Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[SH:39]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:39][C:33]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=2[Cl:31])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccc(Cl)cc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2,4-dichlorothiophenol yielded ((2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2,4-dichloro-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless oil. MS: 454.3 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH2:10][C:11]1[S:12][C:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:15]=1>N1C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[CH2:3][S:4]([NH:10][C:11]1[S:12][C:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:15]=1)(=[O:6])=[O:5]
Reactant: COc1ccc(-c2nc(N)sc2-c2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(NS(=O)(=O)CC(F)(F)F)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
0.92 g of 2,2,2-trifluoroethanesulfonyl chloride was dropped into a solution of 1:56 g of 2-amino-4,5-bis(4-methoxyphenyl)thiazole in pyridine under stirring at room temperature in a nitrogen atmosphere, and the resulting mixture was stirred as such for 1 hour. Then the reaction mixture was poured into ice-water and the crystals thus precipitated were recovered by filtration and recrystallized from diethyl ether/ethyl acetate to give 0.80 g of 2-(2,2,2-trifluoroethanesulfonyl)amino-4,5-bis(4-methoxyphenyl)thiazole. The melting point of this product was from 259° to 261° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][NH2:23])[CH:17]=1.C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:23][N:22]([C:18]2[CH:17]=[C:16]([C:15]([F:14])([F:25])[F:24])[CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:8])[CH3:2]
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2cccc(C(F)(F)F)c2)c1C
Yield: 85.4 %

Procedure:
14.9 grams 3,3-diacetyl-propionic acid-ethyl ester, 14.1 grams (α,α,α-trifluoro-m-tolyl)-hydrazine, 4.8 grams glacial acetic acid and 100 milliliters ethanol were mixed, and the mixture heated to boiling temperature under reflux for 1 hour. The reaction mixture was evaporated and the residue distilled to produce 22.3 grams of crude 3,5-dimethyl-1-(α,α,α-trifluoro-m-tolyl)-pyrazol-4-acetic acid ethyl ester. This ester was saponified as and worked up in accordance with the method described in Example (1b), using 4.0 grams sodium hydroxide as the base. The free acid was precipitated from the alkaline solution obtained in this manner by the addition of 2% acetic acid and of sufficient aqueous hydrochloric acid to complete the precipitation.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1>C(#N)C.CCOC(C)=O.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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4)cc2OCC3)n(C(C)C)n1
Temperature: 150 °C
Yield: 54.9 %

Procedure:
A microwave vial was charged with a suspension of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (0.239 mg, 0.617 mmol) in 3.0 ml ACN/1.0 mL water. To this suspension was added potassium acetate (182 mg, 1.85 mmol) and 1-methylpyrazole boronic acid pinacol ester (154 mg, 740 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and tetrakis(triphenylphosphine)palladium(0) (57 mg, 56 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water×1, saline×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 132 mg of 423 (55% theoretical yield). 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.90 (d, J=23.3 Hz, 2H), 7.36 (dd, J=8.4, 1.6 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 5.83 (dt, J=13.3, 6.6 Hz, 1H), 4.51 (s, 4H), 3.87 (s, 3H), 2.25 (s, 3H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cnc(N)c(N)c1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A mixture of 38 (790 mg, 5.17 mmol), methanol (60 mL), and 5% Pd-C (70 mg) was shaken under H2 (20-30 psi) for 3 h, then filtered and evaporated to give 629 mg (99%) of the diamine 39 as a black thick oil. 1H NMR (CDCl3) δ2.160 (s, 3H), 3.308 (bs, 2H), 4.160 (bs, 2H), 6.740 (s, 1H), 7.459 (s, 1H). It was used for the next reaction without further purification.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@:21]12[CH2:29][C@@H:28](O)[CH2:27][C@H:26]1[CH2:25][S:24][C:23]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:22]2.O>ClCCl>[C:34]([O:33][C:32](=[O:38])[NH:31][C:23]1[S:24][CH2:25][C@@H:26]2[CH2:27][C@@H:28]([F:11])[CH2:29][C@:21]2([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[N:22]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@@H](O)C[C@H]2CS1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@H](F)C[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
[Bis(2-methoxyethyl)amino]sulfur trifluoride (0.0564 mL) was added to a solution of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-fluorophenyl)-6-hydroxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate (51 mg) in dichloromethane (2 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The title compound (51 mg) was obtained by removal of the drying agent and concentration under reduced pressure.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[C:15]([OH:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.N1C=CC=CC=1>C(OCC)(=O)C>[OH:5][C:6]1[C:15]([O:16][C:1](=[O:3])[CH3:2])=[CH:14][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Oc1cc2ccccc2cc1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc2ccccc2cc1O
Temperature: 25 °C

