Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][CH3:28])[C:21](=[O:29])[CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:10])C1C=CC=CC=1.C([Li])CCC.[CH2:35](OC(=O)CCC)[C@@H:36]1[O:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C1COCC1.CN1CCCN(C)C1=O>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:35][C@H:36]([CH2:37][OH:38])[O:8][C:9]2=[O:10])[CH:13]=[CH:14][C:15]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][CH3:28])[C:21](=[O:29])[CH2:20]1
Reactant: COCCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COCCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
5-Benzyloxycarbonylamino-2-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)fluorobenzene (3.2 g) was dissolved in dry THF (100 ml) under argon, cooled to -78° C., and treated with a solution of n-butyllithium (1.6 M in hexane, 5.5 ml), keeping the temperature below -60° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU, 10 ml) was added to the resulting mixture to facilitate stirring and (R)-glycidylbutyrate (0.93 ml) was added. The mixture was stirred at -78° C. for 30 minutes, before allowing the temperature to rise to ambient over 16 hours. Sodium bicarbonate solution (50 ml) was added, and the whole evaporated to dryness. Organic materials were dissolved from the residue using dichloromethane, and purified by chromatography on silica using as eluant a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (1.14 g).
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][C@@H:16]2[CH3:32])=[O:14])[CH:10]=[CH:11][CH:12]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>CN(C=O)C>[CH2:33]([NH:35][C:36](=[O:37])[N:25]([C@H:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([C:13](=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=2)[C@@H:16]([CH3:32])[CH2:17]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:34]
Reactant: CCN=C=O
Reactant: COc1cccc(C(=O)N2c3ccccc3[C@H](Nc3ccccc3)C[C@@H]2C)c1
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCNC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2cccc(OC)c2)c2ccccc21
Temperature: 90 °C

Procedure:
(±)-Cis-3-ethyl-1-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-1-phenyl-urea was synthesized using general procedure A, substituting ethyl isocyanate for acetyl chloride using the following procedure. To a solution of (±)-cis-(3-methoxy-phenyl)-(2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl)-methanone in DMF was added ethyl isocyanate and reaction mixture was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated. Crude mixture was purified by flash chromatography on silica gel using gradient elution hexane-ethyl acetate (5-20%).
Reaction SMILES: O.O[C:3]1[C:11]2[N:10]=[N:9]NC=2C=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([OH:54])=O)=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40].NN1CCCC1>C1COCC1>[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([NH:9][N:10]4[CH2:5][CH2:4][CH2:3][CH2:11]4)=[O:54])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NN1CCCC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reaction time: 8 h
Yield: 85 %

Procedure:
Hydroxybenzotriazole hydrate (64.7 mg; 0.41 mmol), N-ethyldiisopropylamine (181 μL, 1.04 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (81 mg, 0.41 mmol) were added to a mixture of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (150 mg, 0.41 mmol) and 1-aminopyrrolidine (51.8 mg, 0.41 mmol) in THF (15 mL) at room temperature. After stirring overnight the solvent was removed by distillation and the residue was purified by chromatography (silica, dichloromethane:methanol=98:2 to 95:5) afforded the title compound (150 mg, 84%) as a white solid. MS: m/e=429.1 [M−H]−.
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([NH:11][CH2:12][CH2:13][NH2:14])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:22]1[CH2:36][CH:23]1[CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>CO>[OH:22][CH:23]([CH2:36][NH:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1ccccc1OCC1CO1
Reactant: NCCNC(=O)Nc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1OCC(O)CNCCNC(=O)Nc1ccccc1
Yield: 7.5 %

Procedure:
4.8 g of N-phenyl-N'-(2-aminoethyl)urea HCl salt (0.024 mole) was placed in 100 ml of methanol, and 2.5 g of triethylamine (0.024 mole) was added. While this reaction mixture was being stirred, a solution of 5 g of methyl 2-(2,3-epoxypropoxy)benzoate (0.024 mole) in 25 ml methanol was added slowly. The solution was then heated to reflux for 4 hours. The methanol was removed under reduced pressure and the resulting gel-like solid was dissolved in 100 ml of methylene chloride. The organic layer was washed twice with 100 ml of water and dried over anhydrous magnesium sulfate. Removal of the methylene chloride left an oil which was dissolved in 50 ml of methanol/ethyl ether (1:1) from which the product crystallized slowly upon refrigeration to afford 0.7 g (7.5%) of product having a melting point of 133°-134° C. The compound was identified by its NMR spectrum and elemental analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH:11]([N:14](CC)[CH:15](C)C)(C)C.C(N(CC)CC)C.Cl.CNC>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:14]([CH3:15])[CH3:11])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)cc(N(C)C)n1
Yield: 73.5 %

