Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)N(C)C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL) was added dimethylcarbamic chloride (39 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-N,N-dimethylpiperidine-1-carboxamide as a white solid. ESMS m/z 487.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.[ClH:26].O1CCOCC1.C(OCC)C>C(O)(C)C.O1CCOCC1>[ClH:26].[CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(Oc2cccc(C#N)c2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1c(Oc2cccc(C#N)c2)ccc2[nH]ncc12
Yield: 69 %

Procedure:
Under nitrogen, 3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile (299 mg, 0.897 mmol) was dissolved in a mixture of isopropyl alcohol (6 ml) and 1,4-dioxane (6 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (6 ml), and the resulting mixture was stirred at room temperature for 23 hours. After diethyl ether (30 ml) was added thereto and stirred, the precipitate was collected by filtration, washed with diethyl ether and then dried under reduced pressure to obtain 3-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrile hydrochloride (176 mg, yield 69%).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=O)=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)CCl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:24])=[CH:25][CH:26]=3)=[N:14][CH:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCc1ccc(-c2cnc(-c3ccc(C#N)cc3)nc2)cc1

Procedure:
4.2 g. of 4-[5-(4-n-pentylphenyl)-2-pyrimidyl]-benzoic acid amide are reacted under reflux in a mixture of 200 ml. of ethylene chloride and 2.5 ml. of phosphorus oxychloride for 1 hour, with stirring. The reaction mixture is diluted with ether and washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, which has been dried over sodium sulfate, 5-(4-n-pentylphenyl)-2-(4-cyanophenyl)-pyrimidine is obtained and is filtered on a short silica gel column and subsequently recrystallized from methylene chloride/methanol, m.p. 125.5°; cl.p. 242.5°-243°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Br)=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2].[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:21]2[C:22]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=2)=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)c1nc(C)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)c(-c2cccc3ccccc23)s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-methyl-thiazole-2-carboxylic acid ethyl ester (60 mg, 0.24 mmol) in 1,4-dioxane (2 ml) is added 1-naphthaleneboronic acid (50 mg, 0.29 mmol), cesium carbonate (187 mg, 0.58 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol). The reaction mixture is stirred in a sealed tube at 110° C. overnight. After cooling to rt, the mixture is purified by PTLC to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([SH:9])[N:6]2[N:10]=[C:11]([C:13]([O:15]C)=O)[N:12]=[C:5]2[N:4]=1.[NH2:17][OH:18].Cl>CO>[SH:9][C:7]1[N:6]2[N:10]=[C:11]([C:13]([NH:17][OH:18])=[O:15])[N:12]=[C:5]2[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=1
Reactant: COC(=O)c1nc2nc(CO)cc(S)n2n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: O=C(NO)c1nc2nc(CO)cc(S)n2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
Methyl 5-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-2-carboxylate (100 mg) (0.416 mmol) are dissolved in about 5 ml of methanol. 275 mg (8.3 mmol) of hydroxylamine are added thereto at room temperature while stirring within 48 hours. The reaction mixture is made acid (pH 5.5) with 3N aqueous hydrochloric acid. The product is filtered off under suction and crystallized from methanol. There are obtained 60 mg of 7-mercapto-N-hydroxy-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidine-2-carboxamide as beige crystals of melting point 238°-239° C. (dec.).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH2:4][C:3]1=[O:14].[C:15]([O:18][C:19](=O)[CH3:20])(=O)[CH3:16]>CCOC(OCC)(OCC)C1C=CC=CC=1>[C:3]([O:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4](=[C:15]([O:18][CH2:19][CH3:20])[C:16]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[C:3]1=[O:14])(=[O:14])[CH3:4]
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2N1O
Reactant: CC(=O)OC(C)=O
Agent: CCOC(OCC)(OCC)c1ccccc1
Product: CCOC(=C1C(=O)N(OC(C)=O)c2cc([N+](=O)[O-])ccc21)c1ccccc1

Procedure:
300 mg of 1-hydroxy-6-nitro-2-indolinone are dissolved in 4.0 ml of acetic anhydride and 4.0 ml of triethyl orthobenzoate, stirred for 6 hours at 110° C., concentrated by evaporation and purified through a silica gel column with methylene chloride as eluant.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:22])=[C:7]([CH3:21])[CH:8]=2)[N:3]=1.[I-:23].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(=O)CC.C(OCC)(=O)C>[CH2:16]([O:15][P:13]([CH2:12][C:11]1[C:2]([I:23])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:21])=[C:6]([CH3:22])[CH:5]=2)([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: CCOP(=O)(Cc1cc2cc(C)c(C)cc2nc1Cl)OCC
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCOP(=O)(Cc1cc2cc(C)c(C)cc2nc1I)OCC
Yield: 55.2 %

