Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([OH:12])[CH3:11].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5](=[NH:6])[O:12][CH2:10][CH3:11]
Reactant: N#Cc1cccc(Cl)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 54 h
Yield: 84 %

Procedure:
A 500-mL round bottomed flask was charged with 3-chlorobenzonitrile (23.3 g, 169 mmol, 1 eq.), ethanol (8.48 g, 184 mmol, 1.09 eq.), and HCl (4 N in dioxane, 169 mL, 676 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 54 hr. The volatile material was removed under reduced pressure and the residue was treated with ether. The resulting solid was collected by filtration and washed with ether. The product was used in the next step without further purification (26.9 g, 84% yield). 1H NMR (DMSO-d6, 500 MHz) δ 12.0 (br s, 2H), 8.25-8.20 (m, 1H), 8.12-8.08 (m, 1H), 7.90-7.85 (m, 1H), 7.67 (t, J=8.0 Hz, 1H), 4.63 (q, J=7.0 Hz, 2H), 1.48 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Li].Cl[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32])(=[O:22])=[O:21]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32])(=[O:21])=[O:22]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17.5 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 2.34 g, 9.35 mmol, 0.95 eq) was suspended in THF (20 ml) and stirred at 0° C. for 10 minutes. 1,1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 19.5 ml, 20 mmol, 2.0 eq) was added dropwise maintaining the temperature below 30° C. and the reaction mixture stirred for a further 30 minutes. A solution of 4-(chlorosulfonyl)-3-fluorobenzoic acid (Preparation 9, 2.35 g, 9.85 mmol, 1 eq) in THF (15 ml) was added dropwise maintaining the reaction temperature below 30° C. and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with brine (10 ml), extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was slurried in t-butylmethyl ether and stirred at room temperature for 72 hours. The resulting solid was collected by filtration to yield the title compound as a beige solid (744 mg, 1.64 mmol, 17%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]#[N:19])=[CH:9][CH:8]=1>CS(C)=O.O>[OH:3][N:2]=[C:18]([NH2:19])[CH2:17][C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([Br:6])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: N#CCc1cccc2ccc(Br)cc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NC(Cc1cccc2ccc(Br)cc12)=NO
Temperature: 60 °C
Yield: 80.8 %

Procedure:
Hydroxylamine hydrochloride (1.14 g, 16.5 mmol) was dissolved in aqueous sodium hydroxide (1N, 16.5 mL, 16.5 mmol) and the solution diluted with DMSO (50 mL). 7-Bromo-2-naphthalenylacetonitrile (1.35 g, 5.5 mmol) was added in one portion and the resulting mixture heated to 60° C. After a total of 18 hours, the mixture was cooled to room temperature and diluted with water (100 mL) to give a precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuo to give a tan solid (1.24 g, 81%) which was of sufficient purity for use in the subsequent reaction.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[CH:7]=1.[CH3:22]O>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:22])=[O:19])=[CH:16][CH:17]=2)=[C:8]([CH3:21])[CH:7]=1
Reactant: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Yield: 89 %

Procedure:
Thionyl chloride (10 ml) was added dropwise and cautiously to methanol (200 ml) with stirring. 4'-Amino-2'-methylbiphenyl-4-carboxylic acid (D1) (8.44 g, 37 mmol) was added, and the mixture was then stirred at reflux for 3 h. Solvent was then removed in vacuo to yield the title compound (9.16 g, 89%) as the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]#[N:10])([CH3:13])[CH2:11][O:12][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C#N)(CO)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(C)(C#N)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2-(4-bromo-phenyl)-3-hydroxy-2-methyl-propionitrile (25 g, 104.17 mmol) in pyridine (225 mL) was added para-toluene sulphonyl chloride (29.79 g, 156.25 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with a 2N aqueous hydrochloric acid solution (2×50 mL), water (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (10% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid 2-(4-bromo-phenyl)-2-cyano-2-methyl-ethyl ester as a colorless liquid (35 g, 73%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][C:3]=1[F:19].[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C@:25]([OH:29])([C:27]#[CH:28])[CH3:26]>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([C:28]#[C:27][C@:25]([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)([OH:29])[CH3:26])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#C[C@@](C)(O)c1nccs1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)c(F)cc12
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#C[C@@](C)(O)c3nccs3)c(F)cc12

