Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([P:5]([O:11][O:12][CH2:13][CH3:14])([O:7][O:8][CH2:9][CH3:10])=[O:6])=O.O.[NH2:16][NH2:17]>C(O)C>[CH2:9]([O:8][O:7][P:5]([C:3]([NH:16][NH2:17])=[O:2])([O:11][O:12][CH2:13][CH3:14])=[O:6])[CH3:10]
Reactant: CCOOP(=O)(OOCC)C(=O)OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOOP(=O)(OOCC)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
19.6 parts by weight of diethoxyphosphonoformic acid methyl ester are diluted with 10 parts by volume of ethanol, and a solution of 5.0 parts by weight of hydrazine hydrate in 10 parts by volume of ethanol is added at +10 to +20° C. The mixture is stirred at room temperature for 8 hours, the solvent is moved in vacuo and 19.4 parts by weight (yield 99%) of crude diethoxyphosphonoformic acid hydrazide, which is further processed without purification, are obtained.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cccnc2)cc1
Reactant: CN
Solvent: CCO
Product: CNC(C)C/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
A mixture of (4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (5.60 g, 17.66 mmol), methylamine (100 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.60 g (51.6%) of a colorless oil, by 110-120° C. at 0.1 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])([O-])=O.[H][H]>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Nc2ccccc2)cc1N

Procedure:
A mixture of the product obtained at (1a) (19.0 g, 46.3 mmol) in 200 mL of THF was combined with 10% palladium on charcoal (3.0 g) and hydrogenated in a Parr apparatus at ambient temperature for 20 h at 3.5 bar hydrogen pressure. Then the mixture is filtered and the filtrate is concentrated i.vac. The residue is purified by chromatography on silica gel (eluent gradient: dichloromethane/(methanol/conc. ammonia=95:5)=100:0->92:8).
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:6]2[N:7]([N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH2:3][CH3:4].C(N(CC)CC)C>CS(C)=O>[CH3:12][O:11][C:8]1[N:7]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=[C:6]2[C:5]([C:2](=[O:1])[CH2:3][CH3:4])=[CH:10][CH:9]=1
Reactant: CCC(O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
The compound of Example 135 (32.1 g) was dissolved in DMSO (780 mL) in an argon atmosphere. To this solution, triethylamine (163 mL) and sulfur trioxide-pyridine complex (93.1 g) were sequentially added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into ice water and the resulting solid product was collected by filtration. The product was washed with water and dissolved in ethyl acetate. The solution was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as a colorless powder (24.0 g).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N:12]=1)([OH:6])=[O:5].C(OC(=O)C)C>CCOCC>[C:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N:12]=1)([O:6][CH3:3])=[O:5]
Reactant: O=C(O)CCCNc1nc2ccccc2c(=O)o1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)CCCNc1nc2ccccc2c(=O)o1
Reaction time: 3 h

