Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[C:27]([O:31][C:32]([NH:34][C:35]1[CH:58]=[CH:57][C:38]([CH2:39][N:40]2[CH2:44][CH2:43][N:42]([C:45]3[S:49][C:48]([C:50]([O:52]CC)=[O:51])=[C:47]([CH3:55])[CH:46]=3)[C:41]2=[O:56])=[CH:37][CH:36]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:34][C:35]1[CH:58]=[CH:57][C:38]([CH2:39][N:40]2[CH2:44][CH2:43][N:42]([C:45]3[S:49][C:48]([C:50]([OH:52])=[O:51])=[C:47]([CH3:55])[CH:46]=3)[C:41]2=[O:56])=[CH:37][CH:36]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)cc1C
Agent: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Product: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)O
Yield: 64 %

Procedure:
Following the procedure as described in Example 54, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)-thiophene-2-carboxylate with ethyl 5-(3-(4-(tert-butoxycarbonylamino)benzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a pinkish solid in 64% yield: 1H NMR (300 MHz, DMSO-d6) δ 9.35 (br s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.27 (s, 1H), 4.31 (s, 2H), 3.85-3.76 (m, 2H), 3.45-3.36 (m, 2H), 2.39 (5, 3H), 1.46 (5, 9H); MS (ES−) m/z 430.4 (M−1).
Reaction SMILES: [CH3:1][C:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:6][CH2:7][N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[C:9]1=[O:21])[C:3](O)=[O:4].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]1[O:62][NH2:63]>C(Cl)Cl>[CH3:1][C:2]([S:22]([CH3:25])(=[O:23])=[O:24])([CH2:6][CH2:7][N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[C:9]1=[O:21])[C:3]([NH:63][O:62][CH:57]1[CH2:58][CH2:59][CH2:60][CH2:61][O:56]1)=[O:4]
Reactant: NOC1CCCCO1
Reactant: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)O)S(C)(=O)=O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoic acid (109.4 mg, 0.301 mmol) in methylene chloride (3 mL) at ambient temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80.7 mg, 0.421 mmol), 1-hydroxy benzotriazole monohydrate (83 mg, 0.542 mmol), triethyl amine (75 uL, 0.542 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (53 mg, 0.452 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and washed successively with sat. aqueous sodium bicarbonate, aqueous HCl (1 N) and water. The organic extracts were dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated to afford 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 137.3 mg
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16]Br)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=1)[OH:18])=[N+:27]=[N-:28]
Reactant: CS(=O)(=O)Nc1cc(C(O)CBr)ccc1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1
Reaction time: 120 h
Yield: 93.3 %

Procedure:
To a stirred solution of N-[2-benzyloxy-5-(2-bromo-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (15.05 g, 38 mmol) in dimethyl sulfoxide (150 ml) was added sodium iodide (3.76 g, 376 mmol) and sodium azide (9.48 g, 150 mmol). The mixture was stirred for 5 days under nitrogen atmosphere. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was triturated with water and hexanes to give the title compound as a yellow solid (12.85 g, 94%): 1H NMR (300 MHz, CDCl3) δ 2.93(s, 3 H), 3.47(d, J=5.4 Hz, 2 H), 4.84(t, J=5.4 Hz, 1 H), 5.11(s, 2 H), 6.80(s, 1 H), 6.99(d, J=8.4 Hz, 1 H), 7.15(dd, J=8.4 Hz, 2.1 Hz, 1 H), 7.26(s, 1 H), 7.30-7.50(m, 5H), 7.53(d, J=2.1 Hz, 1 H); MS (ES) m/z 361.4 ((M−H)−, 70%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:16]=1)=[O:10].Cl.[CH3:31][O:32][NH2:33]>CO.O>[CH3:31][O:32]/[N:33]=[C:2]1/[C@H:3]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:16]=2)=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7]/1
Reactant: CON
Reactant: O=C(N[C@@H]1CCCCC1=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: Cl
Solvent: O
Solvent: CO
Product: CO/N=C1\CCCC[C@H]1NC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.2 %