Procedure:
The title compound was prepared by the procedure described in Example 2-b by reacting 4-(6-bromo-5-fluoro-3-methylindazol-1-yl)pyrimidin-2-amine with (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.96 (3H, s), 2.55 (3H, s), 7.02 (3H, s), 7.15 (1H, br. s), 7.71 (1H, d, J=3.15 Hz), 7.79 (1H, s), 7.82 (1H, d, J=8.83 Hz), 8.26 (1H, d, J=5.52 Hz), 8.92 (1H, d, J=6.46 Hz); LC-MS m/z=+395.35 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][CH2:20][C:21]1[O:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([CH2:20][Cl:19])[O:22][CH:23]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1coc(CCl)n1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3coc(CCl)n3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-chloromethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a colorless viscous oil. MS (ISP): m/z=403.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:14][CH2:11][C:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:13])=[O:12]
Reactant: COc1cc(C)c(C(C)=O)c(C)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 111.1 %

Procedure:
To a solution of 1-(4-methoxy-2,6-dimethylphenyl)ethanone (5.7 g, 32 mmol) in acetonitrile (64 mL) was added tetrabutylammoniumtribromide (TBABr3, 15.4 g, 32.0 mmol). The reaction was stirred at room temperature for 80 min. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-methoxy-2,6-dimethylphenyl)ethanone (9.14 g), which was used directly for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].P(Cl)(Cl)(Cl)=[O:14].[Li]>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Li]
Product: O=C(O)c1cc(F)c(Cl)nc1Cl

Procedure:
An improved process for the preparation of 2,6-dichloro-5-fluoronicotinoyl chloride is described where a 2,6-dihydroxy-5-fluoronicotinic acid ester is converted in one step using phosphorus oxychloride and a lithium reagent to 2,6-dichloro-5-fluoronicotinoyl chloride and subsequent basic hydrolysis affords 2,6-dichloro-5-fluoronicotinic acid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([NH2:19])[CH:18]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([NH:19][C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:18]=1
Reactant: Clc1nccc2ncccc12
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Product: Clc1ccc(Oc2ccccc2)c(Nc2nccc3ncccc23)c1

Procedure:
The product from Example 228e (0.040 g, 0.24 mmol) was reacted with the product from Example 42b (0.048 g, 0.24 mmol) for 48 h at 100° C. following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.046 g, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.96 (d, J=7.35 Hz, 2H) 7.00-7.10 (m, 2H) 7.22-7.39 (m, 4H) 7.66 (dd, J=8.46, 4.41 Hz, 1H) 7.91 (d, J=1.84 Hz, 1H) 8.07 (d, J=6.25 Hz, 1H) 8.76 (d, J=8.46 Hz, 1H) 9.07 (d, J=3.31 Hz, 1H); MS (ESI+) m/z 348.0 (M+H)+; (ESI−) m/z 346.1 (M−H)−.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2=[C:15]3[C:24](=[CH:25][CH:26]=[C:13]2[C:12]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:11][CH:10]=1)[CH:23]=[C:22]1[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]1)=[CH:16]3.C(O)C>CN(C=O)C>[Br:1][C:23]1[C:24]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[C:14]1[CH:9]=[CH:10][CH:11]=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([CH:31]=[O:32])=[CH:33][CH:34]=3)[C:13]1=[CH:26][CH:25]=2
Reactant: O=Cc1ccc(-c2cccc3c2ccc2cc4ccccc4cc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCO
Product: O=Cc1ccc(-c2cccc3c2ccc2c(Br)c4ccccc4cc23)cc1
Reaction time: 3 h

