Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[C:12]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.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>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[CH:33]=4)[CH:18]=3)[N:13]=[C:12]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(I)cc23)cc1Cl
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(-c4cccc(Cl)c4)cc23)cc1Cl
Yield: 51.6 %

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (1.0 g, 2.10 mmol), 3-chlorophenylboronic acid (0.49 g, 3.13 mmol), Pd(PPh3)4 (0.24 g, 0.210 mmol), K3PO4 (1.34 g, 6.31 mmol) in dioxane (20 mL) and water (2.0 mL) was stirred under reflux for 2 h. Ethyl acetate (20 mL) was added to the cooled mixture and filtered. The filtered solid was recrystallized from DMF and water to give the title compound (0.50 g, 51.6%). 1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.54 (s, 1H), 8.87 (s, 1H), 8.74-8.65 (m, 2H), 8.31-8.23 (m, 2H), 8.04-7.85 (m, 4H), 7.64-7.49 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1.CN1C(=O)CCC1.CCOCC.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)[CH3:15]
Reactant: CC[Mg+]
Reactant: COC(=O)c1ccc(Cl)cc1OC
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCc1ccc(C(=O)OC)c(OC)c1
Yield: 50 %

Procedure:
To a solution of methyl 4-chloro-2-methoxybenzoate (example 18d) (4.16 g, 20.8 mmol) in THF (120 mL) and NMP (12 mL) was added under inert atmosphere Iron(III) acetylacetonate (398 mg, 1.17 mmol) giving a red color. Then EtMgBr (29 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 50 mL). The crude product was extracted with ether and the combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 30% EtOAc in hexanes) to give methyl 4-ethyl-2-methoxybenzoate (2.01 g, 50%) as an oil. 1H NMR (300 MHz, dMSO): δ 1.20-1.22 (t, 3H), 2.65-2.7 (dd, 2H), 3.9 (s, 3H), 6.8 (s, 1H), 6.97 (m, 1H), 7.7 (m, 1H).
Reaction SMILES: Cl.ClCCN1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O-:14])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:14][C:6]1[CH:7]=[CH:8][C:9]([O:14][C:11]2[C:8]3[C:7](=[CH:6][C:11]([O:14][CH3:11])=[CH:10][CH:9]=3)[CH:8]=[CH:9][C:10]=2[C:8]2[CH:7]=[CH:6][CH:7]=[C:10]([O:14][CH3:11])[CH:9]=2)=[CH:10][CH:6]=1
Reactant: ClCCN1CCCCC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(O)cc2)c1
Temperature: 25 °C
Yield: 320 %

Procedure:
A solution of 1.5 g (4 mmol) of 1-(4-hydroxyphenoxy)-2-(3-methoxyphenyl)-6-methoxynaphthalene in 40 mL of DMF was prepared. To this solution was added 920 mg (5 mmol) of 2-chloroethylpiperidine hydrochloride and 5.2 g (16 mmol) of Cs2CO3, the reaction was stirred at ambient temperature under a nitrogen atmosphere for sixteen hours. The solvents were removed by evaporation and the residue partioned between water and EtOAc. The EtOAc layer was washed with water, then brine, dried with Na2SO4, and evaporated to dryness. The residue was dissolved in 10 mL of MeOH ane 1 mL of 5N HCl was added. The solvents were removed by evaporation and the product crystallized from EtOAc. This yielded 1.8 g of the title compound as a white solid, mp 161–162° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N-:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN(C)CCCC[N-][C@H]1CC[C@H](C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCCN[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.1 g of N-(trans-4-methylcyclohexyl ) -4-dimethylaminobutylamide (Example 73) was dissolved in 100 ml of THF. Under an argon stream, the solution was added dropwise to a solution of 7.5 g of lithium aluminum hydride suspended in 400 ml of THF under ice-cooling. After the addition, the solution was reacted for 8 hours, while it was refluxed. After reaction, the solution was allowed to cool to room temperature. Then, 22 g of sodium sulfate decahydrate was added to the solution under ice-cooling. The solution was stirred for 1 hour, and the precipitate was filtered out. The solvent was removed in vacuo, yielding an oily substance. This substance was subjected to vacuum distillation, yielding 5.7 g of N-(4-dimethylaminobutyl)-trans-4-methylcyclohexylamine as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH3:14])[CH:3]=1.Cl.[C:24](OCC)(=O)C>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[CH3:24])[CH3:14])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc(Cl)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (1.53 g) was added 4 M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (810 mg).
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)C(C)(C)CCCC.C([O:34][CH:35]([C:54](C)(C)[CH2:55][CH2:56][CH2:57][CH3:58])[CH2:36][CH2:37][CH2:38][N:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])[C:40](=[O:42])[CH3:41])(=O)C>>[OH:34][C@H:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:36]#[C:37][CH2:38][N:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[C:40](=[O:42])[CH3:41]
Reactant: CCCCC(C)(C)C(CCCN(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Agent: CCCCC(C)(C)C(CCCCl)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 2 except that, in Step B, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-5,5-dimethylnonane (Example G, Step 3). The product in Step B is ethyl 7-[N-(4-acetoxy-5,5-dimethylnonyl)acetamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-5,5-dimethylnonyl)acetamido]-heptanoic acid (C).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:19])[NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[H-].[Na+].O>CN(C)C=O>[O:19]=[C:6]1[NH:5][CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(NC(=O)NCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCCNC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.9 %

