Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[OH-].[Na+]>O>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: CN
Reactant: OCCCCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNCCCCCCCCCO
Temperature: 100 °C
Reaction time: 1 h

Procedure:
400 g a 40% aqueous solution of methylamine and 180 g of 9-chlorononanol were introduced into an autoclave equipped with a stirrer, a thermometer and a pressure pump and heated to 100° C. At the temperature, 93 g of a 48% aqueous solution of sodium hydroxide was forcedly introduced to the autoclave over 6 hours and the resulting mixture was aged for 1 hours. After cooling, the content was taken out from the autoclave and unreacted methylamine and water were removed therefrom under reduced pressure. Then, ethanol was added thereto and sodium chloride thus precipitated was filtered off. Ethanol was distilled off from the filtrate and the resulting solution was further subjected to distillation to give 125 g of 9-(N-methylamino)nonanol.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[C:4]([N:8]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH2:5][CH3:6]>C1(C)C=CC=CC=1.CO>[OH:3][CH2:2][CH2:1][N:18]1[CH2:17][CH2:16][CH:15]([N:8]([C:4](=[O:7])[CH2:5][CH3:6])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19]1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: C1CO1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1CCN(CCO)CC1
Temperature: 15 °C

Procedure:
A solution, cooled to 15° C., containing 100 mmol of ethylene oxide in toluene is added slowly to 100 mmol of 4-(N-propionylanilino)piperidine in solution in 100 ml of anhydrous methanol cooled to 15° C. After returning to room temperature and removal of the azeotrope formed by distillation, the expected product is obtained after evaporation to dryness.
Reaction SMILES: [CH3:1][As:2]([CH3:7])[CH2:3][CH2:4][CH2:5]Cl.[Mg].[Cl-].[CH3:10][Ga+:11][CH3:12]>C(OCC)C>[CH3:1][As:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Ga:11]([CH3:12])[CH3:10]
Reactant: C[As](C)CCCCl
Reactant: C[Ga+]C
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: C[Ga](C)CCC[As](C)C

Procedure:
5.47 g (30 mmol) of (3-dimethylarsinopropyl)chloride are added to 1.44 g (60 mmol) of magnesium chips in 100 ml of diethylether at 20° C., and then the mixture is heated under reflux for two hours. The solution is allowed to come to room temperature, 4.0 g (30 mmol) of dimethylgallium chloride in 50 ml of diethylether are added, and the solution is refluxed again for two hours. The working up is carried out analogously to Example 1. (3-Dimethylarsinopropyl)-dimethylgallium is obtained as a clear liquid with a B. p. of 86° C./0.01 mbar.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=1>CCCCCC.C(OCC)(=O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[CH:21]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-pyridineboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19]OC)=[CH:15][C:14]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)C.[CH3:32][CH2:33][CH2:34]CCC>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:34]=[CH:33][CH:32]=1)=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCCCOC(=O)c1ccc2[nH]c3cnc(C(=O)OCC)c(COC)c3c2c1
Reactant: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)OCc4ccccc4)cc3c2c1C

Procedure:
6-butoxycarbonyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 150°-152° C. (ethanol/hexane); and
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[O:11]=[S:12]1(=[O:35])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]#[N:31])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:32][CH2:33][CH2:34][CH:14]2[NH:13]1>CS(C)=O>[O:35]=[S:12]1(=[O:11])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](=[N:9][OH:10])[NH2:31])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:32][CH2:33][CH2:34][C:14]2=[N:13]1
Reactant: NO
Reactant: N#CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NC(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1)=NO
Reaction time: 0.17 h