Procedure:
A solution of diazomethane in ether is added dropwise to a solution of 2-(3-carboxy-propylamino)-4H-3,1-benzoxazin-4-one in ether. The reaction is monitored by thin layer chromatography (silica gel, 10% ethylacetate in petroleum ether) until completion. A small amount of silica gel is added to the solution. The solution is allowed to stand for 3 hours, then filtered. The filtrate is evaporated to give 2-(3-carbomethoxypropylamino)-4H-3,1-benzoxazin-4-one.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][NH:6][C:7](=[O:9])[CH:8]=1.[Cl:12][C:13]1(F)[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]1(F)F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([N:6]2[C:7](=[O:9])[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:4]=[CH:5]2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:2]([F:11])([F:10])[F:1]
Reactant: O=[N+]([O-])C1=CC(F)(F)C(F)(Cl)C([N+](=O)[O-])=C1Cl
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)ncn1-c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-trifluoromethylpyrimidin-6-one (0.48 g), 2,4-dichloro-3,5-dinitrotrifluorobenzene (0.9 g) and potassium carbonate (0.41 g) in dry dimethylformamide (10 ml) was vigorously stirred at ambient temperature for a period of 15 minutes. The reaction mixture was then poured into water, and extracted into ethyl acetate. After drying and evaporation of the solvent, under reduced pressure, the residue was subjected to chromatography on silica gel using 30% (by volume) ethylacetate in petroleum ether (boiling range 60°-80° C.) as eluent. The required fractions were combined, and the solvent removed under reduced pressure to give a yellow solid, which was then triturated with petroleum ether (boiling range 60°-80° C.). The solid was dissolved in boiling ethanol, filtered, and the solvent removed under reduced pressure. The residue was again triturated with petroleum ether (boiling range 60°-80° C.) and finally recrystallised from petroleum ether (boiling range 60°-80° C.) containing ethylacetate (9% by volume) to give 1-(3-chloro-2,6-dinitro-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one as a yellow solid:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[O:9]([CH2:16][CH2:17][OH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:18][CH2:17][CH2:16][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCOc1ccccc1
Solvent: C1COCCO1
Product: Clc1cncc(OCCOc2ccccc2)n1
Reaction time: 0.08 h

Procedure:
K-t-BuO (1.61 g, 14.3 mmol) was added portionwise to a stirred mixture of 2,6-dichloropyrazine (2.03 g, 13.6 mmol) and 2-phenoxyethanol (2.54 g, 18.4 mmol) in dioxane (8 mL) at 0° C. (ice-bath). After 5 min of stirring, the ice-bath was removed and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ether, filtered and concentrated in vacuo. The oily residue was purified by silica gel chromatography (18×5 cm) using n-hexane/ethyl acetate (92:8) as eluent. This furnished 2.92 g (86%) of the title compound as a white solid. HRMS m/z calcd for C12H11ClN2O2 (M)+ 250.0509, found 250.0511. Anal. (C12H11ClN2O2) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH2:15]>C(O)(C)C.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:15][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CNCCOc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 4-nitro-(2-chloroethoxy)benzene (781 mg, 3.9 mmol) and aqueous methylamine (15 mL, 40 wt. %) in isopropyl alcohol (15 mL) is heated in a sealed tube at 100° for 4 hours. After cooling in an ice water bath, the mixture is poured into brine and extracted 2× with dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-nitro-(2-methylaminoethoxy)benzene (697 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:11][C:4]1[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: NC(=O)c1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Yield: 69.9 %