Procedure:
Acetylchloride (0.71 ml) was added to a solution of 2,3-dihydroxynaphthalene (1.6 g) and pyridine (0.81 ml) in ethyl acetate (20 ml) at 0° C. The mixture was stirred for few hours at room temperature and then washed with water, dried and evaporated to dryness. The crude product was recrystallized from ether. Yield: 0.52 g.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][C:21](N)=[O:22])=[O:19].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:21]([NH:20][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[O:19])=[O:22])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: NC(=O)NC(=O)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccccn1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 14b, from 3-aminoquinuclidine dihydrochloride(1.0 g, 5 mmol), 2-pyridoylurea (0.82 g, 5 mmol) and di-isopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml) by refluxing for 4 days. The pyridine was evaporated and the residue partitioned between ether and 10% aqueous w/v citric acid. The mixture was filtered, the aqueous phase washed with ether, then basified with potassium carbonate to precipitate the title compound (0.60 g) which was converted to the 1:1 fumarate, mp 202°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[C:15](=[NH:18])OC)[CH3:12]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][NH:10][C:15](=[NH:18])[CH:14]([O:19][CH2:20][CH3:21])[O:13][CH2:11][CH3:12]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Yield: 80.7 %

Procedure:
(3,4-Dichlorophenyl)methanamine (2 g, 11.4 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (2.04 g, 12.6 mmol) in methanol (10 ml). The mixture was heated at 70° C. for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate). The desired fractions were concentrated to yield N-(3,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2.8 g, 9.2 mmol, 72.7% yield) as a colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (m, 1H), 7.40 (m, 1H), 7.19 (dd, J=8.09, 1.98 Hz, 1H), 4.94 (s, 1H), 4.43 (s, 2H), 3.47-3.77 (m, 4H), 1.41-1.79 (m, 6H). LC/MS RT=2.15; [M+H]+=305.1.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[N:24]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[OH:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28]2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
To a mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (A2) (2.36 g, 10.2 mmol) and diisopropylethylamine (3.6 ml, 20.4 mmol, 2 eq) in 50 ml CHCl3 at 0° C., ethyl 1-piperazinecarboxylate (1.5 ml, 10.2 mmol, 1 eq) was added. The mixture was stirred for 24 h at room temperature, and then 100 ml of CHCl3 was added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene-hexane (1:1) to yield the title compound HLA16 as white solid. (1.38 g, 42% yield, m.p.=92-93° C.). H1 NMR (250 MHz, CDCl3), 1.25 (dd, J=7.1, 7.1 Hz 3H), 2.42 (s, 4H), 3.43 (s, 4H), 3.81 (s, 2H), 4.14 (dd, j=14.21, 7.12 Hz, 2H), 7.08 (d, J=7.72 Hz, 1H), 7.31 (m, 1H), 7.47 (dd, J=8.52, 4.20 Hz, 1H), 8.66 (dd, J=8.56, 1.58 Hz, 1H), 8.79 (dd, J=4.18. 1.54 Hz, 1H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([OH:25])C=1F)[N:20]([NH:26][CH3:27])[CH:19]=[C:18]([C:28]([OH:30])=[O:29])[C:17]2=[O:31]>CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([OH:25])[C:1]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[N:20]([NH:26][CH3:27])[CH:19]=[C:18]([C:28]([OH:30])=[O:29])[C:17]2=[O:31]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(O)c21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(-n3ccnc3)c(O)c21
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Carbonyldiimidazole (32 mg) was added to a stirred solution of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in Reference example (i) in dry dimethylformamide (2 ml). Stirring was continued at room temperature for 2 hours and then at 80° C. for 5 hours. The solvent was removed under reduced pressure and the residue was suspended in water and the pH was adjusted to pH 5 with acetic acid. The precipitate which separated out was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7-(1-imidazolyl)-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid as pale yellow powder, FAB-MS m/z 319 (MH+); 1H-NMR (d6 -DMSO) δ: 2.82 (3H, s), 7.10 (1H, d, J=10.7 Hz), 7.61 (1H, d), 7.75 (1H, d), 8.62 (1H, s), 8.92 (1H, s), 15.33 (1H, br.s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([C:6]([SH:9])([CH3:8])[CH3:7])[NH2:5].[CH2:11]([C:18](=[CH2:29])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:5][C@@H:4]([C:3]([O:2][CH3:1])=[O:10])[C:6]([S:9][CH2:29][CH:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])([CH3:8])[CH3:7]
Reactant: COC(=O)[C@@H](N)C(C)(C)S
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Product: COC(=O)[C@H](N)C(C)(C)SCC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that described in Example 1, paragraph (d), by adding L-penicillamine methyl ester (J. Chem. Soc. Dalton Trans. 1984, 1333) to benzyl 2-benzylacrylate there was obtained benzyl (RS)-α-[[[(S)-2-amino-2-(methoxycarbonyl)1,1-dimethylethyl]thio]methyl]hydrocinnamate, MS: 416 (M+H)+, as an oil, the amino group of which was protected according to a general procedure known from the literature by reaction with di-tert-butyl dicarbonate. Subsequent oxidation with 3-chloroperbenzoic acid in methylene chloride gave benzyl (RS)-α-[[[(S)-2-(1-tert-butoxyformamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 448 (M-Boc+H)+. p1 (1) Catalytic hydrogenation of benzyl (RS)-α-[[[(S)-2-(1-tert-butoxy- formamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]-methyl]hydrocinnamate analogously to Example 1, paragraph (g), yielded (RS)-α-[[[(S)-2-(1-tert-butoxyformamido)-2-(methoxycarbonyl)-l,1dimethylethyl]sulfonyl]methyl]hydrocinnamic acid as a colourless solid, MS: 401 (M-C4H8)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21]C)=O)[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:24][CH3:23])=[O:21])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Reactant: CN
Solvent: O
Product: CNC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 120 °C