Procedure:
29.4 g (165 mmol) of N-bromosuccinimide are added at 100° C. to a suspension of 49 g (150 mmol) of 4-benz[a]anthracen-4-ylbenzaldehyde in 800 ml of DMF. After 3 h, 500 ml of ethanol are added at room temperature, and the solid is filtered off with suction, washed with ethanol and dried. Yield: 49.3 g (119 mmol), 79%.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[OH:7][CH2:8][CH2:9][NH:10]N>C(O)CCCC>[NH2:5][C:4]1[N:10]([CH2:9][CH2:8][OH:7])[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: C/C(N)=C/C#N
Reactant: NNCCO
Solvent: CCCCCO
Product: Cc1cc(N)n(CCO)n1
Yield: 63.8 %

Procedure:
To a solution of 16.4 g (0.2 mol) of 3-aminocrotononitrile in 100 cm3 of n-pentanol were added 16.7 g (0.22 mol) of β-hydroxyethylhydrazine and the mixture was then heated at reflux for 12 hours. The n-pentanol was subsequently distilled off under reduced pressure. A thick oil was obtained, which crystallizes by addition of 150 cm3 of isopropyl ether. A beige solid was obtained, which was filtered off on a sinter funnel. After drying under vacuum at 40° C., 18 g of the expected product were obtained in the form of a beige solid, the melting point of which was from 66 to 68° C.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24](OC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH2:37]([NH2:45])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24]([NH:45][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)NCCc3ccccc3)c2)cc1)OCC
Yield: 49.4 %

Procedure:
A solution of 1.75 g (3 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate, 0.46 mL (3.7 mmol) of phenethylamine, in 20 mL of dimethylformamide is heated at 80° C. for 2 hours. After addition of water, the reaction medium is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 0.7 g (50%) of ethyl (Z)-2-ethoxy-3-[3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]acrylate is obtained.
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:32]2[CH:37]=[CH:36][C:35]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH3:30])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[C:44]([C@@H:41]1[CH2:42][CH2:43][C@H:38]([C:35]2[CH:34]=[CH:33][C:32]([C@H:14]([C:15](=[O:31])[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[CH3:30])=[CH:21][CH:22]=3)[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:48])=[O:5])=[CH:8][CH:9]=3)=[CH:37][CH:36]=2)[CH2:39][CH2:40]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1cc(Cl)ccc1-c1ccc(NC(=O)[C@H](Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)[C@H](Cc2ccc(C(=O)O)cc2)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 431 mg of 4-[(R)-2-[4-(4-(cis)-tert-Butyl-cyclohexyl)-phenyl]-2-(4′-chlor-2′-methyl-biphenyl-4-ylcarbamoyl)-ethyl]-benzoic acid tert-butyl ester in dichloromethane (10 mL) was treated with trifluoroacetic acid (2 mL) and concentrated aqueous hydrochloric acid (1 mL). The resulting mixture was stirred for 16 h at room temperature. The organic phase was separated, washed with water and dried over magnesium sulfate. Concentration left a residue that was used without further purification.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-])=O)=[O:23])[CH:16]=2)[C:11]2[N:34]=[CH:35][CH:36]=[CH:37][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.O1CCOCC1>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:22](=[O:23])[NH:21][C:17]1[CH:16]=[C:15]([N:12]2[C:13](=[O:14])[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][C:10]3[CH:37]=[CH:36][CH:35]=[N:34][C:11]2=3)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
A mixture of 2-benzyl-4-[3-[3-(2-nitrophenyl)ureido]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (120 mg) and 10% palladium on carbon (40 mg) in methanol (2 ml) and 1,4-dioxane (2 ml) was stirred under hydrogen (3 atm) at room temperature for 4 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was crystallized from methanol to give 4-[3-[3-(2-aminophenyl)ureido]phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (97 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH:6]=[CH:5]2
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-hydroxy-naphthalene-2-carboxylic acid (2.0 g, 10.6 mmol, Aldrich) and benzylamine (1.7 g, 15.9 mmol, Aldrich) in DMF (40 mL, Aldrich) at 0° C. was added EDC (3.05 g, 15.9 mmol, Aldrich). The reaction was warmed to RT and stirred for 16 h. The volatile portion was removed in vacuo. The residue was diluted with 100 mL of EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in EtOAc and passed through a short silica gel column and the filtrate was concentrated in vacuo. Recrystallization with 50% EtOAc/hexane provided the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[CH3:7].[N-:9]=[N+:10]=[N-:11].[Na+]>O.C(O)(C)(C)C>[N:9]([CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[CH3:7])=[N+:10]=[N-:11]
Reactant: CC(=O)OCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)OCCCN=[N+]=[N-]
Yield: 59.7 %