Procedure:
5-Bromo-3-nitropyridine-2-carboxamide (400 mg, 1.63 mmol), ammonium chloride (435 mg, 8.15 mmol) and iron powder (273 mg, 4.89 mmol) were suspended in methanol (6 mL) and water (3 mL), and stirred at 100° C. for 20 hours. After cooled to room temperature, this was filtered through Celite, and the Celite was washed with methanol. The mother liquid was concentrated, and the residue was dissolved in chloroform and washed with water. The organic layer was concentrated under reduced pressure to obtain the intended compound (246 mg, 70%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[C:22]([OH:24])=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:41]([CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:53](=[N:55]O)[NH2:54])[CH:38]=3)[C:33]2=[O:57])=[CH:28][CH:27]=1>CN(C=O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]1[C:22]1[O:24][N:54]=[C:53]([C:37]2[CH:38]=[C:39]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:57])[N:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[C:41]([CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:40]3)[N:55]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(-c3noc(C4Cc5ccccc5C4)n3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
CDI (21.45 mg, 0.132 mmol) was added to a stirred, room temperature mixture of 2-indanecarboxylic acid (17.88 mg, 0.110 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 2 h. tert-butyl 5-(2-(4-fluorophenyl)-6-(N′-hydroxycarbamimidoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (50 mg, 0.110 mmol) was added, and the resultant mixture was kept stirring at 100° C. for overnight. The reaction was checked with LCMS and starting material disappeared. The mixture was cooled to room temperature, precipitate formed, filtered and washed with water (20 mL), dried in vacuum oven to give tert-butyl 5-(6-(5-(2,3-dihydro-1H-inden-2-yl)-1,2,4-oxadiazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (51 mg, 0.088 mmol) as a light tan solid.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([S:26]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N+:34]([O-])[CH:33]=[CH:32]3)(=[O:28])=[O:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[N:40]1C=CC=CC=1>>[NH2:40][C:35]1[C:36]2[C:31](=[CH:30][C:29]([S:26]([N:22]3[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]3)(=[O:28])=[O:27])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccc3c[n+]([O-])ccc3c2)CC1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccc3c(N)nccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
310 mg of p-toluenesulfonyl chloride was added to a pyridine (20 mL) solution of 510 mg of 6-(4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 2-oxide obtained in Step 1 of Example 53, and the mixture was stirred at room temperature for 16 hours. Then, the reaction solvent was distilled off under reduced pressure. To the obtained residue, 9 mL of 2-ethanolamine was added, and the mixture was stirred at room temperature for 6 hours. After the completion of reaction, the reaction solution was poured into ice water, and the deposited white crystal was collected by filtration. The obtained crystal was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 380 mg of the compound of interest as a white crystal (75%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:39]([CH2:41][C:42](O)=[O:43])#[N:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:39]([CH2:41][C:42]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)=[O:43])#[N:40]
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Reactant: N#CCC(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (75 mg, 0.14 mmol) was dissolved in 4 mL DMF. To it were added 2-cyanoacetic acid (36 mg, 0.42 mmol), DIEA (250 μL, 1.40 mmol) and then PyBOP (150 mg, 0.28 mmol). The mixture was stirred at RT for 45 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (500), as HCl salt (76 mg). LC-MS (ESI): m/z (M+1) 575.3. UV: λ=262, 329, 337 nm.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[OH:10][C@:11]([CH3:47])([CH2:45][OH:46])[C:12](=[O:44])[C@@H:13]([NH:21][C:22](=[O:43])[C@@H:23]([NH:27][C:28](=[O:42])[C@@H:29]([NH:33][C:34]([C:36]1[S:40][C:39]([CH3:41])=[N:38][CH:37]=1)=[O:35])[CH2:30][O:31][CH3:32])[CH2:24][O:25][CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]([F:9])([F:8])[CH2:3][S:4]([O:46][CH2:45][C@:11]([OH:10])([CH3:47])[C:12](=[O:44])[C@@H:13]([NH:21][C:22](=[O:43])[C@@H:23]([NH:27][C:28](=[O:42])[C@@H:29]([NH:33][C:34]([C:36]1[S:40][C:39]([CH3:41])=[N:38][CH:37]=1)=[O:35])[CH2:30][O:31][CH3:32])[CH2:24][O:25][CH3:26])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:6])=[O:5]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)CC(F)(F)F

Procedure:
Prepared according to procedures described above, by reacting 2,2,2-trifluoroethanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C27H35F3N4O10S2 m/z: 697 (M+H)+.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.C([O:36][C:37](=O)[C:38]1[C:39](=[CH:50][CH:51]=[C:52]([Cl:54])[CH:53]=1)[NH:40][C:41](OC1C=CC=CC=1)=[O:42])C1C=CC=CC=1>>[Cl:54][C:52]1[CH:53]=[C:38]2[C:39](=[CH:50][CH:51]=1)[NH:40][C:41](=[O:42])[N:28]([S:25]([C:14]1[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=1)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:37]2=[O:36]
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3ccc(Cl)cc3c2=O)ccc1C(=O)O
Yield: 26 %