Procedure:
A mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5.0 g, 26 mmol), N,N-diisopropylethylamine (3.1 g, 26 mmol), triethylamine (7.15 mL, 51 mmol), and N,N-dimethylamine hydrochloride (2.09 g, 26 mmol) in tetrahydrofuran (50 mL) was heated at reflux for 16 hours. The solvent was removed and the crude material was redissolved in EtOAc and washed with a solution of citric acid (2×100 mL), followed by water (2×100 mL) and brine (2×100 mL). The organic layers were combined, dried over anhydrous MgSO4, concentrated and purified by flash chromatography [eluent: EtOAc/hexane (1:19)], giving the desired product (3.89 g, 73%).
Reaction SMILES: ClC1C=C(Cl)C2C(=CC=CC=2)N=1.[CH2:13]([NH:17][C:18](=[O:43])[CH:19]=[C:20](C)[CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:40]=[C:39]([Cl:41])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)[CH:14]([CH3:16])[CH3:15].CCOC(/C=C/CP(OCC)(OCC)=O)=O>>[CH2:13]([NH:17][C:18](=[O:43])/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:40]=[C:39]([Cl:41])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C=CCCCCCCCOc1cc(Cl)c2ccccc2n1)=CC(=O)NCC(C)C
Agent: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: Clc1cc(Cl)c2ccccc2n1
Product: CC(C)CNC(=O)/C=C/C=C/CCCCCCCOc1cc(Cl)c2ccccc2n1

Procedure:
Starting from 2,4-dichloroquinoline (see Compound 14) and triethyl 4-phosphonocrotonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)N3CCCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and pyrrolidine to give 2-Pyrrolidinylcarbonyl-7-methoxybenzofuran (Compound 309a). Successively, it was formylated to give 2-pyrrolidinylcarbonyl-4-formyl-7-methoxybenzofuran (Compound 309b), then compound 309b was reacted with methylamine hydrochloride to give compound 309 as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])[C:9](=[O:22])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[F:21])[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[F:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[N:10]1[CH:11]([CH3:12])[C:5]2[C:6](=[N:7][C:2]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:3][CH:4]=2)[N:8]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])[C:9]1=[O:22]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)c(F)c1
Reactant: Nc1ccccc1
Solvent: CO
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Temperature: 110 °C

Procedure:
(±)-3-[7-Chloro-3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (1.03 g; 2.42 mmol) (from Example 9a supra) was combined with aniline (1.00 mL; 10.97 mmol) (Aldrich) and heated at 110° C. for 1 hour. At this point, the reaction mixture was a solid mass. Methanol (75 mL) was added and the mixture was heated at 110° C. for 20 minutes with vigorous stirring (solid remained insoluble). Upon cooling, the solid was collected, washed with methanol and then ether and dried under high vacuum to give (±)-3-[3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile. (Yield 1.00 g; 85.6%). A portion of this material was recrystallized from dichloromethane-ether-petroleum ether for characterization and testing. (Yield 0.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCC1>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]2([NH:9][C:7](=[O:8])[C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(Br)ccc1O2
Temperature: 72 °C
Yield: 250.3 %

Procedure:
Three batches of 5-bromo salicylamide (5.00 g each, 23.1 mmol), N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) and pyrrolidine (1.64 g, 23.1 mmol) were heated in different flasks at 72° C. under MW irradiation for 1 h. Further N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) was added and the mixtures were heated for 1 h at 72° C. The resulting precipitates were collected by filtration and washed with MeOH to give 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester (17.2 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([F:11])=[C:4](C#N)[C:3]=1[F:14].FC1C(C=O)=C(F)C(F)=C(C=O)C=1F>>[F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]([F:11])=[C:6]([F:10])[C:7]=1[CH2:8][NH2:9]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Agent: O=Cc1c(F)c(F)c(C=O)c(F)c1F
Product: NCc1c(F)c(F)cc(F)c1F

