Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[C:24]([O:23][C:21]([N:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:28])=[O:2])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cccc(CN(Cc2ccc(Cl)cc2Cl)C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)O)c1)Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
0.85 g (2.00 mmol) of 3{[tert-Butoxycarbonyl-(2,4-dichloro-benzyl)-amino]-methyl}-benzoic acid methyl ester was dissolved in 20 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was stirred for 5 h then poured into water. The resulting solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 3. The product was extracted 3 times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[O:26][CH3:27])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41].[O:44]1CCOC[CH2:45]1>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:27][O:26][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH:13]=2)[C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:45]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:44]
Reactant: C1COCCO1
Reactant: CS(N)(=O)=O
Reactant: COc1cccc(-c2ccc3c(-c4cccc(I)c4)c(OC)ccc3c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(-c2ccc3c(-c4cccc(C(=O)NS(C)(=O)=O)c4)c(OC)ccc3c2)c1
Reaction time: 0.25 h

Procedure:
1-(3-Iodophenyl)-2-methoxy-6-(3-methoxyphenyl)naphthalene (150 mg, 0.32 mmol, 1 eq), Mo(C0)6 (85 mg, 0.32 mmol, 1 eq), Pd(OAc)2 (7.2 mg, 0.03 mmol, 0.01 eq), DBU (145 μl, 0.96 mmol, 3 eq), methylsulfonamide (91.7 mg, 0.96 mmol, 3 eq) and 1,4-dioxane (1 ml) are charged into a reaction vessel. The reaction is performed in a microwave oven at 110° C. for 15 min. After cooling, the reaction mixture is dissolved in dichloromethane, and purification by column chromatography with dichloromethane and 2% methanol as eluents was performed. The compound was obtained in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:14])[NH:22][CH3:21])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.6 mmol), methylamine (0.25 mL, 2M in THF) and DIPEA (0.29 mL, 1.6 mmol) in DMF (2 mL). MS (LC-MS): 633.0 [2M]+; tR (HPLC conditions c): 4.55 min.
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:46]=[C:45]([O:47][CH3:48])[C:42]([CH:43]=O)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37].C(Cl)(Cl)Cl>O1CCCC1>[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:46]=[C:45]([O:47][CH3:48])[C:42]([CH:43]=[CH:14][C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN(CCCC)c1cc(OC)c(C=O)c(OC)c1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1cc(OC)c(C=Cc2cccs2)c(OC)c1
Temperature: 0 °C
Yield: 62.6 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 3.76 g of a 19% phenyllithium solution (8.5 mmol), and 0.78 g (1.98 mmol) of thiophene-2-ylmethyltriphenylphosphonium bromide was added thereto under cooling. After the mixture was well-stirred, 0.58 g (1.98 mmol) of 4-dibutylamino-2,6-dimethoxybenzaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 1.5 hours. After the mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 463 mg (yield: 62%) of 2-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene as a dark purple crystal (mp: 90° C.)
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1c(F)cccc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (1.0 g, 4.02 mmol) in N,N-dimethylacetamide (6 mL) was added 2,6-difluoroaniline (2.03 g, 15.8 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 5 hours and then diluted with ethyl acetate (40 mL). The organic solution was washed with 1 N HCl (2×15 mL and 3×30 mL) and saturated NaCl (30 mL). The organics were concentrated, ethanol (10 mL) was added, and the mixture was concentrated to give ethyl 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1)([CH3:3])=[CH2:2].[H][H]>CCO.C1COCC1.[Pd]>[CH:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)C)c3o2)cc1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
7-Isopropenyl-5-methoxy-2-(4-methoxy-phenyl)-benzofuran 116 (0.28, 0.9 mmol) was hydrogenated over an atmosphere of hydrogen with 10% Pd/C (0.05 g) in EtOH/THF (10 ml). After 2 hr, the reaction was filtered through celite and concentrated to give 117 as a solid (0.27 g, 95%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([CH3:25])[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:5]1=O.C1(C)C=CC=CC=1.S(=O)(=O)(O)O>CO>[CH3:3][C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:17][CH:18]=1)[C:9]([CH3:23])=[C:8]([CH3:24])[C:7]=2[CH3:25]
Reactant: Cc1c(C)c2c(c(-c3ccc(C(C)(C)C)cc3)c1C)CC(C)C2=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1=Cc2c(c(C)c(C)c(C)c2-c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
