Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1.N12CCN(CC1)CC2.Cl[C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:36].O>CS(C)=O>[CH:29]1([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:36])=[C:19]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:5][CH2:6]4)[CH:28]=3)[C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25]2)[CH2:30][CH2:31]1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(C4CC4)CC3)c(F)cc2c1=O
Yield: 32.3 %

Procedure:
1.3 g of 1-cyclopropylpiperazine and 2.2 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane are added to 2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 25 ml of dimethyl sulphoxide, and the mixture is heated at 140° for 5 hours. 40 ml of water are added to the suspension and the precipitate is filtered off with suction, washed with water and boiled up with 20 ml of methanol. 1.2 g of 1-cyclopropyl-7-(4-cyclopropyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 226°-229° (with decomposition) are obtained.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O.C(#N)C.CO>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:34]
Reactant: O=C1CCNCC1
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C1CCN(C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-piperidone hydrochloride monohydrate (0.32 g, 2.1 mmol) was dissolved in DCM (7 ml), and to this was added MP-Carbonate resin (0.8 g). This was stirred at room temperature for 2 h. Separately, 2-thiophenecarboxylic acid (0.32 g, 2.52 mmol), N,N-4-dimethylaminopyridine (cat.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.3 mmol) and TEA (0.25 ml) were dissolved in DCM (7 ml) and stirred at room temperature for 2 h. The 2 reaction mixtures were then combined and stirred at room temperature for 18 h. The resulting solution was then filtered and washed with HCl (1M), sodium bicarbonate then brine. The organic layers were combined and dried over MgSO4 and evaporated to dryness. The crude mixture was purified using flash chromatography (0-100% ethyl acetate in hexane), to yield a white solid. 220 mg, (56%), mp. 81-83° C., LCMS tr=2.29 min (50% MeOH and 50% water at 0.5 ml/min), m/z M+H 210.11, HPLC tr=1.89 min (Isocratic 90% acetonitrile and 10% water at 1.0 ml/min), 100%, 1HNMR (CDCl3, 270 MHz) δ 2.47 (4H, t, J=6.2 Hz, CH2), 3.94 (4H, t, J=6.4 Hz, CH2), 7.00 (1H, dd, J=3.5, 4.9 Hz, ArH), 7.31 (1H, dd, J=1.2, 3.7 Hz, ArH), 7.43 (1H, dd, J=1.2, 4.9 Hz, ArH).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18].C(N(CC)CC)C.[C:26]([O:30][C:31](=[O:38])[NH:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([N:35]3[CH2:36][CH2:37][C@H:33]([NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:38])[CH2:34]3)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Yield: 88.2 %

Procedure:
To a solution of 3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 24a) (50.0 mg, 0.20 mmol) and triethylamine (74 mg, 0.74 mmol) in acetonitrile (3 mL) is added (S)-pyrrolidin-3-yl carbamic acid tert-butyl ester (74 mg, 0.40 mmol). The solution is refluxed for 18 hours, the solvent is removed under reduced pressure, and the residue triturated with water. The solid is collected by filtration and air dried to afford 74 mg of the title compound. MS CI: m/z 420 (MH+).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1.C(N(CC)CC)C>>[O:7]([C:8]([C:15]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nnn[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1nnn[nH]1
Reaction time: 0.25 h

