Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@H:14]([C@H:16]1[O:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[CH2:17]1)Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:16]1[O:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[CH2:17]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](Br)COCc2ccccc2)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CC(C)[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 40 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
5.10 g of sodium azide (78.5 mmol) was added to a solution of 22.33 g of (3S,5S)-5-[(1R)-2-benzyloxy-1-bromoethyl]-3-isopropyldihydrofuran-2-one obtained in Example (1d) (65.4 mmol) in N,N′-dimethylpropyleneurea (130 ml) at room temperature, and the mixture was stirred at 40° C. for three days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1) to obtain 10.19 g of the title compound (yield: 51%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[C:21]1(=[O:27])[NH:25][C:24](=[O:26])[CH2:23][CH2:22]1>>[O:26]=[C:24]1[CH2:23][CH2:22][C:21](=[O:27])[N:25]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: O=C1CCC(=O)N1
Product: CN(C(=O)Oc1ccc(CCN2C(=O)CCC2=O)cc1)c1ccccc1
Yield: 85 %

Procedure:
The title compound was prepared in 85% yield as crystals using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and succinimide. 1H NMR (400 MHz; CDCl3): δ 2.65 (s, 4H), 2.86 (t, 2H), 3.41 (br s, 3H), 3.72 (t, 2H), 7.04 (br d, 2H), 7.19 (d, 2H), 7.26–7.42 (m, 5H); HPLC-MS: m/z=353.2 (M+1); Rt=3.17 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:20]1[CH2:21][CH2:22][C@H:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:18][CH2:19]1)[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2n1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3n2)CC1

Procedure:
6-bromo-2-hydroxyquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline was then exposed to n-butyllithium and DMF, providing 6-formyl-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. This aldehyde was then treated with 3-aminopropionic acid and sodium cyanoborohydride to afford the title compound, 3-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoic acid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:20]4([O:27][CH3:28])[CH2:25][CH2:24][O:23][CH2:22][CH:21]4[OH:26])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:29].CI.[CH2:32]1OCCOCCOCCOCCOC1>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:20]4([O:27][CH3:28])[CH2:25][CH2:24][O:23][CH2:22][CH:21]4[O:26][CH3:32])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:29]
Reactant: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1O
Reactant: C1COCCOCCOCCOCCO1
Solvent: CI
Product: COC1COCCC1(OC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 78 %