5 g (131 mmol) of sodium borohydride and 21 g (80 mmol) of 2,5,6,7-tetramethyl-4-(4′-tert-butylphenyl)-1-indanone (3d) together with 200 ml of toluene were placed in a reaction vessel. At 50° C., 25 ml of methanol were added slowly and the reaction mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, 35 ml of 2 N sulfuric acid were added and the mixture was stirred for 30 minutes. After phase separation, the organic phase was washed twice with a total of 60 ml of 2 N sulfuric acid, most of the solvent was removed and the residue was taken up in 200 ml of toluene and admixed with 0.2 g of p-toluenesulfonic acid. Water was distilled off from this reaction mixture by refluxing for 1.5 hours on a water separator until reaction was complete. The reaction mixture was washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was dried in an oil pump vacuum. Crude product was purified by recrystallization in heptane. This gave 9.0 g of (3e).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:23]=[CH:22][C:20](N)=[CH:19][CH:18]=1.C([N:26](CC)CC)C>>[OH:16][C:17]1[CH:23]=[CH:22][C:20]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(O)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2nc(N)nc(-c3ccc(O)cc3)c2cc1OC

Procedure:
A mixture of 448 mg (2 mmol) of 4-chloro-6,7-dimethoxyquinazoline (7) and 2.5 mmol of 4-hydroxyaniline in 20 ml of alcohol (EtOH or MeOH) was refluxed for 8 hours. After cooling triethylamine was added to basify the solution, and the solvent was concentrated to give material that was recrystallized from DMF to give compound (1); 84.29%; m.p. 245.0-248.0° C.; 1H NMR (DMSO-d6): δ 11.21(s, 1H, —NH), 9.70(s, 1H, —OH), 8.74(s, 1H, 2-H), 8.22(s, 1H, 5-H), 7.40(d, 2H, J=8.9 Hz, 2′,6′-H), 7.29(s, 1H, 8-H), 6.85(d, 2H, J=8.9 Hz, 3′,5′-H), 3.98(s, 3H, —OCH3), 3.97(s, 3H, —OCH3). UV(MeOH) λmax(e): 203.0, 222.0, 251.0, 320.0 nm. IR(KBr)umax: 3428, 2836, 1635, 1516, 1443, 1234 cm−1.GC/MS m/z 298 (M++1, 100.00), 297(M+, 26.56), 296(M+−1, 12.46).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=2)=[O:18])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C>O>[C:7]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:26]=2)=[O:18])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(Cl)n2)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(N3CCOCC3)n2)no1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Morpholine (0.01 mL, 0.115 mmol) is added to a solution of (2S,4R)-1-(2-chloro-pyrimidin-4-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (42 mg, 0.115 mmol) and diisopropylethylamine (0.02 mL, 0.115 mol). The reaction is stirred at 60° C. overnight. More morpholine (0.01 mL, 0.115 mmol) is added and the reaction is stirred at 80° C. for 3.5 hours. The reaction is diluted with water and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound. ESI m/z 417 [M+H+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2([C:35](O)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:10]([NH:12][C:35]([C:29]2([O:28][C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:36])[CH3:11])=[CH:5][CH:4]=1
Reactant: O=C(O)C1(Oc2ccc(Cl)cc2)CCCCC1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)C1(Oc2ccc(Cl)cc2)CCCCC1)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (Diastereomer α, Reference Example 1) (60 mg, 0.19 mmol) and 1-(4-chlorophenyloxy)cyclohexanecarboxylic acid (60 mg, 0.24 mmol) in 1 mL of methylene chloride was added N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) and tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.10 g, 0.19 mmol). After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column eluted with 6:1 hexane/ether to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.22 (d, 2H), 7.19 (d, 2H), 7.03 (d, 2H), 6.99 (d, 2H), 6.91 (d, 2H), 6.71 (d, 2H), 4.24 (m, 1H), 2.99 (dd, 1H), 2.80 (ddd, 1H), 2.63 (dd, 1H), 2.3-1.2 (m, 10H), 0.82 (d, 3H). LC-MS: m/e 530 (M+H)+ (5.0 min).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[I-].[Na+].C(#N)C.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:33][CH2:32]1
Reactant: O=C1CCc2ccc(OCCCCBr)cc2N1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Yield: 80.8 %

Procedure:
A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of sodium iodide with 600 ml of acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of 1-(2,3-dichlorophenyl)piperazine and 33 ml of triethylamine and the whole mixture was further refluxed for 3 hours. After the solvent was removed by evaporation, the residue thus obtained was dissolved in chloroform, washed with water then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue thus obtained was recrystallized from ethanol twice, to yield 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3, 4-dihydrocarbostyril,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH2:19][C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.COC1C=CC(C(NCCC2CCCCC2)C2C=C([NH2:41])C=CC=2)=CC=1.C[O:52][C:53]1[C:54](=O)[C:55](=O)[C:56]=1[O:57]C>CO>[NH2:41][C:55]1[C:56](=[O:57])[C:53](=[O:52])[C:54]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:11]=1
Reactant: COc1ccc(C(NCCC2CCCCC2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NCCC2=CCCCC2)c2cccc(N)c2)cc1
Solvent: CO