Procedure:
From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, a peak of the tetrafluoroterephthalonitrile as a raw material was below the detection limit, and the amount of tetrafluoroterephthalaldehyde was 68.9 mol %. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 14.8 mol % of 2,3,5,6-tetrafluorobenzylamine was confirmed. The results are set forth in Table 1.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.Cl.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH:28]3[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:25])[CH:18]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]pyrimidine-4-carboxylic acid, 110 mg (0.48 mmol) ethyl 2,3-dihydro-1H-indole-2-carboxylate hydrochloride, 150.0 mg (0.47 mmol) TBTU and 150 μL (1.1 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was filtered through a syringe filter and the solution was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[F:29][C:30]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:31]=1[C:32]([NH:34][C:35]1[CH:39]=[CH:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47]CC3C=CC=CC=3)=[CH:43][C:42]=2[CH3:55])[N:36]=1)=[O:33]>[Pd].C(OCC)(=O)C>[F:29][C:30]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:31]=1[C:32]([NH:34][C:35]1[CH:39]=[CH:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:42]=2[CH3:55])[N:36]=1)=[O:33]
Reactant: Cc1cc(OCc2ccccc2)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(O)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 1.5 h

Procedure:
To 10% palladium on carbon 50% wt water, degussa type E101 NE/W (406 mg, 3.82 mmol) was added under vacuum a solution of 2,6-difluoro-N-[1-({2-methyl-4-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]benzamide (for a preparation see Example 47)(1.79 g, 4.13 mmol) in ethyl acetate (30 ml). The suspension was hydrogenated at ambient temperature for 1.5 h. The suspension was filtered through a celite cartridge (10 g) and the cartridge washed with methanol (100 ml). The solvent was removed in vacuo to give the title compound as a grey foam (1.34 g);
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:24][CH2:25][O:26][CH3:27]>CS(C)=O>[CH3:27][O:26][CH2:25][CH2:24][N:16]1[CH:17]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=[C:15]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COCCBr
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-c2ccccc2)cn1CCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Potassium tert-butoxide (780 mg, 6.96 mmol) was added in three portions over a period of 10 min to a stirred solution of ethyl 4-phenyl-1H-pyrrole-2-carboxylate (1.0 g, 4.63 mmol) in dimethylsulfoxide (10 mL) at 10° C. and maintained at this temperature for 30 min. A solution of 1-bromo-2-methoxy-ethane (770 mg, 5.50 mmol) in dimethylsulfoxide (2 mL) was added dropwise to the reaction mixture at 10° C. and then stirred for 2 h at room temperature. The reaction mixture was poured into ice water (25 mL) and the aqueous layer extracted with diethyl ether (3×20 mL). The combined organic layer was washed with water, brine (2×20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford ethyl 1-(2-methoxyethyl)-4-phenyl-pyrrole-2-carboxylate (1.15 g, 91%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1N2CCN(CC2)C1.[O:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[N:14][C:13]([O:16][C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:32])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1c(Cl)cc(-c2ccc(OC(=O)N3CCOCC3)nn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
1.27 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 1.12 L g of triethylenediamine were suspended in 25 ml of acetonitrile, and then 1.5 g of morpholinocarbonyl chloride were added dropwise thereto. When the addition was complete, the mixture was stirred at room temperature for 30 minutes and then the white precipitate thus produced was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure and then extracted with chloroform. The solvent was distilled under reduced pressure from the extract, giving a crude product which, after recrystallization from a mixture of benzene and hexene, gave 1.72 g (94%) of the desired Compound No. 10, melting at 155°-159° C.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@@H:5]1[N:16]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][CH2:18][C:17]1=[O:24])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][C@@H:5]1[N:16]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][CH2:18][C:17]1=[O:24]
Reactant: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a solution of the product of Step 7 (8.50 g, 25.3 mmol) in tetrahydrofuran (85 mL) was added triphenylphosphine (6.65 g, 25.3 mmol) and H2O (0.91 g, 50.7 mmol). The solution was stirred at reflux for 3 hours and then cooled to room temperature and concentrated. The residue was dissolved in 4.0 N aqueous HCl (200 mL) and extracted with chloroform (200 mL). The aqueous layer was basified to pH 10 with concentrated aqueous ammonium hydroxide solution and the resulting mixture was extracted with chloroform (2×300 mL). The combined organic extracts were dried over sodium sulfate and concentrated to afford 7.84 g (99%) of the product as a solid. MS m/z 310.3 (AP+100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11]CC)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].ClC1C=C(C(O)=O)NC=1C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cc(Cl)c(CC)[nH]1
Agent: Cc1[nH]c(C(=O)O)cc1Cl
Product: CCc1[nH]c(C(=O)O)cc1Cl