Procedure:
2.51 ml (18.0 mmol) of triethylamine are added to a solution of 1.25 g (18.0 mmol) of hydroxylamine hydrochloride in 4 ml of DMSO and the suspension is stirred for 10 minutes. The precipitate is filtered off and the filtrate is concentrated. 992 mg (3.00 mmol) of the product of Step A of Example 27 are added to the filtrate and the solution is stirred at 75° C. for 1 hour 30 minutes. The solution is allowed to return to ambient temperature, and precipitation of the reaction mixture is brought about using water. The precipitate is filtered off to yield the title product.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].C([Li])CCC.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>O1CCCC1>[CH3:1][N:2]1[C:34]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:37][CH:36]=2)=[CH:10][C:9]2[O:8][N:7]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[C:3]1=[O:4]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Reactant: CN1CCN(Cc2ccc(C#N)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(-c3cc4onc(-c5ccccc5)c4c(=O)n3C)cc2)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
In a 500 ml flask, 10.0 g (46.3 mmol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid methylamide is suspended in 150 ml of tetrahydrofuran (THF) under argon. At −70° C. a solution of butyl lithium (63 ml, 1.6M in hexane, 101 mmol, 2.2 eq.) is slowly added. After 1 h at this temperature, the solution is warmed to −10° C. and a solution of 11.9 g (55.5 mmol, 1.2 eq.) of 4-(4-methyl-piperazin-1-ylmethyl)-benzonitrile in 80 ml of THF is slowly added. Under warming to room temperature, the red solution is stirred for another hour, then quenched with 2 ml of water and concentrated. The yellow residue is then taken up in 75 ml of dioxane and kept at 5° C. Then, 230 ml of a 4M solution of HCl in dioxane is carefully added and the suspension stirred for 20 h at room temperature. Then, the solvent is removed and the residue dissolved in ethyl acetate and carefully neutralised with sat. NaHCO3-solution. The phases are separated and the organic phases washed with brine, dried over Na2SO4 and concentrated. Chromatographic purification (CH2Cl2/MeOH 95:5 to 90:10) yields 7.9 g (41%) of 5-methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one as a white solid. Mass spectrum: m/z (M+H)+: 415.0
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH:25]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: CCOc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 66B (220 mg, 0.502 mmol) in 5 mL dichloromethane was added 2,2,2-trifluoroacetic acid (0.387 ml, 5.02 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was dried under high-vacuum for 2 hours. The residue was dissolved with 3 mL methanol, and the mixture was treated with excess 2 M hydrochloric acid/diethyl ether followed by stirring for 20 minutes. The mixture was then diluted with 50 mL diethyl ether, and the solid was collected by filtration. The collected solid was dried under high-vacuum to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H) 9.64 (s, 2H) 9.08 (s, 1H) 7.42-7.59 (m, 2H) 7.32 (dd, J=9.16, 4.27 Hz, 1H) 6.80 (d, J=35.71 Hz, 2H) 4.15 (q, J=6.92 Hz, 3H) 3.84 (s, 2H) 3.31 (s, 2H) 2.77 (s, 1H) 1.07-1.28 (m, 3H). MS (ESI+) m/z 339.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([N:13]=[C:14]=[O:15])=[O:12].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C=NC(=O)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C1CN(c2cccc(Br)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromoaniline (1.0 mL, 9.18 mmol) and chloroacetyl isocyanate (0.780 mL, 9.18 mmol) in dioxane (100 mL) was stirred at room temperature for 2 hr. Dioxane (50 mL) and DBU (3.40 mL, 23.0 mmol) were added and the solution stirred at room temperature for 16 hr. The solution was concentrated in vacuo and the residue taken up in EtOAc and H2O. The mixture was then acidified with 1N HCl, then the aqueous phase extracted with EtOAc. The combined organics were then washed with H2O and brine and dried over Na2SO4. The solution was concentrated in vacuo and the residue recrystallized from EtOAc/hexanes to give 1-(3-bromophenyl)-2,4-imidazolidinedione as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 2H), 7.24-7.30 (m, 2H), 7.50-7.52 (m, 1H), 7.87 (s, 1H), 11.27 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.[OH-:21].[K+].O>O.C(O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:21])=[CH:16][C:3]1=2
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Yield: 73.7 %