Procedure:
The title compound was prepared according to the procedure described in Tetrahedron Letters, 1977, 1935. Accordingly, phenylchloroformate (6.73 g, 43 mmol) was added dropwise into a solution of tetrazole (42.84 mmol, 3 wt % in 100 mL acetonitrile) containing triethylamine (4.35 g, 43 mmol) at 0° C. The mixture was stirred for 15 minutes and the solvent was removed without heating at reduced pressure. Ethyl acetate (80 mL) was added to the white solid and passed through a plug of silica gel, eluting with 3% triethylamine in ethyl acetate to afford phenoxycarbonyltetrazole in 85% yield (6.9 g). 1H-NMR (CDCl3): δ 7.34-7.54 (m, 5H); 9.34 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccnc2ccccc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(C(Nc2ccnc3ccccc23)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of 4-aminoquinoline (H. Shinkai et al., J. Med. Chem., 2000, 43, pp. 4667-4677) (251 mg), chlorotriphenylmethane (533 mg), and triethylamine (266 μL) in methylene chloride (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% ethyl acetate-hexanes) to give quinolin-4-yltritylamine as a pale yellow foam (610 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:18][NH:19][O:20][CH3:21])#[N:14]>>[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:18][N:19]([O:20][CH3:21])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)#[N:14]
Reactant: CONCc1ccc(F)c(C#N)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)c(C#N)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-cyano-4-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 119-120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.75 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.36 (1H, s, CH), 7.17 (1H, t, aromatic), 7.58-7.64 (2H, m, aromatics). Anal. calcd for C16H15F2NO5: C, 57.48; H, 4.52; N, 8.38. Found: C, 57.39; H, 4.61; N, 8.32.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[O:11]([C:8]1[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cnc(Oc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(Oc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of 2-phenoxy-pyrimidine-5-carboxylic acid methyl ester (0.5 g, 2.17 mmol) in THF (10 mL) and water (5 mL) is added LiOH (105 mg, 4.35 mmol). The reaction is stirred at 0° C. for 1 h. The THF is evaporated and the aqueous reissue is washed with ether, acidified with 2 M aqueous HCl. The resulting precipitate is filtered and dried to afford 2-phenoxy-pyrimidine-5-carboxylic acid (0.34 g, 73%) as a solid. MS: 217 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.20-7.35 (m, 3H), 7.47 (t, 2H) 9.16 (s, 2H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([C:32](O)=O)[N:23]=2)=[CH:18][C:17]=1[CH3:35]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[C:24]([C:32]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:23]=2)=[CH:18][C:17]=1[CH3:35]
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)n2)ccc1Cl

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.74 mmol) and 4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.7) (0.16 g, 0.50 mmol) according to the general procedure V. Obtained as a white solid (0.046 g, 19%). MS (ISP) 496.2 [(M+H)+]; mp 246° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(=O)=O.CC(C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: COC(=O)c1ccc2nc(-c3cccs3)oc2c1
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2nc(-c3cccs3)oc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6.1 g (23.53 mmol) methyl 2-thiophen-2-yl-benzoxazole-6-carboxylate are dissolved in 300 ml THF and cooled with dry ice/acetone, then 40 ml (40.00 mmol) of 1M lithium aluminium hydride dissolved in THF are slowly added dropwise. The mixture is stirred for 30 min at 0° C., then 4 ml of water dissolved in 20 ml THF are added dropwise, followed by 4 ml of 4N sodium hydroxide solution and another 4 ml of water. The resulting suspension is mixed with magnesium sulphate and filtered through kieselguhr, the filtrate is concentrated by rotary evaporation i. V. and the residue is purified on silica gel (eluant: cyclohexane/EA).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH2:27])[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][N:16]=1)=[O:14])=[O:5].[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40](O)=[O:41])=[CH:34]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH:27][C:40]([C:35]1[NH:36][C:37]2[C:33]([CH:34]=1)=[CH:32][C:31]([F:30])=[CH:39][CH:38]=2)=[O:41])[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][N:16]=1)=[O:14])=[O:5]
Reactant: CC(C)(C)[C@H](N)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[C@H](NC(=O)c1cc2cc(F)ccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Yield: 47.7 %

