Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:39]1[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:56])[CH3:55])[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:40]1[O:41][C:42](=[O:44])[CH3:43])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C(OCC)(=O)C>[C:47]([O:46][C@H:45]1[C@@H:40]([O:41][C:42](=[O:44])[CH3:43])[C@H:39]([N:15]2[CH:14]=[N:13][C:12]3[C:16]2=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=3[NH:10][CH2:9][CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:51][C@@H:50]1[CH2:52][O:53][C:54](=[O:56])[CH3:55])(=[O:49])[CH3:48]
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A suspension of N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulfonamide hydrochloride (Preparation 8) (0.21 g, 0.42 mmol) in 1,1,1-trichloroethane (10 ml) was treated with N,O-bis(trimethylacetamide) (0.6 ml, 2.45 mmol) and the mixture was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was azeotroped with toluene (×2). The residue was dissolved in toluene (10 ml) and treated with the β-D-ribofuranose-1,2,3,5-tetraacetate (0.16 g, 0.50 mmol) and trimethylsilyltriflate (0.1 ml, 0.5 mmol). The mixture was then heated at reflux for 4 hours. The mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and brine and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2 by volume) gradually changing to dichloromethane:methanol (95:5 by volume) to afford the title compound as a 1:3 mixture of α-and β-anomers (188 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.FC1C=CC(O)=CC=1.C([O:29][C@@H:30]1[C@H:34]([O:35]C(=O)C2C=CC=CC=2)[C@@H:33]([CH2:44][O:45]C(=O)C2C=CC=CC=2)[O:32][C@H:31]1[N:54]1[CH:62]=[N:61][C:60]2[C:55]1=[N:56][C:57]([Cl:64])=[N:58][C:59]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:64][C:57]1[N:58]=[C:59]([NH:10][C@H:8]([CH3:9])[CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[C:60]2[N:61]=[CH:62][N:54]([C:55]=2[N:56]=1)[C@@H:31]1[O:32][C@H:33]([CH2:44][OH:45])[C@@H:34]([OH:35])[C@H:30]1[OH:29]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)COc1ccc(F)cc1
Agent: Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](COc1ccc(F)cc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
(R)-1-(4-fluorophenoxy)-2-propylamine (0.29 g, 1.4 mmol)(prepared from 4-fluorophenol by the method desrcribed in example 2) was reacted with 9-(2',3',5'-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.89 g, 1.4 mmol) in dioxan (30 ml) in the presence of triethylamine (0.42 g, 3 mmol). The reaction mixture was stirred at room temperature for 18 h, and heated at 60° C. for 4 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash chromatography. The resultant 2',3',5'-tri- O-benzoyl-2-chloro- N-[(R)-1-(4-fluorophenoxy)-2-propyl]adenosine was deprotected using methanolic ammonia to provide the title 2-chloro- N-[(R)-1-(4-fluorophenoxy)-2-propyl]adenosine (0.21 g, 40%)(after column chromatography), mp 172°-173° C.; 1H NMR (DMSO-d6)δ 1.29 (3H, d, --CH3), 3.52-3.60 (1H, m, H-5'a), 3.64-3.72 (1H, m, H-5'b), 3.92-4.00 (2H, m, H-4' and --C--H), 4.05-4.20 (2H, m, H-3' and --C--H), 4.53 (1H, m, H-2'), 4.65 (1H, m, --CH3C H--), 5.08, 5.24, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.86 (1H, d, H-1'), 6.89-7.15 (4H, 2 m, Ar--H), 8.30-8.46 (2H, m, H-8 and N--H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogen carbonate (2.87 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(4-methylbenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.53 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)NC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (2.0 g, 6.8 mmol), 2-amino-N-(1-methylethyl)benzamide (1.2 g, 7.1 mmol), di-isopropyl-ethylamine (1.4 mL, 8.1 mmol) and 30 mL isopropanol. The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to 0° C. and filtered and solid was washed with diethyl ether to afford 2-[(2,5-dichloro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (2.0 g, 90%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.[CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])[CH3:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:27]([N:30]1[CH2:35][CH2:34][N:33]([C:19]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:25])[CH2:32][CH2:31]1)([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 197.8 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.4 g, 21.9 mmol) in DCM (100 mL) was carefully added DMAP (5.3 g, 43.8 mmol) and triphosgene (3.2 g, 10.95 mmol) portionwise. After stirring at rt for 2 h, 1-isopropylpiperazine (3.3 g, 26 mmol) was added and the reaction mixture was stirred at rt for 5 h. The reaction was quenched with saturated NH4Cl (100 mL) solution and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with saturated NH4Cl (2×100 mL) and brine (50 mL) sequentially, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid (7.7 g, 99%). [LCMS: Rt=1.67 min, m/z 356.3 (M+H)+].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=CC=1)[C:5]([NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6].[O:20]1C=CC(C(O)=O)=C1.C(N)/C=C/C1C=CC=CC=1>>[CH2:8]([NH:7][C:5]([C:4]1[CH:3]=[CH:2][O:20][CH:17]=1)=[O:6])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccoc1
Reactant: O=C(NC/C=C/c1ccccc1)c1cccc(Cl)c1
Agent: NC/C=C/c1ccccc1
Product: O=C(NC/C=C/c1ccccc1)c1ccoc1

