Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCc4ccccn4)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A starting compound (N-{2-chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-(chloromethyl)pyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give 54 mg (yield 55%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12]([C:24]3[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1c(Br)cnn(-c2ccc(F)c(Cl)c2)c1=O
Agent: N
Product: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound is prepared according to the method of Example 6 starting with 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone and substituting 4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 3.2 g, 63%). 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 4.13 (s, 3H), 7.25 (t J=9 Hz, 1H), 7.35 (d, J=9 Hz 2H), 7.52 (d, J=9 Hz, 2H), 7.55-7.64 (m, 1H), 7.78 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (s, 2H). MS (DCI/NH3) m/z 377 (M+H)+, 394 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[N:34]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A mixture of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.536 g) and 7-(2-ethoxycarbonyl-1-methyl-ethyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (396 mg, Reference Example 19) in tetrahydrofuran (10 ml) containing 4 Angström molecular sieves (0.5 g) was treated with triethyl amine (638 μl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (518 mg) and 4-dimethyl-aminopyridin (14 mg). After stirring for 5 hours further aliquots of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.178 g) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (172 mg) were added and stirring was continued for a further 18 hours. The reaction mixture was filtered through a celite and the filter pad was washed with ethyl acetate (50 ml). The combined filtrate and washings were washed three times with aqueous saturated ammonium chloride (20 ml), then dried over magnesium sulfate and then evaporated (40° C., 40 mbar). The residue (1.2 g) was submitted to chromatography (36 g silica, 0.040-0.063 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (70:30, v/v) to afford the title compound as a white powder (379 mg). TLC: RF=15/65 (cyclohexane:ethyl acetate, 1:1). 1H NMR (400 HMz, (CD3)2SO, at room temperature, we observe a mixture of rotamers): δ1.14 (t, J=7 Hz, 31); 1.24 (d, J=7 Hz, 3H); 1.48 (s, 9 H); 2.26 (s, 3H); 2.58 (d, J=7.5 Hz, 2H); 3.17 (m, 1H); 3.64 (m, 2H); from 3.75 to 3.90 (m, 7H); 4.04 (q, J=7 Hz, 2H); from 6.55 to 6.85 (very broad band, 2H); 6.96 (t, J=7.5 Hz, 1H); 7.00 (broad d, J=8 Hz, 1H); from 7.10 to 7.20 (m, 2H); 7.46 (broad band, 1H); 7.64 (broad s, 1H); 7.78 (d, J=8 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.48 (s, 1H); 8.54 (broad s, 1H). MS (EI): 644 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.B1([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)OCCCO1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.ClCCl.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>[Cl:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH:16]=[N:15][CH:14]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccc(Br)cc1
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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H](Nc1cncc(Cl)n1)c1ccc(-c2cccnc2)cc1

Procedure:
Under a nitrogen atmosphere a mixture of N-[(1S)-1-(4-bromophenyl)ethyl]-6-chloropyrazin-2-amine (0.117 g, 0.37 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (67 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.06 mmol) and toluene (4 mL) was treated with 2M aqueous sodium carbonate solution (0.2 mL). The resulting mixture was stirred vigorously whilst being heated under reflux for 24 hours. Upon cooling, the solution was diluted with methanol and dichloromethane and the mixture dried (MgSO4) and filtered. Removal of solvent in vacuo then yielded the crude product which was purified by column chromatography using dichloromethane-diethyl ether (90:10) then dichloromethane-methanol (99:1) as eluent (50 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2C(O)=O)=[CH:4][CH:3]=1.C([N:16](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:16])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N[C@@H]1C[C@H]1c1ccc(F)cc1

Procedure:
To a solution of the product from step c) (2.6 g) and triethylamine (2.7 ml) in acetone/water (10:1, 33 ml) at 0° C. was added ethyl chloroformate (2.0 ml) over 5 min. The solution was maintained at 0° C. for 30 minutes before addition of sodium azide (1.52 g) in water (6 ml). After a further hour, water (350 ml) was added and the reaction mixture extracted with toluene (3×100 ml). The organic extracts were combined and dried, then heated at reflux for 2 hours behind a blast screen. After cooling the solution, 6M HCl (50 ml) was added and the mixture heated at reflux for 3 hours. Water (150 ml) was added and the aqueous phase basified with 2M NaOH (aq), then extracted into dichloromethane (3×100 ml). The organic phase was dried and concentrated to give the subtitle compound as a colourless oil (1.31 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:28][OH:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F

