resulting mixture was stirred at −78° C. for 1 h, then a solution of 3-morpholinoquinoxaline-6-carbaldehyde (486 mg, 2.0 mol, 1.0 eq.) in THF (20 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, then quenched by the addition of NH4Cl solution. The mixture was extracted with EA (20 mL×3) and the combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (MeOH/DCM=1/50, v/v) to afford N-(2,4,5-trifluoro-3-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (620 mg, 65.2%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C(O)(=O)C>[CH3:18][C:17]1[N:12]([C:9]2[CH:10]=[CH:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: Nc1ccn(-c2ccccc2)n1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-phenyl-1H-pyrazol-3-ylamine (32.7 g) in acetic acid (330 ml) was added 2,5-hexanedione (25 ml), and the mixture was stirred for 3 hours at reflux. This reaction solution was cooled to room temperature, and then acetic acid was concentrated under reduced pressure, and then toluene (100 ml) was added thereto, and the mixture was further concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 100/1 to 20/1) to give the titled compound (41.8 g).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[CH3:16][O:17][CH2:18]Cl>C1C=CC=CC=1>[CH3:16][O:17][CH2:18][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: COCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COCOc1ccccc1O

Procedure:
110 parts by weight of pyrocatechol is dissolved in 400 parts by weight of benzene. At room temperature there are simultaneously dripped into this solution 101 parts by weight of triethylamine and 81 parts by weight of chloromethyl methyl ether in such a manner that the reaction medium has a weakly alkaline reaction. Subsequently the mixture is heated for an hour under reflux and then allowed to cool. The hydrochloride is removed by suction filtration and the product is washed, dried over Na2SO4, concentrated and distilled in vacuo.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 22 mg, 0.55 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (135 mg, 0.56 mmol) in THF (1.0 mL) at 0° C. After 1 h at 0° C., [(Z)-4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester (150 mg, 0.56 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 16.5 h at rt, the reaction was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% →60% EtOAc/CH2Cl2, gradient) afforded 91 mg (42%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=2[N:3]=1.[C:15]([C:19]1[O:23][N:22]=[C:21]([NH2:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(O)(C)C.Cl>[C:15]([C:19]1[O:23][N:22]=[C:21]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=3[N:3]=2)[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: Cn1c(Cl)nc2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: CC(C)O
Product: Cn1c(Nc2cc(C(C)(C)C)on2)nc2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Yield: 317.1 %

Procedure:
To a solution of 2-Chloro-1-methyl-5-nitro-1H-benzoimidazole (200 mg, 0.19 mmol) and 5-tert-Butyl-isoxazol-3-ylamine (265 mg, 1.90 mmol) in isopropanol (15 ml) was added a solution of HCl (3 drops, 4.0 m in dioxane). The reaction was heated to 80° C. and after 20 h. the reaction mixture was cooled to rt. The solvent was evaporated to dryness and the resultant solid was dissolved in EtOAc and neutralized by a 10% NaHCO3 water solution. The combined organic layers were washed with water, dried over MgSO4 and concentrated to give a foam. The crude material was purified through silica gel to give the title compound as a yellow solid (190 mg, 63%). MS (ESI) m/z=316 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C=C(C(Cl)=O)C2C(=CC=CC=2)N=1.S(Cl)(Cl)=O.[CH3:33][O:34][CH2:35][CH2:36][N:37]1[C:41]([CH3:42])=[C:40]([CH3:43])[S:39][C:38]1=[NH:44].CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](/[N:44]=[C:38]2\[S:39][C:40]([CH3:43])=[C:41]([CH3:42])[N:37]\2[CH2:36][CH2:35][O:34][CH3:33])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Agent: O=C(Cl)c1cc(Cl)nc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)nc2ccccc12
Yield: 33.6 %

Procedure:
The 2-chloroquinoline-4-carboxylic acid (TCI-JP, 0.29 g, 1.4 mmol) was converted to 2-chloroquinoline-4-carbonyl chloride with 5 mL of thionyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and 2-chloroquinoline-4-carbonyl chloride in 30 mL THF were processed as in Example 134B to afford the title compound (0.14 g, 0.37 mmol, 35% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.33 (s, 3H), 2.35 (s, 3H), 3.31 (s, 3H), 3.78 (t, J=5.3 Hz, 2H), 4.49 (t, J=5.3 Hz, 2H), 7.66 (ddd, J=8.5, 7.1, 1.4 Hz, 1H), 7.81 (ddd, J=8.5, 7.1, 1.4 Hz, 1H), 7.94 (s, 1H), 7.99 (dt, J=8.5, 0.7 Hz, 1H), 8.83 (dd, J=8.6, 1.2 Hz, 1H); MS (DCI/NH3) m/z 376 (M+H)+; Anal. calculated for C18H18ClN3O2S: C, 57.52; H, 4.83; N, 11.18. Found: C, 57.44; H, 4.59; N, 10.97.
Reaction SMILES: [C:1]1([C:7]2[C:21]3[C:20]4[C:22]5[C:16]([CH:17]=[CH:18][CH:19]=4)=[C:15](B(O)O)[CH:14]=[CH:13][C:12]=5[C:11]=3[C:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Br:47])[CH:43]=2)[CH:38]=1>>[Br:47][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:15]1[CH:14]=[CH:13][C:12]3=[C:22]4[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]4[C:21]1[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:8]4[CH:35]=[CH:34][CH:33]=[CH:32][C:9]4=[C:10]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:11]=13)[CH:46]=[CH:45]2
Reactant: OB(O)c1ccc2c3c(cccc13)-c1c-2c(-c2ccccc2)c2ccccc2c1-c1ccccc1
Reactant: Brc1ccc2cc(Br)ccc2c1
Product: Brc1ccc2cc(-c3ccc4c5c(cccc35)-c3c-4c(-c4ccccc4)c4ccccc4c3-c3ccccc3)ccc2c1

Procedure:
It was carried out in a similar manner as Synthesis Example 1 except that 7,12-diphenylbenzo[k]fluoranthene-3-yl boronic acid was employed instead of 9,9-dimethyl-911-fluorene-2-yl boronic acid, and that 2,6-dibromo-naphthalene was employed instead of 3-bromo-7,12-dibenzo[k]fluoranthene in Synthesis Example 1 to obtain 3-(6-bromonaphthalen-2-yl)-7,12-diphenylbenzo[k]fluoranthene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[CH:10]N(C)C.[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:27][C:25](=[O:26])[C:24]([C:22]#[N:23])=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
A solution of the crude product from step A dissolved in 80 mL of DMF containing 4.4 mL methanol and 4.61 g cyanoacetamide was transferred by cannula into a flask containing a suspension of NaH (4.98 g, 60% dispersion in mineral oil, freed of excess oil by washing with hexane just prior to use) in DMF (40 mL). The solution was heated to 95° C. for 2.5 hours then concentrated. The residue was dissolved in ethyl acetate, washed twice with 10% aqueous NaHSO4, and twice with water before concentrating to a solid. The solid was suspended in warm ethanol and then cooled, and the title compound was subsequently isolated by filtration and dried in vacuo.