Procedure:
(E)-N-Cinnamyl-3-furancarboxamide may be obtained in the following manner: working as in Example 21 for the preparation of (E)-3-chloro-N-cinnamylbenzamide, but starting with 3-furancarboxylic acid (4 g) and (E)-cinnamylamine (4 g), and after recrystallization in isopropyl ether, (E)-N-cinnamyl-3-furancarboxamide (3.9 g), m.p. 115° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N[C@@H:11]([C:16]([OH:18])=[O:17])[C:12]([SH:15])([CH3:14])[CH3:13].C(=O)([O-])[O-:20].[K+].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:7][C@@H:11]([C:16]([OH:18])=[O:17])[C:12]([SH:15])([CH3:14])[CH3:13])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(S)[C@@H](NC(=O)c1ccc(Cl)cc1)C(=O)O

Procedure:
27.5 g (0.2 mole) 4-chlorobenzonitrile, 29.8 g (0.2 mole) D-penicillamine and 13.8 g (0.1 mole) potassium carbonate were heated in 350 ml methanol and 150 ml water for 6 hours at the boiling point. After the mixture was acidified with concentrated hydrochloric acid to pH 4, it was heated one hour under nitrogen at the boiling point. After it cooled off, 42.6 g (74% of theory) of a colorless precipitate was isolated, which had a melting point of 174° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=2)[C:6]=1CC#N.[OH-:25].[Na+].[CH2:27]([OH:29])[CH3:28]>>[Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=2)[C:6]=1[CH2:28][C:27]([OH:25])=[O:29]
Reactant: CCO
Reactant: [OH-]
Reactant: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC#N)ccc1O
Agent: [Na+]
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Reaction time: 4 h

Procedure:
4-Chloro-5-cyanomethyl-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole (1 g) was dissolved in 10 ml of ethanol, and 10 ml of 2 N-sodium hydroxide was added. The mixture was boiled for 4 hours and evaporated to dryness, and the residue was shaken with 20 ml each of chloroform and water. The aqueous layer was washed with chloroform and 10 ml of 2N-hydrochloric acid was added. The resulting syrupy precipitate was recrystallized from aqueous ethanol to give 0.5 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 192°-195° C. (decompn.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH2:11].C(N(CC)CC)C.[C:20](Cl)(Cl)=[O:21].C1(C)C=CC=CC=1.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[N-]=C=O>C1COCC1>[CH3:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][C:20]([S:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21])=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1cc(C)ccc1N
Reactant: Sc1ccccc1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)ccc1NC(=O)Sc1ccccc1
Reaction time: 1 h