Procedure:
Title compound was synthesized from ethyl 4-chloro-5-ethyl-1H-pyrrole-2-carboxylate (Intermediate 72) by an analogous method to Intermediate 8.
Reaction SMILES: C(O)C.[CH3:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[OH:13])=O.C(O)(=O)C>[Ni].O>[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[OH:13])[CH3:4]
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCc1ccc(O)cc1O

Procedure:
In a three necked round bottom flask (equipped with a condensor, additional funnel and mechanical stirrer) was added 15.2 g of a combination of Raney Nickel and Ni supported on silica. (50:50). 100 ml of a mixture of 50:50 ethanol:water was added and the reaction was heated at reflux conditions. 15.2 g of 2,4-dihydroxy acetophenone in 100 ml of water:ethanol and 10 ml of acetic acid was placed in the additional funnel and slowly added to the mixture (dropwise). The reaction was filtered through a milipore filter to give a pale yellow solution. Concentration of this solution in vacuo gave a solid. This solid was crystalized from 1,2-dichloroethane to give 4-ethyl resorcinol in 80% isolated yield. The unreacted 2,4-dihydroxy acetophenone was recovered (−17%) form the reaction mixture and was recycled. The structure of 4-ethyl resorcinol and 2,4-dihydroxy acetophenone were characterized by NMR, Gas Chromatography, IR and Mass spectroscopy
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([C:6]1([OH:9])[CH2:7][CH2:8][C:3]([N:2]([CH3:1])[CH3:18])([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:4][CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CN(C)C1(Cc2cccc(F)c2)CCC(=O)CC1
Solvent: C1CCOC1
Product: CN(C)C1(Cc2cccc(F)c2)CCC(O)(Cc2ccccc2)CC1

Procedure:
4.67 g 4-dimethylamino-4-(3-fluorobenzyl)cyclohexanone were reacted with 1.0 molar benzylmagnesium chloride solution in THF analogously to the preparation of 4-dimethylamino-4-(4-fluorobenzyl)-1-phenethylcyclohexanol. After chromatography over silica gel, the nonpolar diastereoisomer of 1-benzyl-4-dimethylamino-4-(3-fluorobenzyl)cyclohexanol obtained was converted into 261 mg of the corresponding hydrochloride as described for example 4.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:19])[N:7]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:8](=[O:14])[NH:9]2)([O-:3])=[O:2].[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:19])[N:7]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:8](=[O:14])[N:9]2[CH3:20])([O-:3])=[O:2]
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2c(=O)n1CC1CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CC2CC2)c(=O)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Step 2 intermediate (5 g, 19.15 mmol) in dry DMF (56 ml) was added anhydrous K2CO3 (3.17 g, 22.98 mmol) and the mixture was stirred at room temperature for 30 min. Methyl iodide (1.43 ml, 22.98 mmol) was added drop-wise and the mixture was further stirred at room temperature for 24 h. The reaction mixture was diluted with water (100 ml) and the solid precipitated out was filtered and washed with water and dried to give 5.5 g of the product as off white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz): 7.90 (t, J=7.8, 1H); 7.66 (d, J=8.7, 1H); 7.55 (d, J=7.8, 1H); 3.76 (d, J=7.2, 2H); 3.55 (s, 3H); 1.20-1.10 (m, 1H); 0.47-0.40 (m, 2H); 0.35-0.28 (m, 2H).