Procedure:
A mixture of ethyl 4-aminobenzoate (496 mg) and pyridine (60 μL) was dissolved in dichloromethane (3 mL), 1-chloro-3-isocyanatopropane (323 μL) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg). The obtained ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (250 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated from the organic layer. To the obtained residue was added diisopropyl ether, and the precipitate was collected by filtration to give the title compound (84 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[CH2:10]([C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC/C=C/c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCc1ccc(N)cc1
Yield: 85.8 %

Procedure:
A MeOH (20 mL) solution of compound (E)-1-nitro-4-(oct-1-enyl)benzene (2.121 g, 9.0 mmol) and Pd—C (200 mg, 0.9 mmol) was stirred at r.t. for 2 h under hydrogen atmosphere. Then the mixture was filtered and the filtrate was evaporated to give product the title compound (1.586 g, 85%) as a pink liquid. 1H NMR (300 MHz, CDCl3) δ 6.962 (d, 2H), 6.636 (d, 2H), 3.487 (b, 2H), 2.484 (t, 2H), 1.581-1.467 (m, 2H), 1.291-1.166 (m, 10H), 0.874 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:21][C@@H:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:43](OC(=O)C)(=[O:45])[CH3:44].O>N1C=CC=CC=1>[C:43]([NH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:21][C@@H:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1N
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-4′-[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-4-biphenylcarboxylate (532 mg) in pyridine (600 μl) was added acetic anhydride (400 μl) and stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride aqueous solution and brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 3-(acetylamino)-4′-[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-4-biphenylcarboxylate (381 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[S:7]1(=[O:16])[C:8]2[CH:13]=[C:12]([NH:14][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:25])[CH:11]=[CH:10][C:9]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:25])=[CH:17][C:6]1=2
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Product: O=C(Nc1ccc2c(c1)S(=O)(=O)c1cc(NC(=O)c3ccccc3)ccc1-2)c1ccccc1

Procedure:
The procedure of Example 60 was followed using 3,7-diamino-dibenzothiophene S,S-dioxide and benzoyl chloride giving the desired product as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1.BrCCOC1C=C(C2C=CC(C(N)=O)=CC=2)C=CC=1.Cl.[CH3:40][C:41]1([CH3:48])[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1.C(N(CC)CC)C>CO.C(OCC)(=O)C>[ClH:1].[CH3:40][C:41]1([CH3:48])[CH2:46][CH2:45][CH:44]([NH:47][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:43][CH2:42]1
Reactant: CC1(C)CCC(N)CC1
Reactant: NC(=O)c1ccc(-c2cccc(OCCCl)c2)cc1
Agent: Cl
Agent: NC(=O)c1ccc(-c2cccc(OCCBr)c2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CCC(NCCOc2cccc(-c3ccc(C(N)=O)cc3)c2)CC1