Procedure:
2-Amino-5-methylbenzoic acid methyl ester (122 mg, 0.79 mmol) and triethylamine (0.28 ml, 1.96 mmol) were dissolved in THF (10 ml). A 20% solution of phosgene in toluene (0.74 ml, 1.6 mmol) was added, causing immediate formation of a white precipitate. After 1 h, excess phosgene was purged with a stream of nitrogen, the vented gas being passed through a base scrubber. Thiophenol (81 μl, 0.79 mmol) was added to this crude isocyanate solution, which was then stirred for 1 h. The mixture was filtered to remove triethylamine hydrochloride, the solid being washed with ether. After concentration of the filtrate, the residue was purified by flash chromatography (5% to 10% EtOAc/petrol) to give 5-methyl-2-phenylsulfanylcarbonylaminobenzoic acid, methyl ester: m/z (ES+) 300 (M−H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([CH:16]([C:18]2[CH:28]=[CH:27][C:21]3[O:22][C:23]([F:26])([F:25])[O:24][C:20]=3[CH:19]=2)O)[CH2:15][CH2:14]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[CH:13]1([CH:16]([C:18]2[CH:28]=[CH:27][C:21]3[O:22][C:23]([F:25])([F:26])[O:24][C:20]=3[CH:19]=2)[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:14][CH2:15]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc2c(c1)OC(F)(F)O2)C1CC1
Agent: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from Example 8A and 644 mg (2.82 mmol) of the compound from Example 157A in analogy to the synthesis of the compound from Example 227. A difference was that stirring at RT was for 45 min. 661 mg (60% of theory) of the target compound were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7](=[O:21])[C:8]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:9]=3[NH:10][C:11](=[O:15])[C:12]=2[O:13]C)=[CH:2]1>Cl.C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:8]2[C:7](=[O:21])[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[C:12]([OH:13])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: COc1c(-c2ccsc2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccsc2)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
A solution of 4-(3-thienyl)-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.74 g) in 2.4N HCl/THF (1:1, 600 mL) was allowed to stir at room temperature for 48 hours. The reaction mixture was partitioned between ether and water. The organic portion was dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized twice from ethyl acetate/hexanes (2:1) to afford the title compound (0.173 g); mp 248 C. (dec.); NMR: 11.75 (bs, 1), 10.45 (bs, 1), 7.80 (d, 1, J=8.6), 7.64 (m, 1), 7.48 (m, 2), 7.33 (dd, 1, J=8.6, 2.0), 7.15 (dd, 1, J=5.0, 1.2). Analysis for C14H803NSCl: Calculated: C, 55.00; H, 2.64; N, 4.58; Found C, 54.77; H, 2.81; N, 4.56
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:47])[NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][C:19]([S:26]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([O:39]C6C=CC(C)=CC=6)(=[O:38])=[O:37])[CH:31]=5)(=[O:28])=[O:27])=[CH:20][C:21]=4[OH:25])[CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:48]([NH:51][C:52]2[CH:53]=[C:54]([S:58]([O:61]C3C=CC(C)=CC=3)(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=2)(=[O:50])=[O:49])[CH:3]=1.[Na+].[Na+].S(C1C=C(NS(C2C=C3C(C=CC(NC(NC4C=C5C(C=CC(S([O-])(=O)=O)=C5)=CC=4)=O)=C3)=CC=2)(=O)=O)C=CC=1)(O)(=O)=O.S(C1C=C(NS(C2C=C3C(C=CC(NC(NC4C=C5C(C=CC(S([O-])(=O)=O)=C5)=CC=4)=O)=C3)=CC=2)(=O)=O)C=CC=1)(O)(=O)=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:47])[NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][C:19]([S:26]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([OH:39])(=[O:37])=[O:38])[CH:31]=5)(=[O:28])=[O:27])=[CH:20][C:21]=4[OH:25])[CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:48]([NH:51][C:52]2[CH:53]=[C:54]([S:58]([OH:61])(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=2)(=[O:50])=[O:49])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(NS(=O)(=O)c3cc(O)c4ccc(NC(=O)Nc5ccc6c(O)cc(S(=O)(=O)Nc7cccc(S(=O)(=O)Oc8ccc(C)cc8)c7)cc6c5)cc4c3)c2)cc1
Agent: O=C(Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1)Nc1ccc2ccc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1
Agent: [Na+]
Product: O=C(Nc1ccc2c(O)cc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1)Nc1ccc2c(O)cc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1