Procedure:
To a solution of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.0 g) in ethanol (20 ml) was gradually added sodium borohydride (92 mg) under stirring and ice-cooling and the resultant mixture was further stirred for 25 minutes. The resultant mixture was adjusted with 0.1 N hydrochloric acid to pH 4 to 5. The ethanol was removed under reduced pressure without heating so much, and water was added to the residue to give crystals. The crystals were collected by filtration to give crude crystals (1.2 g). These were recrystalized from a mixture of diethyl ether and n-hexane to give pure crystals of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 147° to 148.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:18]([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Br)cc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 4-bromo-6-(trifluoromethyl)-1H-indole (1 g, 3.79 mmol) in DMF (6 mL) was added 60% sodium hydride (0.182 g, 4.54 mmol), and the mixture was stirred for 30 min. 2-bromopropane (0.533 mL, 5.68 mmol) was added and the mixture was stirred overnight. The reaction was then quenched with 10% NaHCO3 and extracted with EtOAc (3×). The extract was dried over Na2SO4 and concentrated. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give the title compound (460 mg, 40%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56-1.61 (m, 6 H), 4.66-4.79 (m, 1 H), 6.65 (d, J=3.03 Hz, 1 H), 7.27-7.31 (m, 1 H), 7.45 (d, J=3.03 Hz, 1 H), 7.54 (s, 1 H), 7.63 (s, 1 H). MS: (M+H)+=306.2.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1.[C:41]([O:45][C:46](=[O:54])[NH:47][CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][NH2:51])([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][NH:47][C:46](=[O:54])[O:45][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of 6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-yl)amino)nicotinic acid (340 mg), tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (316 mg) and TBTU (501 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude product, tert-butyl 3-(6-(6-(4-hydroxybenzylamino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate, which was purified by silica gel chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: O[C@H]1CC[C@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@H](O)CC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using trans-4-{[3-(Piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 42, Step 1) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:31]([O:30][C:24]([C:25]1[C:26]([CH3:28])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:29])[CH3:32]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 83 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, ethyl acetoacetate and acetic acid, concentrated sulfuric acid was added, followed by the same treatment as in Reference Example 1, to yield 6,7-dimethoxy 4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylic acid ethyl ester (83%), which was then recrystallized from ethanol to yield a colorless prismatic crystal having a melting point of 147 to 148° C.
Reaction SMILES: [C:1]([C:6]([OH:8])=[O:7])#[C:2][C:3](O)=[O:4].[CH2:9]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[S:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO.O1CCCC1>[CH2:24]([N:23]1[C:3](=[O:4])[C:2](=[CH:1][C:6]([OH:8])=[O:7])[S:22][C:21]1=[N:20][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCCCCCCNC(=S)NCCCCCCCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
Acetylenedicarboxylic acid (4.8 g, 40 mmoles) is added to a warm solution of N,N'-diundecylthiourea (15.0 g, 39 mmoles) in methanol (200 mls) and tetrahydrofuran (100 mls). The mixture is stirred for 16 hours at ambient temperature, then concentrated under reduced pressure and cooled. The precipitate is filtered off, rinsed with cold methanol and dried. Recrystallization from methanol afforded the product (15.3 g), mp 67°-68° C.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[OH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:18]([O:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=2)=[O:19])[CH2:5][CH2:4]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
To a solution of 4-hydroxypiperidine hydrochloride (3.0 g, 21.8 mmol) in a mixture of methylene chloride (90 ml) and pyridine (15 ml) were added chloroformic acid p-nitrobenzyl ester (15.4 g, 72.0 mmol) and triethylamine (13.1 ml, 93.8 mmol) in an ice bath. The mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, yield 48%) as pale yellow crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(C)ccc4C)c3O2)cc1
Product: CNCC1Cc2cccc(-c3cc(C)ccc3C)c2O1

Procedure:
The title compound was prepared (0.091 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.091 g, 0.22 mmol) and methylamine (0.069 g, 2.22 mmol). mp 186-189° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]1([C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CS(C)=O.C(OCC)(=O)C>O>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:31]1[CH:32]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]=[CH:30]1)([O-:14])=[O:13]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(-c4ccccc4)c3)cc2c1=O
Temperature: 120 °C
Yield: 76.8 %

Procedure:
A mixture of 50 mg (0.156 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 139 mg (0.936 mmol) of 4-phenyl-1H-imidazole and 0.25 ml of DMSO is heated to 120° C. for 3.5 hours. After cooling to room temperature, the reaction mixture is distributed between ethyl acetate and water, the organic phase is separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using tetrahydrofuran-hexane (80:20) and the fractions containing the desired product are combined and evaporated giving 53 mg (77%) of the title compound. MS (ES−): m/e=441 (M−1−).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 26.1 %

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-methoxyphenylboronic acid 66 mg, sodium carbonate 69 mg and polymer-carried bis(acetato)triphenylphosphine palladium(II) 31 mg at room temperature, and it was stirred under application of pressure at 160° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was stirred under application of pressure at 180° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was stirred under application of pressure at 200° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was stirred under application of pressure at 220° C. for 5 minutes. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 0.5 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL and ethanol 4.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour and 30 minutes. 0.7 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture, the organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(4-methoxyphenyl)benzoic acid 19 mg of pale yellow solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].[C:21]([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:15][C:16]=1/[CH:21]=[CH:20]/[N+:17]([O-:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(SCc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccccc1SCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of 4-benzylsulfanyl-benzaldehyde (840 mg 3.68 mmol) described in Manufacturing Example 205-1-2, nitromethane (997 μL, 18.4 mmol), ammonium acetate (567 mg, 7.36 mmol), and acetic acid (10 mL) was stirred for 2 hours at 100° C. This mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (950 mg). The title compound was used in the following reaction without any further purification.