Procedure:
A mixture of 3′-[(2-chloroethyl)oxy]-4-biphenylcarboxamide and 3′-[(2-bromoethyl)oxy]-4-biphenylcarboxamide (Example II-1) (0.15 g), 4,4-dimethylcyclohexylamine hydrochloride (0.13 g, 0.8 mmol) (prepared according to J. Med. Chem. 1971, 14, p. 600-614) and triethylamine (0.14 g, 1.35 mmol) in methanol (2 mL) was placed in a microwave at 160° C. until the reaction was complete as monitored by LC/MS. The reaction mixture was poured into ethyl acetate and washed several times with 5% Na2CO3 (aq). Silica gel was added to the organic phase and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography. The fractions containing the desired product were combined and concentrated in vacuo. Dissolved the residue in ethanol, added 1.0N HCl in Et2O until acidic, added ethyl ether until turbid and let stand at room temperature. The resulting solid was filtered, washed with ethyl ether and dried to give 3′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-4-biphenylcarboxamide hydrochloride as an off-white solid. (M+H) 367, 1.83 min. (LC/MS method A)
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1)#[N:9].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:9][CH2:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=[O:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Add triethylamine (0.3 mL, 2.12 mmol) to a solution of 4-cyano-benzylamine (1.0 g, 7.58 mmol) in DCM (11 mL) and cool the mixture at 0° C. Add 2,2-dimethyl-propionyl chloride (0.93 mL, 7.58 mmol) dropwise and allow to stir the mixture at 0° C. for 15 min and at room temperature for 2 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (1.23 g, 75%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:9]([O-])=[O:10].[Na+].Cl.O>C(OCC)C>[OH:10][N:9]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(=NO)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 46.45 g (0.4 mol) of methyl acetoacetate in 200 ml of diethylether, 30.4 g (0.44 mol) of sodium nitrite was added and the mixture was cooled in an ice bath and treated dropwise with 40 ml (0.48 mol) of a concentrated hydrochloric acid. After stirring for 1 hour at room temperature, 200 ml of water was added and the mixture was extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off to obtain 50.09 g (yield: 86%) of a crude methyl 2-hydroxyiminoacetoacetate as a pale yellow oil. (2) Synthesis of methyl 2-benzyloxyiminoacetoacetate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH2:62])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1>C1COCC1.C(Cl)(Cl)Cl>[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH:62][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=3[O:2][CH3:1])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c(OC)c1

Procedure:
From 2,4-dimethoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+21.7° (c=0.50, CHCl3), ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:13]=2)[CH:10]=1.CO>O1CCCC1>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([CH:11]=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[N:13]=3)[CH:10]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])cc3F)ccc2n1)C1CC1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Temperature: 40 °C
Yield: 91.6 %

Procedure:
To a suspension of N-[6-(2-fluoro-4-nitrophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (10 g, 28.1 mmol) in tetrahydrofuran (80 mL)/methanol (80 mL) were added iron chloride•hexahydrate (0.5 g), hydrazine•monohydrate (8.2 mL, 168 mmol) and activated carbon (1.0 g), and the mixture was heated under reflux for 16 hr. After cooling to 40° C., the mixture was filtered through celite and washed with methanol. The solvent of the filtrate was evaporated under reduced pressure, and the precipitate was washed with water/methanol (=10/1) and collected by filtration to give the title compound (8.4 g, 92%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:17]2[CH2:18][CH:19]([CH3:21])[CH2:20][CH:15]([CH3:14])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CNCC(C)C1
Reactant: CC#CCOc1ncnc(F)c1F
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
0.53 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine and 0.39 g of 3,5-dimethylpiperidine (mixture of about cis:trans=7:3) were added to 1 ml of toluene, then the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.6 g of 4-(2-butynyloxy)-5-fluoro-6-(3,5-dimethylpiperidino)pyrimidine (referred as the present compound (4) hereinafter).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[S:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[C:6]([OH:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1Sc1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of ethyl 4-amino-3-(2,4-difluorophenylthio)benzoate (1.1 g) and methanesulfonyl chloride (0.93 g) in pyridine (5 ml) was stirred at 60° C. for 2 hours. The reaction mixture was evaporated. The residue was dissolved in methanol and treated with potassium hydroxide (2 g). The mixture was concentrated and the residue was dissolved in water and washed with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The solid residue was recrystallized from ethanol to give 3-(2,4-difluorophenylthio)-4-(methanesulfonamido)benzoic acid (0.66 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH:34]1([NH:37][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:21])=[O:22])[CH2:36][CH2:35]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC4CC4)c3)n2)n1
Yield: 43.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available cyclopropylamine (0.14 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.090 g, 43%) as a white solid. MS (ISP) 510.2 [(M+H)+]; mp 150° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([CH2:20][NH:21]C(OC(C)(C)C)=O)[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:30])[C:6]([C:31]([OH:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:34]>C(O)C>[ClH:34].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:30])[C:6]([C:31]([OH:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(N2CCC(CNC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: CCO
Product: Cc1c(N2CCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
To 1-cyclopropyl-7-[3-(t-butoxycarbonylaminomethyl)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g) are added 10% hydrochloric acid (4 ml) and ethanol (2 ml), and the mixture is reacted at 70° C. for 10 minutes. After concentrating, the resulting residue is crystallized by adding thereto diethyl ether and then recrystallized from ethyl acetate-methanol to give 1-cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (45 mg), as yellow crystals, m.p. 195°-200° C.