Procedure:
This compound was prepared from compound 11 according to the procedure described for the synthesis of compound 12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[C:10]([CH3:16])[CH:11]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.6 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-5-carboxylic acid (1.4 g), 5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.9 g) and diethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.3 g), melting point: 165° C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TsCl (7.22 g, 37.9 mmol) was added portionwise to a solution of alcohol (9) (4.0 g, 34.44 mmol), Et3N (7.0 g, 69 mmol) and DMAP (0.05 g, 0.35 mmol) in dry DCM (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and further stirred for 1 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzene-sulfonate (10) as white solid. Yield (8.5 g, 91%); 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 3.87 (d, J=6.4 Hz, 2H), 3.78 (dd, J=11.2, 4.2 Hz, 2H), 3.22 (dt, J=11.6, 1.6 Hz, 2H), 2.42 (s, 3H), 1.88-1.79 (m, 1H), 1.46 (dd, J=12.8, 1.6 Hz, 2H), 1.18-1.07 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1>>[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@@H:27]([NH:30][CH2:2][CH2:3][OH:4])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1
Reactant: Cc1cncc2cccc(N[C@H]3CC[C@@H](N)CC3)c12
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: Cc1cncc2cccc(N[C@H]3CC[C@@H](NCCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 120 to obtain the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].[CH2:29]([NH2:33])[CH:30]([NH2:32])[CH3:31]>>[NH2:32][CH:30]([CH3:31])[CH2:29][NH:33][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:26])([F:25])[F:27])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CC(N)CN
Product: CC(N)CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 140 °C
Yield: 85 %

Procedure:
A mixture of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid methyl ester (0.200 g, 0.502 mmol) and propane-1,2-diamine (2 mL) was heated in a sealed tube at 140° C. for 12 hours. The mixture was cooled and concentrated under high vacuum to remove excess amount of propane-1,2-diamine. The residue was purified by column chromatography to afford 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-aminopropyl)amide (0.188 g, 85%) as a white foam. 1H NMR (300 MHz, MeOH-d4) δ 7.92 (d, J=9.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.78-7.61 (m, 2H), 7.50 (d, J=7.3 Hz, 1H), 7.30 (d, J=9.6 Hz, 1H), 4.00-3.82 (m, 4H), 3.72 (t, J=4.9 Hz, 2H), 3.45-3.23 (m, 5H), 1.10 (d, J=6.3 Hz, 3H). MS (ES+) m/z 437.0 (M+1).
Reaction SMILES: Cl([O-])=O.[Na+].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[F:14].C([OH:19])(C)(C)C.O>C(OCC)(=O)C>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:19])=[O:11])=[CH:8][C:7]=1[F:14]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CC(C)(C)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Cl)c(F)c1
Reaction time: 96 h

Procedure:
Sodium chlorite (17 g) was added dropwise to a mixture of 4-chloro-3-fluorobenzaldehyde (10 g), amidesulfuric acid (18 g), tert-butyl alcohol (50 mL), and water (50 mL) under ice cooling. The temperature of the mixture was returned gradually to room temperature, and the mixture was stirred for 4 days. The reaction mixture was diluted with ethyl acetate, and the resultant mixture was washed with water, 1N hydrochloric acid, and saturated brine. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The residue was recrystallized from a solvent mixture of diisopropyl ether and hexane, to thereby give the title compound (11.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.C(Cl)CCl.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(c1ccc(Br)cc1F)N1CCOCC1
Temperature: 25 °C
Yield: 77 %

Procedure:
4-Bromo-2-fluorobenzoic acid (5.00 g, 22.8 mmol, 1.00 equiv) and EDC (5.23 g, 27.4 mmol, 1.20 equiv) were dissolved in dichloromethane (100 mL). Morpholine (4.77 mL, 54.8 mmol, 2.40 equiv) was added and the solution was maintained at room temperature for 19 h. The reaction mixture was concentrated en vacuo and diluted with EtOAc and 1N HCl. The phases were separated and the organic phase was washed sequentially with water, saturated NaHCO3, and saturated NaCl. The organic phase was subsequently dried over Na2SO4, filtered and concentrated to afford 5.06 g (81%) of a colorless oil which was used without further purification in the next step. MS (ES) m/e 289 [M+H]+.