Procedure:
From 300 mg (0.74 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 310 mg (0.81 mmol) of 5-chloro-2-N-phenoxycarbonylanthranilic acid benzylester in a similar manner to Preparation Example 17, 75 mg (yield 26%: 4 steps) of the title compound was obtained. Property: colorless crystals, melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6): 7.13-7.20 (2H, m), 7.56 (1H, s), 7.72 (1H, d), 7.82 (1H, s), 7.90 (1H, d), 11.68 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: NCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)NCc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a mixture of 4-(dimethylamino)benzoic acid (915 mg, 5.54 mmol) and triethylamine (772 μL, 5.54 mmol) in CH2Cl2 (25 mL) at 0° C. was added BOP-Cl (1.50 g, 6.09 mmol), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added (4-aminomethylphenyl)methanol (760 mg, 5.54 mmol) and triethylamine (1.54 mL, 11.08 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a 50% aqueous NaHCO3 solution (50 mL), and the mixture was extracted with 5% MeOH in CHCl3 (100 mL×1, 40 mL×2). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by MPLC on silica gel (2% MeOH in CHCl3) to afford the titled compound (1.04 g, 66%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:27]1([CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2[CH2:39][NH2:40])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C(Cl)(Cl)Cl>[C:27]1([CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2[CH2:39][NH:40][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)=[O:13])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: NCC1CCCN1CC1=CCCCC1
Reactant: O=C(O)c1cc(Cl)cc2c1OCC2
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCN1CC1=CCCCC1)c1cc(Cl)cc2c1OCC2
Reaction time: 0.5 h

Procedure:
32 g of 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 130 ml of chloroform and 16 g of triethylamine were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0°-5° C. and 17.5 g of ethyl chloroformate were then added dropwise and the mixture was stirred for 1 hour and 30 minutes. A solution of 34 g of 1-cyclohexenylmethyl-2-aminomethylpyrrolidine in 68 ml of chloroform was then poured in dropwise, between 5° and 10° C., and the mixture was then stirred for 1 hour at 5° C. and for 1 hour at ambient temperature.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]([NH2:28])([CH3:27])[CH2:25][NH2:26]>CN(C=O)C>[NH:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[C:2]([NH:26][CH2:25][C:24]([CH3:27])([NH2:28])[CH3:23])[CH:3]=[CH:4][CH:5]=2)=[N:9]1
Reactant: CC(C)(N)CN
Reactant: Brc1cccc(-c2n[nH]c3ncccc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(N)CNc1cccc(-c2n[nH]c3ncccc23)n1
Temperature: 150 °C
Yield: 65.3 %

Procedure:
A mixture of 3-(6-bromo-2-pyridyl)-1H-pyrazolo[5,4-b]pyridine (50 mg,), potassium carbonate (150.6 mg, 1.09 mmol) and 2-methylpropane-1,2-diamine (40.1 mg, 0.45 mmol) in DMF (0.7 mL) was heated at 150° C. for 24 hours. The mixture was allowed to cool, filtered and the resultant filtrate purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (33.5 mg, 36% Yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[CH3:2][O:3][C:4](=[O:13])[CH:5]([N:12]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(N)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(N=Cc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 8 (40.3 g, 0.2 mol) in dichloromethane (600 mL) was added triethyl amine (24.24 g, 0.24 mol) dropwise. After stirring for 30 min, benzaldehyde (21.2 g, 0.2 mol) was added dropwise, followed by the addition of MgSO4 (240 g, 2 mol). The mixture was stirred overnight. After filtration, the filtrate was evaporated to give compound 9 (49 g, 96.8%). 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 5.22 (s, 1 H), 7.30-7.39 (m, 6 H), 7.53-7.56 (m, 2 H), 7.82-7.85 (m, 2 H), 8.34 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH2:13][OH:14])C(O)=O)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:15])[CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](CCO)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H](CCO)c1ccc(F)cc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (S)-2-(4-fluorophenyl)-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (S)-1-(4fluorophenyl)-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>O1CCCC1.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1F

Procedure:
A solution of 2,5-difluoronitrobenzene in tetrahydrofuran containing Raney nickel catalyst, in a Parr shaker, was treated with hydrogen at room temperature to give 2,5-difluoroaniline (2A).