Procedure:
To 50 mg of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetamide was added 0.4 g of potassium hydroxide in 4 ml of water/ethanol (1:1), and the mixture was refluxed for 3 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and then a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was recrystallized from acetone to give 37 mg (yield: 72%) of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 181°-184° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[C:29]1([CH2:28][O:7][C:8]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
K2CO3 (203 mg, 1.47 mmol) was added to a stirred solution of methyl 2-hydroxy-5-(1-piperidinylsulfonyl)benzoate (may be prepared as described in Description 67; 400 mg, 1.34 mmol) in acetone (20 ml), followed by the addition of (bromomethyl)benzene (251 mg, 1.47 mmol). The mixture was heated at reflux for 16 h, and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to yield the title compound as a colourless oil. 300 mg.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH2:38]([O:40][C:41](=[O:48])[C@@H:42]1[CH2:46][C@@H:45]([OH:47])[CH2:44][NH:43]1)[CH3:39].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[CH2:38]([O:40][C:41](=[O:48])[C@@H:42]1[CH2:46][C@@H:45]([OH:47])[CH2:44][N:43]1[C:16]([C@@H:9]1[NH:8][C:7](=[O:19])[C@@H:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:18])[CH3:39]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@H]1CCCCCC[C@H](CSC(C)=O)C(=O)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The enantiomer of trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid of Example 16(0.23 g, 0.80 mmol), 1-hydroxybenzotriazole (0.11 g, 0.80 mmol), 4-methylmorpholine (0.22 mL, 2.0 mmol), and L-hydroxyproline ethyl ester hydrochloride (0.16 g, 0.80 mmol) are dissolved in methylene chloride (5.0 mL), and the reaction is cooled to 0° C. To this solution is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (0.31 g, 1.60 mmol), and the reaction is allowed to warm up to room temperature and stirred overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (80% ethyl acetate/hexane) to give N-[[trans 3-(acetylthiomethyl)-2-oxo-1-aza-cyclodecan-10-yl]-carbonyl]-trans 4-hydroxy-L-proline ethyl ester as a single enantiomer, [α]D +5.73° (c=4.1 mg/ml, CH2Cl2) which is assigned the 3R, 10S configuration.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[C:10]([CH3:18])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1cccc(C#N)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)ccc1-c1cccc(C#N)c1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
1-(3-Cyanophenyl)-2-methyl-4-nitrobenzene (3.0 gm, 12.61 mmol) and tin(II) chloride dihydrate were suspended in ethanol (30 mL) and heated to 70° C. for 30 mins. After being cooled, the mixture was poured onto ice, and neutralised by the addition of sodium bicarbonate. The mixture was then extracted with dichloromethane (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give 4-amino-1-(3-cyanophenyl)-2-methylbenzene (1.8 gm, 69%) as a yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.C(N(CC)CC)C>CC#N>[NH2:24][C:19]1[N:20]=[C:21]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:10]([C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:11]2)[CH:22]=[C:17]([Cl:16])[N:18]=1
Reactant: O=C(Nc1ccccc1)[C@H]1CCCNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)Nc3ccccc3)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To (3S)—N-phenyl-3-piperidinecarboxamide (327 mg, 1.6 mmol) in CH3CN (10 mL) was added 4,6-dichloro-2-pyrimidinamine (289 mg, 1.760 mmol) and triethylamine (0.446 mL, 3.20 mmol), and the solution was allowed to stir overnight at 50° C. The reaction was then quenched with water (2 mL), and extracted 3× with EtOAc. The organics were combined, dried (Na2SO4), filtered and concentrated to afford the crude title compound (350 mg) as a solid. LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl>Cl>[ClH:11].[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][NH2:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(C(=O)O)c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 5-amino-2-chlorobenzoic acid (10.3 g, 60 mmol) in concentrated HCl at 0° C. is treated with an aqueous solution of NaNO2 (4.8 g, 70 mmol) at a rate to maintain a reaction temperature of <10° C., stirred for 0.5 h at 0° to 10° C., treated with a solution of tin chloride dihydrate (33.9 g, 150 mmol) in aqueous HCl at a rate to maintain a reaction temperature of <10° C., aqueous HCl is added periodically, as needed to facilitate stirring, stirred at 5° C. for an additional 1 h and filtered. The filtercake is recrystallized from water to afford the title product as white crystals, 9.6 g (71% yield), identified by HNMR analysis.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:42]([N:49]([CH2:57][C:58]1[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][N:59]=1)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C>[C:42]([N:49]([CH2:57][C:58]1[CH:66]=[CH:65][C:61]([C:62]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[O:63])=[CH:60][N:59]=1)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cn1
Yield: 107.6 %