Product: COc1ccc(C(NCCC2CCCCC2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1c), a solution of the mixture (2.15 g) of 3-{(4-methoxyphenyl)-[2-(cyclohexen-1-yl)ethylamino]methyl}phenylamine and 3-[(4-methoxyphenyl)-(2-cyclohexylethylamino)methyl]phenylamine [prepared as described in step (b) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (953 mg) were reacted, to afford a crude product, which was purified by reverse phase medium pressure chromatography using a 50:50 by volume mixture of acetonitrile and an aqueous acetic acid buffer solution (water/acetic acid/triethylamine=1000/2/2) as the eluant, to afford the title compound (815 mg) as a pale orange foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl.N>O>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: O=c1ccocc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.0 g), 4H-pyran-4-one (0.52 g), water (20 ml), and concentrated hydrochloric acid (0.41 ml) was heated under reflux for 31/2 hours. The resultant solid was dissolved in the minimum of hot water and the solution was neutralised with aqueous ammonia to give the crude product, 1.16 g, m.p. 249°-256° C. The product was recrystallised first from water to which a little 2N NaOH was added, and then from water alone to give the pure title compound, 0.82 g, m.p. 254°-256° C. (after melting and resolidifying at about 150° C.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:23]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:24]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:23]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cn1
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionate (1.03 g), 1N aqueous sodium hydroxide solution (8 ml), ethanol (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature. The reaction mixture was poured into water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain crystals of 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionic acid from the fraction eluted with acetone-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane to obtain colorless prisms (740 mg, yield: 74%). Melting point: 123–124° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:5]1.[I-].[K+].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:30]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:7]=[C:8]2[C:9]1=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)nn1CCBr
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2cc(-c3ccc(F)cc3)nn2CCN1Cc1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
To a solution of Intermediate 1C (80 g, 234 mmol) and potassium iodide (78 g, 469 mmol) in acetonitrile (800 mL) was added benzyl amine (28.2 mL, 258 mmol) and the reaction mixture was stirred at 90° C. for 12 h. Acetonitrile was removed under reduced pressure, crude was diluted with water and the aqueous layer was extracted with DCM (3×500 mL). The combined organic layer washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (120 g REDISEP® column, eluting with 1-2% methanol in chloroform). Collected fractions were concentrated together to afford Intermediate 1D (35 g, 46%). MS(ES): m/z=322 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.71-7.83 (m, 2H), 7.29-7.42 (m, 5H), 7.14 (s, 1H), 7.06-7.12 (m, 2H), 4.78 (s, 2H), 4.32-4.40 (m, 2H), 3.63-3.75 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[S:25]1[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[CH:26]1.C(#N)C>O>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][N:30]([C:27]2[CH:28]=[CH:29][S:25][CH:26]=2)[CH3:31])=[N:12]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: CNc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CCOc1cccc(-c2noc3ccsc23)c1)c1ccsc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, thiophen-3-yl-methylamine (prepared according to Synthetic Metals, 26 (1988)153–168) and acetonitrile essentially as described above in example 18, except that water (0.40 mL) is added to the reaction mixture before heating. Purity by LC/MS (APCI)=100%, [M+H]+=357.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][N:15]([C@@H:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N:42]([C:45]1[CH:55]=[CH:54][C:48]([C:49]([O:51]CC)=[O:50])=[CH:47][CH:46]=1)=[C:43]=[O:44].O>C1(C)C=CC=CC=1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:43]([NH:42][C:45]2[CH:55]=[CH:54][C:48]([C:49]([OH:51])=[O:50])=[CH:47][CH:46]=2)=[O:44])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
To a solution of 300 mg of tert-butyl {[4-(3-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 3.0 mL of toluene was added 0.136 mL of triethylamine and 149 mg of ethyl 4-isocyanatobenzoate at room temperature, followed by stirring at 100° C. for 2 days. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 8 mL of THF, 4 mL of methanol, and 4 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 24 hours. The reaction mixture was neutralized by addition of 4.1 mL of 1 M hydrochloric acid, then concentrated under reduced pressure, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 356 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(3-fluorophenyl)piperidin-1-yl]carbonyl}amino)benzoic acid as a colorless foamy substance. ESI+: 626