Procedure:
Using the methylation procedure described in the portion of Example 1 which is connected with the preparation of starting materials, (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3-hydroxy-4-methoxytetrahydropyran was reacted with methyl iodide in the presence of 15-crown-5 to give (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3,4-dimethoxytetrahydropyran in 78% yield, as a glass.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([F:18])[CH:10]=2)[CH:7]=1.[Li][CH2:21]CCC.CCCCCC.C[Si](C)(C)[O:33][C@@H:34]1[C@@H:39]([O:40][Si](C)(C)C)[C@H:38]([O:45][Si](C)(C)C)[C@@H:37]([CH2:50][O:51][Si](C)(C)C)[O:36][C:35]1=[O:56].CS(O)(=O)=O>C1COCC1.CO>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([C@@:35]2([O:56][CH3:21])[C@H:34]([OH:33])[C@@H:39]([OH:40])[C@H:38]([OH:45])[C@@H:37]([CH2:50][OH:51])[O:36]2)=[CH:7][C:6]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([F:18])[CH:10]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1F
Reactant: [Li]CCCC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-[(5-bromo-2-chloro-phenyl)methyl]-1-ethoxy-2-fluoro-benzene 4e (7.36 g, 21.4 mmol) was dissolved in 30 mL THF and cooled to −78° C., followed by dropwise addition of a solution of nBuLi in n-hexane (10.27 mL, 25.7 mmol). After stirring for 1 hour at −78° C., a solution (20 mL) of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-one 2f (11 g, 23.6 mmol) in THF was added before the reaction mixture was stirred for 2 hours at −78° C. Then the reaction mixture was warmed and stirred for 16 hours at room temperature after 2.8 mL methylsulfonic acid and 71 mL methanol were added. Thereafter, the reaction mixture was concentrated under reduced pressure after 100 mL saturated sodium carbonate solution were added. The residue was dissolved in 50 mL saturated sodium chloride, extracted with ethyl acetate (100 mL×3). The organic extract was combined, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4f (5.7 g, white solid), yield: 58.3%. 1H NMR (400 MHz, CD3OD): δ 7.56 (s, 1H), 7.48 (dd, 1H), 7.37 (dd, 1H), 6.95-6.87 (m, 3H), 4.08-4.07 (m, 4H), 3.91 (m, 1H), 3.93-3.73 (m, 2H), 3.56-3.53 (m, 1H), 3.45-3.43 (m, 1H), 3.30 (s, 2H), 3.08 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:11][C:12]1[N:20]2[C:15]([C:16](N3C=NC=N3)=[N:17][CH:18]=[N:19]2)=[C:14]([C:26]2[CH:27]=[N:28][N:29]([CH3:38])[C:30]=2[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:13]=1>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:16]2[C:15]3=[C:14]([C:26]4[CH:27]=[N:28][N:29]([CH3:38])[C:30]=4[C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[N:13]=[C:12]([CH3:11])[N:20]3[N:19]=[CH:18][N:17]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Cc1ccc(-c2c(-c3nc(C)n4ncnc(-n5cncn5)c34)cnn2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(-c3nc(C)n4ncnc(N5CCC5)c34)cnn2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine (27.0 μL, 0.400 mmol) and cesium carbonate (97%, 202 mg, 0.601 mmol) were added to a solution of 7-methyl-5-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine (material from the previous reaction, ≦0.16 mmol) in N,N-dimethylformamide (3.0 mL), and the reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with ethyl acetate, washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane), followed by azeotroping with heptane, provided the product as a white solid. Yield: 35 mg, 0.097 mmol, 61% over 2 steps. LCMS m/z 360.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.20-2.28 (m, 2H), 2.35 (s, 3H), 2.64 (s, 3H), 3.5-3.9 (v br m, 2H), 3.90 (s, 3H), 3.9-4.3 (v br m, 2H), 7.21 (AB quartet, JAB=8.1 Hz, ΔvAB=32.1 Hz, 4H), 7.64 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][CH2:15][N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:17][CH2:18]Cl.O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(CCCl)CCCl)cc1
Reactant: N#CCc1ncccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN2CCC(C#N)(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 3-chloro-2-pyridylacetonitrile [prepared by the method described in JP08295663] (1.46 g, 9.57 mmol) in DMSO (19 mL) was slowly added to NaH (60% oil dispersion, 1.01 g, 25.3 mmol), and the mixture was stirred at room temperature for 1 h. A solution of N,N-bis(2-chloroethyl)-p-methoxybenzylamine (2.21 g, 8.43 mmol) in DMSO (19 mL) was added, and the resulting mixture was stirred at 75° C. for 4 h. After cooling, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give 4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine 1 (1.91 g, 60%) as an orange oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[N:9]=[C:8]([NH:15][CH2:16][CH3:17])[N:7]=1.[CH:18](N)(C)C>>[Cl:14][C:10]1[C:11]([C:12]#[N:13])=[C:6]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:7]=[C:8]([NH:15][CH:16]([CH3:17])[CH3:18])[N:9]=1
Reactant: CC(C)N
Reactant: NC1CC1
Reactant: CCNc1nc(Cl)c(C#N)c(Cl)n1
Product: CC(C)Nc1nc(Cl)c(C#N)c(NC2CC2)n1

Procedure:
This compound was prepared in the manner of Example XVII, substituting 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile and cyclopropylamine for 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile and isopropylamine, producing 4-chloro-6-cyclopropylamino-2-isopropylamino-5-pyrimidinecarbonitrile. Upon recrystallization from methylcyclohexane, the melting point was 157°-160°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccc(CCN3CCN(c4nsc5ccccc45)CC3)cc2o1

Procedure:
To a 125 ml round-bottomed flask equipped with condenser were added 4.82 grams (0.022 mol) of N-(3-benzoisothiazolyl)piperazine (prepared according to the procedure given in U.S. Pat. No. 4,411,901), 5.32 grams (0.022 mol) of 6-(2-bromo)ethylbenzoxazolone, 2.33 grams (0.022 mol) of sodium carbonate, and 50 ml of methyl isobutyl ketone. The mixture was refluxed for 18 hours. The reaction was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was isolated, washed with water and saturated aqueous sodium chloride solution dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using ethyl acetate as eluent, and the product fractions collected and triturated with methylene chloride/isopropyl ether to give a white solid, 1 m.p. 185°-187° C. NMR (CDCl3): 1.7 (bs, 1H), 2.8 (m, 8H), 3.6 (m, 4H), 6.9-8.0 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9](I)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCI
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccnc1Br
Reaction time: 2.5 h