Procedure:
A solution of [(1S)-2,2-dimethyl-1-({(1S,4S)-5-[(5-phenyl-2-pyridinyl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]amine (100 mg, 0.25 mmol), 5-fluoro-1H-indole-2-carboxylic acid (48 mg, 0.26 mmol), EDC (58 mg, 0.3 mmol), HOBt (7 mg, 0.05 mmol), NMM (77 mg, 0.76 mmol) in CH2Cl2 (3 mL) was stirred at room temperature for 2 h. The mixture was washed with 1N sodium hydroxide (2×3 mL), water (2×10 mL). The combined aqueous washes were extracted with CH2Cl2 (2×5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered concentrated to give the crude product, which was purified by reverse phase HPLC. Concentration of the desired fractions containing product afforded the title compound (66 mg) as a pale yellow solid. LCMS (m/z): 554.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm: 0.90-1.10 (m, 9H), 1.80-2.15 (m, 2H), 3.45-4.20 (m, 4H), 4.60-5.55 (m, 3H), 6.90-7.60 (m, 10H), 7.80-8.10 (m, 2H), 8.55-8.90 (m, 1H), 9.20-9.55 (m, 1H)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.[N:14]1([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.[I-].[Na+].C(O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([N:14]2[CH2:15][CH2:16][N:17]([CH2:2][CH2:3][C:4]3[CH:13]=[CH:12][C:7]4[NH:8][C:9](=[O:11])[O:10][C:6]=4[CH:5]=3)[CH2:18][CH2:19]2)=[N:21][CH:22]=1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2ccc(CCN3CCN(c4ncnc5ccccc45)CC3)cc2o1
Yield: 68.6 %

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.22 g (5.05 mmol) of 6-bromoethylbenzoxazolone, 1.08 g (5.05 mmol) of 4-piperazinylquinazoline, 0.85 g (8.0 mmol) of sodium carbonate, 2 mg of sodium iodide, and 35 ml of ethanol. The reaction was refluxed for 3 days, cooled, diluted with water, and the pH adjusted to 4 with 1N HCl. The aqueous layer was separated, the pH adjusted to 7 with 1N NaOH, and the product extracted into ethyl acetate. The ethyl acetate layer was washed with brine, dried, and evaporated to give 1.3 g of a yellow oil. The oil was crystallized form chloroform (1.1 g), dissolved in ethyl acetate, ethyl acetate saturated with HCl gas added, and the mixture concentrated to dryness. The residue gave 0.9 g (58%) of a yellow salt, m.p. 200° C. NMR (d, CDCl3): 2.72 (m, 6H), 2.86 (m, 2H), 3.83 (m, 4H), 6.9-7.9 (m, 7H), 8.72 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:34]#[C:33][CH2:32][OH:35])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: C#CCO
Reactant: Fc1ccc(I)cc1C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: OCC#Cc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A mixture of 2-fluoro-5-iodobenzotrifluoride (5.00 g), copper(I) iodide (65.5 mg), triphenylphosphine (226 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (356 mg), propargyl alcohol (1.12 ml), diisopropylethylamine (12.0 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.26 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:4]=1.[F:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[F:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([O:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:6][CH:7]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1nc(OCCN2CCCC2)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(CCCF)cc1
Solvent: c1ccncc1
Product: COc1nc(OCCN2CCCC2)ccc1NS(=O)(=O)c1ccc(CCCF)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.4 %

Procedure:
After a solution of 2-Methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-ylamine (200 mg, 0.84 mmol) in pyridine (3 ml) was stirred at room temperature for 30 minutes 4-(3-fluoro-propyl)-benzenesulfonyl chloride (200 mg, 0.84 mmol) was added. The mixture was stirred at room temperature for 16 h, thereafter the solvent was evaporated under reduced pressure. The residue was taken up in toluene and the solvent was evaporated. This procedure was repeated once. The residue was purified by silica gel chromatography with dichloromethane/methanol (100:0; 95:5; 0:100) as eluent to give 20 mg (5.4%) of the title compound.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1C(C)CCCN1.[NH2:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH:19]([OH:20])[CH2:18][CH2:17][CH2:16][NH:15]1
Reactant: Nc1ncccc1O
Agent: CC1CCCNC1=N
Solvent: CC(=O)O
Product: N=C1NCCCC1O