Procedure:
Acetic acid 3-bromo-propyl ester (6.7 g, 37 mmol) was suspended in water (50 mL) and tert-butanol (20 mL). To the resulting mixture was then added sodium azide (2.76 g, 42.6 mmol) and the reaction mixture was heated to reflux for 18 hours, then concentrated to half of its volume. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with water, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the acetic acid 3-azido-propyl ester (3.16 g) as an oil which used in the next step without further purification.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18]C(=O)C1C=CC=CC=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][C:31]1[CH:33]=[CH:34][C:28]([F:27])=[CH:29][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Reactant: Cc1cc(F)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(CO)cccc2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
A solution of 3-butyryl-4-chloro-8-(benzoyloxymethyl)quinoline (3.68 g, 10 mmol) and 4-fluoro-2-methylaniline (1.67 ml, 15 mmol) in dioxan (40 ml) was heated at reflux for 3 hours, cooled, filtered and the solid discarded. The solution was evaporated and the residue taken up in 1% methanolic sodium hydroxide (100 ml) and stirred 2 hours at room temperature. The solid was filtered off and recrystallised from methanol to give 3-butyryl-4-(2-methyl-4-fluorophenylamino)-8-(hydroxymethyl)quinoline (1.56 g, 44%), m.p. 168°-170°.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH:15]2[CH2:17][CH2:16]2)[CH:13]([C:18]([O:20]CC)=[O:19])[O:12][CH:11]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH:15]2[CH2:17][CH2:16]2)[CH:13]([C:18]([OH:20])=[O:19])[O:12][CH:11]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)C1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C2OC(C(=O)O)[C@H](C3CC3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.5 %

Procedure:
(1)Ethyl (45, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture) obtained in Example 6(1) is purified by column chromatography to give ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate. A 87 mg of lithium hydroxide is added under ice-cooling to a solution of 1.03 g of ethyl (4S,SR)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate in a mixture of 20 ml of methanol and 10 ml of water. The mixture is stirred at room temperature for 30 minutes. The reaction n-tixture is evaporated under reduced pressure to remove methanol. The pH of the solution of the residue in ethyl acetate is adjusted to pH 2 with 1N hydrochloric acid under ice-cooling. After the mixture is extracted with ethyl acetate, the extract is washed with brine, dried and evaporated to remove the solvent to give 1.20 g of (4S,SR)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylic acid quantitatively.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccccc1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)(=O)OCC)C.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH:40]=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>O1CCCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]/[CH:40]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
Potassium tert-butoxide (5.78 g, 50.0 mmol) was added to a solution of 4-(trifluoromethyl)benzylphosphonic acid diethyl ester (14.8 g, 50.0 mmol) in tetrahydrofuran solution (40 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, a tetrahydrofuran solution (10 ml) of 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (11.4 g, 50.0 mmol) was added thereto dropwise at 0° C., warmed to room temperature, and then stirred overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=86:14) to afford the title compound as a colorless oil (8.6 g, yield 47%).