Procedure:
A mixture of 2-bromopyridin-3-ol (3.00 g), ethyl iodide (3.44 ml), anhydrous potassium carbonate (4.28 g) and dry dimethylformamide (34 ml) is stirred under nitrogen at 80°-85° for 2.5 hrs, concentrated to remove solvent, diluted with ethyl acetate (75 ml) and water (40 ml), and the layers are separated. The aqueous phase is extracted with ethyl acetate (75 ml) and the combined organic phase is washed with saline (30 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 7.97, 7.20, 7.12, 4.11 and 1.50δ.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP([CH2:16][CH2:17][CH3:18])(=O)O1)=O.Cl.[O:20]1[C:25]2([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH2:24][NH:23][CH2:22][CH2:21]1.[CH3:38][C:39]1[S:43][C:42]([C:44](O)=[O:45])=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:24][CH2:25][CH2:26][CH:17]([CH3:16])[CH3:18].[CH3:38][C:39]1[S:43][C:42]([C:44]([N:23]2[CH2:24][C:25]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[O:20][CH2:21][CH2:22]2)=[O:45])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Reactant: Cc1ccc(C(=O)O)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C)C
Product: Cc1ccc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Reaction time: 16 h

Procedure:
1-Propanephosphonic acid cyclic anhydride (1.57M solution in THF, 0.64 mL) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.26 g), 5-methylthiophene-2-carboxylic acid (0.142 g) and triethylamine (0.84 mL) in DMF (8 mL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic solutions were washed with water (2×100 mL) and brine (100 mL), then dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate:isohexane, 1:1 to give the subtitled compound as a clear oil. Yield 0.32 g.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:40][OH:41]>C1COCC1.C(O)(C)(C)C>[OH:41][NH:40][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][NH:14][C:12]([C:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])[CH:21]=[CH:20][CH:19]=1
Reactant: NO
Reactant: O=C(O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a solution of 4-{[3-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]oxy}butanoic acid obtained in Reference Example 44 (90.0 mg, 0.236 mmol) in THF (2 mL) were added DMF (0.02 mL) and oxalyl chloride (59.9 mg, 0.472 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added a mixed solution of 50% aqueous hydroxylamine solution (0.5 mL), tert-butanol (0.5 mL) and THF (0.5 mL) at 0° C., and the mixture was stirred for 15 min. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm) to give a yellow powder. The obtained powder was recrystallized from ethyl acetate-hexane to give the title compound as a pale-yellow powder (8.0 mg, 9%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([NH:40][C:41]3[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=3)[C:37]3=[C:53]([CH3:57])[N:54]=[C:55]([CH3:56])[N:36]3[N:35]=2)=[CH:30][CH:29]=1>>[CH3:57][C:53]1[N:54]=[C:55]([CH3:56])[N:36]2[C:37]=1[C:38]([NH:40][C:41]1[CH:42]=[C:43]([O:51][CH3:52])[C:44]([O:49][CH3:50])=[C:45]([O:47][CH3:48])[CH:46]=1)=[N:39][C:34]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:1](=[O:5])[CH2:2][CH3:3])=[CH:33][CH:32]=1)=[N:35]2
Reactant: CCC(=O)O
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCC(=O)Nc1ccc(-c2nc(Nc3cc(OC)c(OC)c(OC)c3)c3c(C)nc(C)n3n2)cc1