Procedure:
The method of preparation of 2-imino-3-methylpiperidine acetate, EXAMPLE 6, was used to convert 2-amino-3-hydroxypyridine to the title compound which was obtained as a white solid. The analysis of the product was found to be consistent with the proposed structure. m.p. 128-130° C. MH+=115 ; 1H NMR (D2O): δ4.34-4.28 (m, 1H); 3.20-3.10 (m, 2H); 2.05-1.50 (m, 4H); 1.71 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#N)=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.Cl.[OH2:25]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:25])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)c2ccccc12
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of 4-(bromomethyl)-1-naphthonitrile (8 g, 33 mmol) in toluene (100 mL) at 0° C. was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0° C. for 1 h. 3 N HCl in water (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3 x100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116° C.; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16]C3CCCCC3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CCO.O>[CH:1]1([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OC2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cyclohexyl 6-(cyclohexyloxy)pyrimidine-4-carboxylate (2.00 g; 6.57 mmol) in THF/EtOH/H2O (3/2/1, total volume 200 mL) was treated with a 5N solution of sodium hydroxide (3.94 ml; 19.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and then water was added. The aqueous layer was washed with DCM then acidified to pH 5 by addition of 1N HCl solution. The aqueous layer was washed with EtOAc (150 mL), then lyophilized and the obtained solid was washed with DCM. The suspension was filtered off and the filtrate was concentrated under vacuum to afford the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1N
Reactant: ClCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCC1OCCO1

Procedure:
2,6-Dimethylaniline (75 grams), 2-chloromethyl- 1,3-dioxolane (25 grams), potassium carbonate (35 grams) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux for a period of about 18 hours. After this time the mixture was filtered and distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl-2,6-dimethylaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17])([O-])=O.N>O.C(O)C.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCCC(=O)Nc1n[nH]c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g of iron sulphate heptahydrate dissolved in 50 cm3 of hot water are added to a solution of 2.05 g of N-[5-nitro-1H-indazol-3-yl]butanamide, described in Example 23, in 80 cm3 of ethanol; the mixture is stirred for 30 minutes at room temperature, 24 cm3 of 28% aqueous ammonia are added and the mixture is then refluxed for 2 hours, 10 cm3 of 28% aqueous ammonia are added and the mixture is stirred for a further 10 minutes. The precipitate is filtered off while hot, on a sinter funnel packed with Celite, rinsed with methanol until the filtrate is colourless, and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and is washed with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After drying (90 Pa; 50° C.) 870 mg of N-(5-amino-1H-indazol-3-yl)butanamide are obtained in the form of a purple powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:11](O)[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:9])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([NH:36][C:35]2[CH:37]=[CH:38][C:32]([Cl:31])=[CH:33][CH:34]=2)[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:9])=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(NC(O)C(=O)c1cccc2ccccc12)c1ccc(Br)cn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(NC(Nc1ccc(Cl)cc1)C(=O)c1cccc2ccccc12)c1ccc(Br)cn1
Temperature: 50 °C
Yield: 36.9 %

Procedure:
5-bromo-N-(1-hydroxy-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide 113 (0.74 g, 1.93 mmol) in chloroform (20 mL) was reacted with PCl5 (0.43 g, 1.96 mmol). The mixture was heated to 50° C. for 30 minutes and cooled to 0° C. 4-Chloroaniline 114 (0.512 g, 4.01 mmol) in THF (10 mL) was added and allowed to react for 1 hour. The reaction was quenched with water and the product was extracted with ethyl acetate. The organic solution was dried over MgSO4, filtered and concentrated onto silica gel. The product was purified by auto flash column chromatography (30 to 50% CH2Cl2: hexane) followed by titration with diethyl ether to give 5-bromo-N-(1-(4-chlorophenylamino)-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide (Compound-1, 352 mg, 37%). 1H NMR (300 MHz, CDCl3): δ=8.83 (d, J=8.7 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.46 (d, J=9.6 Hz, 1H), 8.39 (dd, J=1.2, 7.2 Hz, 1H), 8.07-8.03 (m, 2H), 7.93 (dd, J=2.4, 8.7 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.68-7.63 (m, 1H), 7.56 (t, J=7.8 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.09-7.03 (m, 1H), 6.82 (d, J=9.0 Hz, 2H) 5.41 (d, J=8.1 Hz, 1H).