Procedure:
The compound obtained in Example 8-6 (165.3 mg) was dissolved in DMF (3 ml). After the addition of WSCI hydrochloride (78.5 mg), HOBt (40.1 mg), and the compound obtained in Example 12-3 (90.4 mg), the mixture was stirred for 23 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform and washed with 1 mol/l aqueous solution of hydrochloric acid, 1 mol/l aqueous solution of sodium hydroxide, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (10 g, chloroform/methanol=20/1) to obtain the title compound (167.6 mg) as white foam.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:8][N:9]2[C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[C:14]([F:22])[C:13]=2[F:23])=[CH:4][C:3]=1[F:30]>CO.C(O)(=O)C.[Pd]>[NH2:18][C:16]1[CH:17]=[C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:30])=[C:2]([Cl:1])[N:11]=3)[C:6](=[O:29])[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:8]2)[C:13]([F:23])=[C:14]([F:22])[C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(N)c(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-(2,3,4-trifluoro-5-nitrophenyl)-1,8-naphthyridine-3-carboxylate (780 mg) was dissolved in 5 ml of methanol and 10 ml of acetic acid, to which was added 80 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred overnight at room temperature. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 200 mg of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([SH:14])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br)([O-:17])=[O:16].O>O1CCCC1>[Cl:3][C:4]1[C:5]([S:14][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N+:15]([O-:17])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: FC(F)(F)c1cnc(S)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccccc1CSc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.3 %

Procedure:
2 g of 60 wt % sodium hydride were added to 45 ml of tetrahydrofuran under stirring at room temperature, followed by drop-wise addition thereto of a solution of 9.9 g of 3-chloro-2-mercapto-5-trifluoromethylpyridine in 40 ml of tetrahydrofuran. After completion of the drop-wise addition, the reaction mixture was heated under reflux for 30 minutes, and cooled to room temperature, followed by drop-wise addition thereto of a solution of 10 g of 2-nitrobenzyl bromide in 60 ml of tetrahydrofuran. After completion of the drop-wise addition, stirring was continued at room temperature for 15 hours. The reaction mixture was poured into water, subjected to extraction with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent:methylene chloride:hexane=4:1) to obtain 12 g of 2-(3-chloro-5-trifluoromethyl-2-pyridylthiomethyl)nitrobenzene.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)[C:7](O)=[O:8].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:5][C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)[C:7]([Cl:3])=[O:8]
Reactant: CC(=Cc1ccc(Oc2cccnc2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=Cc1ccc(Oc2cccnc2)cc1)C(=O)Cl

Procedure:
5 g of thionyl chloride was added dropwise to a mixture of 6 g of 2-methyl-3-[4-(3-pyridyloxy)phenyl]propenoic acid, 80 ml of pyridine and 50 ml of chloroform under ice-cooling with stirring, followed by stirring for one hour to obtain a solution of 2-methyl-3-[4-(3-pyridyloxy)phenyl]propenoic acid chloride. 8 g of cyclohexylamine was added to the solution, and the mixture was stirred for one hour and poured into water. The mixture was rendered basic with sodium carbonate, and the organic layer was separated by filtration, washed with water and dried over magnesium sulfate. The solvent was distilled off and the resulting oily substance was purified by silica gel chromatography (eluted with chloroform-diethyl ether, 1:2 by volume). The resulting crystals were converted into the hydrochloride in the same manner as described in Example 4 and recrystallized from a mixture of ethanol and diethyl ether to obtain 4.5 g (51% yield) of N-cyclohexyl-2-methyl-3-[4-(3-pyridyloxy)phenyl]propenamide hydrochloride having a melting point of 162°-166° C.