Procedure:
13 mg (0.17 mmol) of propionic acid, 23 mg (0.17 mmol) of HOBt, 47 mg (0.46 mmol) of 4-methylmorpholine, 33 mg (0.17 mmol) of EDC and 65 mg (0.21 mmol) of N-[2-(4-aminophenyl)-5,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are reacted analogously to example 2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.[ClH:14].O1CCOCC1>C(O)C.C(OCC)C>[ClH:14].[N:9]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: c1cn[nH]c1
Reactant: Nc1cc(I)ccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1cc(-n2cccn2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 20 mL reaction vessel was charged with 4-iodopyridin-2-amine (1.5 g, 6.8 mmol) and 1H-pyrazole (4.0 g, 58.9 mmol). Concentrated hydrochloric acid (1.5 ml) and 1,4-dioxane (1.5 mL) were added, and the reaction vessel was sealed. The mixture was irradiated in a microwave oven at 120° C. for 45 min and then at 130° C. for 60 min. The mixture was cooled to rt and then diethyl ether (6 ml) and ethanol (3 ml) were added. The mixture was sonicated for 10 min, and the solid was collected by filtration and washed with diethyl ether and n-hexane to give 4-(1H-pyrazol-1-yl)pyridin-2-amine hydrochloride (1.2 g, 90%) as a white solid. LCMS (ESI) m/z 161 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH3:16])=[CH:12]OCC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:17][OH:18].[CH2:19](O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[N:17][O:18][C:12]=2[CH3:19])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCO
Reactant: CCOC=C(C)S(=O)(=O)c1ccc(Cl)cc1
Solvent: O
Product: Cc1oncc1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 10 gram suspension of 2-(4-chlorophenylsulfonyl)-1-ethoxypropene in 30 ml of ethanol was added with a solution of 1.1 equivalent of hydroxylamine in 20 ml of water. The mixture was then stirred at room temperature for 2 hours, chilled in an ice-water bath for 30 minutes and filtered. The resulting solid was crystallized in ethanol and water to provide 8.0 grams of 4-(4-chlorophenylsulfonyl)-5-methylisoxazole.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19]>CCO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:9]([C:8]([OH:13])=[O:12])[C:20]2[C:18](=[CH:17][C:16]([O:15][CH3:14])=[C:22]([O:23][CH3:24])[CH:21]=2)[N:19]=1
Reactant: CC(=O)C(=O)O
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1cccs1
Solvent: CCO
Product: COc1cc2nc(-c3cccs3)cc(C(=O)O)c2cc1OC
Reaction time: 8 h

Procedure:
To a boiling solution of 2-thiophenecarboxaldehyde (1.22 ml), pyruvic acid (0.904 ml) and 50 ml absolute EtOH is added dropwise a solution of 3,4-dimethoxyaniline (2.00 g) in 100 ml EtOH. The mixture is refluxed for approximately 4 hours, then stored at room temperature overnight. The greenish-yellow precipitate is collected by filtration, washed with fresh EtOH then with ether and allowed to air dry to obtain 2-(thien-2-yl)-4-carboxy-6,7-dimethoxyquinoline (m.p. 260°-263° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.OCC1C=CNN=1.[Na].[CH2:16]([OH:19])[CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][O:19][CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1
Reactant: ClCc1cc[nH]n1
Reactant: OCCO
Agent: OCc1cc[nH]n1
Agent: [Na]
Product: OCCOCc1cc[nH]n1

Procedure:
3-Chloromethylpyrazole, prepared by reacting 3-hydroxymethylpyrazole witth thionyl chloride, is reacted with the sodium salt of ethylene glycol to give 3-(2-hydroxyethoxymethyl)pyrazole. Treatment of 3-(2-hydroxyethoxymethyl)pyrazole with thionyl chloride gives 3-(2-chloroethoxymethyl)pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.C[N:19](C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(N(C(C)C)C(C)C)C.[F:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][C:50]=1[C:51]1[C:52]([C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)=[N:53][C:54]([NH2:58])=[C:55](N)[CH:56]=1>CN(C=O)C>[NH2:58][C:54]1([NH:19][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][N:9]=[CH:10][C:2]=2[Cl:1])[NH:53][C:52]([C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)=[C:51]([C:50]2[CH:49]=[CH:48][N:47]=[CH:46][C:45]=2[F:44])[CH:56]=[CH:55]1
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1(NC(=O)c2ccncc2Cl)C=CC(c2ccncc2F)=C(c2cccnc2)N1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-chloroisonicotinic acid (0.075 g, 0.48 mmol), N—[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (0.178 g, 0.47 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.15 mL, 0.86 mmol) in DMF (1 mL) was stirred 15 minutes. Finally, 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.11 g, 0.39 mmol) in DMF (2.9 mL) was added and the mixture was stirred at room temperature 3.5 hours. The crude mixture was extracted between ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue (0.195 g) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[CH3:34][NH:35][CH3:36].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:35]([CH3:36])[CH3:34])=[O:20])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 50, a tetrahydrofuran solution (2.0M, 0.21 ml, 0.42 mmol) of dimethylamine, 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) at room temperature, followed by stirring at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (35 mg, 0.066 mmol, 90%) as a white powder.