Procedure:
A mixture of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.45 g, 1.5 mmol) and 20 mL of methylamine (40% aqueous solution) was heated at 120° C. in a sealed tube for 16 hours. After cooling, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to afford 0.4 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a white solid, mp: 88–89° C. Anal. Calc'd for C16H13FN4O+0.4H2O: C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N, 18.35.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([NH:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH2:17]([N:24]([CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNCc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Product: CN(Cc1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
1-(4-Nitrophenyl)-4-piperidone was reacted in a similar manner to Example 2 with N-benzyl-N-methylamine and then with fumaric acid. 4-(N-benzyl-N-methylamino)-1-(4-nitrophenyl)piperidine fumarate was obtained. Melting point 183° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](=[O:28])[CH2:12][C:11]3=[O:29])=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:34](O)(C(F)(F)F)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([CH:21]5[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([O:28][CH3:34])=[CH:12][C:11]3=[O:29])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1CCC(c2ccc(C3C(=O)CC(=O)N3c3ccc4[nH]cnc4c3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COC1=CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(C2CCC(=O)CC2)cc1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-5-(4-(4-oxocyclohexyl)phenyl)pyrrolidine-2,4-dione (1.5 g, 3.87 mmol) and thionyl chloride (1.1 g, 9.1 mmol) according to method 6 described above. The compound was further treated with TFA (5 ml) at room temperature for 1 h. The volatiles were evaporated and the residue was partitioned between sodium bicarbonate solution and MeOH/CHCl3 (5/95). The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[ClH:13]>C(OCC)(=O)C>[Cl:13][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: Cl
Reactant: COC(=O)c1cccc(CO)n1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the product from step (i) (2.75 g) in ethyl acetate (10 ml) was added 1M ethereal HCl (10 ml). The mixture was stirred for 10 minutes and the precipitate filtered off. This was dissolved in thionyl chloride (20 ml) at 0° C. After 2 hours the mixture was warmed to room temperature. Diethyl ether (100 ml) was added and the precipitate filtered off and used directly in the next step. Yield 1.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CC[C@@H:23]([OH:26])[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:22][C@@H:23]([OH:26])[CH2:20]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: O[C@@H]1CCNC1
Product: COc1cc(N2CCC(N3CC[C@@H](O)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
(R)-1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol was prepared in an analogous fashion to [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine of Example 475a replacing Dimethylamine with (R)-Pyrrolidin-3-ol. The crude material was purified via trituration with Et2O to yield a yellow solid, MP 137-139° C. (248 mg, 64%). LC/MS (E/I+) 322.16 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([OH:23])=O)=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[CH:28]=[CH:29][CH:30]=1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([NH:24][C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH3:34])[CH:28]=[CH:29][CH:30]=3)=[O:23])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)O
Reactant: C[C@@H](C(=O)Nc1cccc(N)c1)N(C)C(=O)OC(C)(C)C
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1

Procedure:
By using 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C2) and (S)-tert-butyl (1-((3-aminophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (B9), (S)-tert-butyl (1-((3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C7) was obtained as white solid in the same manner as that of Example 7, (9).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].N([O-])=O.[Na+].[ClH:25]>CN(C)C=O.O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:25])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: Cl
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product (10 g) from paragraph (a) was dissolved in dimethyl formamide (150 ml), cooled to 5°-10° C. and concentrated hydrochloric acid (40 ml) added dropwise, the temperature being kept at 10°-15° C. The mixture was then kept at 5° C. while sodium nitrite (5.2 g) in water (20 ml) was added dropwise with stirring over a period of 30 minutes. The solution so prepared was added dropwise to a solution of cuprous chloride (19 g) in concentrated hydrochloric acid (150 ml) kept at 10° C., giving a thick green suspension. When addition was complete, the mixture was left to stand overnight and then heated to 60° C. for 30 minutes. The white solid was filtered off, dried, and recrystallised from petroleum (100°-120° C.) to give 3(2,4-dichlorophenoxy)benzoic acid (5.1 g) with a melting point of 143°-144° C. This compound was used as starting material for compound no 19 of Table 1.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH2:16][CH3:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:23][OH:24]>CO.O>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[N:23][OH:24])[CH2:16][CH3:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)CC)c2C1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C(CC)=NO)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a solution of 2-di-n-propylamino-8-propionyl-1,2,3,4-tetrahydronaphthalene (0.7 g, 2.4 mmol) (prepared as in Example 21) in methanol (40 ml) was added a solution of hydroxylamine hydrochloride (1.7 g, 24 mmol) in water (10 ml). The solution was stirred at room temperature overnight. The reaction was poured into water, the pH was adjusted to 12 and then extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give 760 mg of crude 2-di-n-propylamino-8-(1-oximinopropyl)-1,2,3,4-tetrahydronaphthalene sufficiently pure to be used in the next step.