Procedure:
2-Chloro-3-diethylphosphonomethyl-6,7-dimethylquinoline (0.40 g, 1.17 mmol), prepared as described in Example 4 was dissolved in 2-butanone (20 ml) and treated with sodium iodide (0.39 g, 2.6 mmol) and p-toluenesulfonic acid (0.11 g, 0.58 mmol). The mixture was refluxed for 10 hours. Ethyl acetate and saturated sodium hydrogen carbonate were added. The organic phase was separated and filtered through a pad of silica gel. Evaporation of solvents gave 0.28 g of 3-diethylphosphonomethyl-6,7-dimethyl-2-iodoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH3:43][C:44]1[N:45]=[C:46]([CH:50]([NH2:52])[CH3:51])[S:47][C:48]=1[CH3:49]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][CH:50]([C:46]2[S:47][C:48]([CH3:49])=[C:44]([CH3:43])[N:45]=2)[CH3:51])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(C(C)N)sc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nc(C)c(C)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4,5-dimethyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (18 mg, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=2)[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:33][C:34]([Cl:38])([Cl:37])[C:35]#[N:36]>C(OCC)C>[Cl:33][C:34]([Cl:38])([Cl:37])[C:35](=[NH:36])[O:13][CH:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:7]=2)[CH:3]=[C:2]([Cl:1])[CH:10]=1)[CH3:12]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (0.54 g, 1.65 mmol) was dissolved in diethyl ether (5 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (50 μL, 0.33 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (250 μL, 2.48 mmol) dropwise over 10 min. The reaction was allowed to warm to room temperature overnight and concentrated. Flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 600 mg (77%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.56 (d, J =1.5 Hz, 1H), 7.33 (m, 1H), 6.62 (q, J=6.2 Hz, 1H), 5.68 (s, 2H), 3.59-3.65 (m, 2H), 1.79 (m, 3H), 0.88-0.94 (m, 2H), 0.05 (s, 9H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]([O:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].C1COCC1.[NH2:22][OH:23].[C-]#N.[K+]>O.CO>[OH:23][NH:22][C:3](=[O:2])[CH2:4][CH2:5][CH:6]([O:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13]
Reactant: COC(=O)CCC(OC)c1ccccc1C
Reactant: NO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(CCC(=O)NO)c1ccccc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution prepared by dissolving 4-methoxy-4-o-tolyl-butyric acid methyl ester (230.0 mg, 1.03 mmol) into 3 mL of a mixture of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) was added KCN (6.0 mg, 0.03 mmol). The reaction mixture was stirred for 3 days at room temperature and then quenched by the addition of 10 mL of 1M aqueous HCl. The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layers washed with brine (2×10 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to afford 184 mg of the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:40])[CH:17]([C:24]3[N:25]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:26]=[C:27]4[C:32]=3[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([F:41])[CH:10]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([N:25]2[C:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[CH:10][C:11]=3[F:41])=[O:40])=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:26]2)=[CH:38][CH:37]=1
Reactant: COC(=O)C1(Oc2ccc(NC(=O)C(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(OC2(C(=O)O)CC2)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-1-(4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless foam. MS: m/e=566.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])C(=O)C(F)(F)F)[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:41][CH2:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CS(=O)(=O)CCN(CCCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)CCNCCCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 34.9 %

Procedure:
In 2.6 ml of a mixture (1:1) of tetrahydrofuran and methanol was dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(4 (N-(2-(methanesulfonyl)ethyl)-2,2,2-trifluoroacetamido)butyloxyimino)quinazoline (V-14, 40 mg), and 86 μl of 1 mol/L aqueous sodium hydroxide solution was added, followed by stirring at room temperature for 14 hours, and at 40° C. for 2 hour. After the reaction, the reaction mixture was extracted with ethyl acetate, the organic layer was dried, and filtrate was concentrated. The concentrated residue was purified by chromatography (eluting with 0 to 3% methanol-contenting ethyl acetated) using an amino column, and the resulting pale yellow oil was powdered with a mixture of hexane and ethyl acetate to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(4-(2-(methanesulfonyl)ethylamino)butyloxyimino)quinazoline (V-15, 12 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2Cl)cc1
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCCc1ccc(-c2ccc(F)cc2Cl)cc1
Yield: 84 %

Procedure:
Prepared analogous to Example 1 from 4-(2'-chloro-4'-fluoro-4-biphenylyl)-4-oxo-butyric acid. Yield: 84% of theory; m.p. 81°-82° C. (petroleum ether-cyclohexane). Melting point of the cyclohexylamine salt: 148°-149° C. (from ethyl acetate/methanol 9:1).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])([CH3:5])[CH2:3][OH:4].Cl.N.[C:16](O)(=O)[CH3:17]>>[CH3:16][C:17]1[N:6]([C:2]([CH3:1])([CH3:5])[CH2:3][OH:4])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(C)(CO)Nc1ccccc1N
Reactant: CC(=O)O
Agent: Cl
Agent: N
Product: Cc1nc2ccccc2n1C(C)(C)CO

Procedure:
A mixture of 2-(1,1-dimethyl-2-hydroxyethyl)aminoaniline (from Preparation 2(a)) (8.4 g), acetic acid [4.2 g], and 4N hydrochloric acid [50 ml] were refluxed for 30 hours. The reaction was cooled and neutralised with concentrated aqueous ammonia. The solution was extracted with a mixture of tetrahydrofuran (1 part) and dichloromethane (3 parts) (3×100 ml). The organic phases were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was recrystallised from ethyl acetate yielding the title compound as a white solid 3.8 g (40%), m.p. 180°-181° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>COC>[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1cc2ccccc2c2ccccc12
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Under an argon atmosphere, 25.7 g of 9-bromophenanthrene, 16.5 g of 2-formylphenylboronic acid and 2.31 g of tetraxis(triphenylphosphine)palladium(0) were placed in a flask. 340 mL of dimethyl ether (DME) and 170 mL of a 2M aqueous sodium carbonate solution were added to this flask, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase which had been separated was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 25.0 g (yield: 89%) of 9-(2-formylphenyl)phenanthrene was obtained.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1.C(N(CC)CC)C>CN(C)C=O>[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)=[O:33]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (8.76 g) in dimethylformamide (80 ml) were added (2S)-2-(hydroxymethyl)pyrrolidine (8.72 g) and triethylamine (3.86 ml) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:48][N:49]([CH2:51][CH2:52]O)[CH3:50].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:16]([CH2:52][CH2:51][N:49]([CH3:50])[CH3:48])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Nc1ccccc1NCCOc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCN(c1ccccc1NCCOc1ccc(Cl)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 59.6 %

Procedure:
The product of Example 1 (10.71 g), triphenylphosphine (9.63 g), and dimethylaminoethanol (3.27 g) were dissolved in tetrahydrofuran (60 ml). To the resultant solution diisopropyl azodicarboxylate (7.43 g) was added dropwise over 30 min with stirring on ice. After completion of dropwise addition of the solution, the mixture was further stirred for one hour at room temperature and the solvent was removed under reduced pressure. The residue was purified through two steps: NH silica gel column chromatography (solvent=hexane:ethyl acetate=3:1,) and silica gel column chromatography (solvent=hexane:ethyl acetate=1:1 and chloroform:methanol=10:1). The resultant product was re-crystallized from ether-hexane, to thereby obtain the target product (7.42 g) in the form of crystals. Mp.: 99° C.; 1H-NMR(270 MHz, CDCl3) δ: 7.65 (2H, d, J=8.58 Hz), 7.41 (2H, d, J=8.58 Hz), 7.25 (2H, d, J=8.91 Hz), 7.18 (1H, m), 6.87 (2H, d, J=8.91 Hz), 6.72 (1H, d, J=8.25 Hz), 6.47 (2H, m), 5.78 (1H, brs), 4.08 (3H, m), 3.51 (2H, m), 3.12 (1H, m), 2.42 (1H, m), 2.22 (1H, m), 2.20 (6H, s).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.[CH2:18](I)[CH3:19]>>[N+:14]([C:10]1[CH:9]=[C:8]([CH:7]([CH2:18][CH3:19])[C:6]([OH:5])=[O:17])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CCI
Product: CCC(C(=O)O)c1cccc([N+](=O)[O-])c1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using ethyl iodide (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 2-(3-nitrophenyl)butyric acid.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH:32]4[CH2:34][CH2:33]4)=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[C:30]([CH3:31])=[CH:29][C:28]([CH:32]5[CH2:34][CH2:33]5)=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)nc2)C1=O
Yield: 11.5 %

Procedure:
Using 1-acetyl-2-imidazolidinone (316 mg) and (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (900 mg) described in Preparation Example 135 and by the reaction and treatment in the same manner as in Example 1, the title compound (116 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[N:14]1C=CC=C[CH:15]=1.N>CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][O:12][C:5]1([C:15]#[N:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:2]=[CH:3][CH2:4]1
Reactant: COc1ccc(Br)c2c1CCCC2
Reactant: c1ccncc1
Agent: N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1(C#N)CC=CC2=C1CCCC2

Procedure:
4-Bromo-1-methoxy-5,6,7,8-tetrahydronaphthalene (1) (2.5 g, 10.4mM) cuprous cyanide (1.07 g, 5.4mM), pyridine (1.5 ml) and hexamethylphosphoramide (0.3 ml) were stirred at 192° C. for 16 hours. The mixture was poured into aqueous ammonia and extracted with ether. The ether was washed with ammonia, water, dilute hydrochloric acid and then saturated brine. The ether solution was then dried and evaporated to give the nitrile (2) (1.90 g).