Procedure:
To a solution of 100 mg of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid ((R)-2-oxo-cyclohexyl)-amide in 0.5 ml methanol and 0.5 ml water, was added 98 mg O-methylhydroxylamine hydrochloride and the mixture was stirred at ambient temperature for 3.5 h. The solvents were evaporated and the residue was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 91 mg of the title compound as white foam. MS (EI): 457.3 (M+H).
Reaction SMILES: [CH2:1]([C@:3]1([C:32]([O:34]C)=[O:33])[CH2:7][CH2:6][CH2:5][C@H:4]1[N:8]([CH3:31])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:2].[OH-].[Na+].Cl.C(N(CC)CC)C>>[CH2:1]([C@:3]1([C:32]([OH:34])=[O:33])[CH2:7][CH2:6][CH2:5][C@H:4]1[N:8]([CH3:31])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH3:2]
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC[C@]1(C(=O)O)CCC[C@H]1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 100 °C

Procedure:
According to the procedure of Example 56, Step 4, methyl (1S,2R)-1-ethyl-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (147 mg, 0.296 mmol), 5M sodium hydroxide solution (0.30 mL), triethylamine hydrochloride (936.7 mg, 7 mmol) were heated in a microwave (100° C., 110 min) to provide crude (1S,2R)-1-ethyl -2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid. To this crude residue were added BOP (677 mg, 1.53 mmol), hydroxylamine hydrochloride (634 mg, 9.06 mmol), and triethylamine (2 mL) to provide (1S,2R)-N-hydroxy-1-ethyl-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (79.2 mg, 0.159 mmol, 54%) as a colorless solid after purification via HPLC, eluting with a gradient of 15-100% MeCN/H20 (10 min). LCMS (M−H): 2.53 min, 496.2; 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 0.79-0.85 (m, 3H) 1.13-1.24 (m, 1H) 1.36-1.47 (m, 4H) 1.61-1.73 (m, 1H) 2.12-2.20 (m, 1H) 2.48-2.51 (m, 3H) 2.64-2.66 (m, 3H) 3.89-3.96 (m, 1H) 5.59 (d, J=1.01 Hz, 2H) 7.17-7.22 (m, 2H) 7.50 (s, 1H) 7.55 (ddd, J=8.34, 6.95, 1.14 Hz, 1H) 7.69-7.75 (m, 3H) 7.95-8.03 (m, 2H) 9.21 (s, 1H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][N:15]=2)=[N:8][CH:9]=1)=[O:3].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:18]2[C:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][N:15]=[C:14]([NH:13][CH2:12][CH2:11][NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:2]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:3])=[CH:9][N:8]=3)[N:19]=2)=[CH:21][CH:22]=1)#[N:27]
Reactant: CCOC(=O)c1cnc(NCCNc2ccc(C(=O)Cl)cn2)nc1-c1ccc(C#N)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(NCCNc2ccc(C(=O)N3CCOCC3)cn2)nc1-c1ccc(C#N)cc1

Procedure:
The solution of ethyl 2-({2-[(5-(chlorocarbonyl)(2-pyridyl))amino]ethyl}amino)-4-(4-cyanophenyl)pyrimidine-5-carboxylate in dichloromethane prepared in Step 1 of Example 71 (1.0 ml) was treated at room temperature with a solution of morpholine (150 μL) in dichloromethane (1 ml). After 1 hour the solvent was removed in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:22]([CH2:31][CH3:32])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:22]([CH2:31][CH3:32])=[CH:21][C:20]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCC#N
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCC#N
Reaction time: 24 h
Yield: 70.5 %

Procedure:
4-fluorobenzene boronic acid (1.14 g) was dissolved in ethanol (7 mL). To this was added 1-(benzyloxy)-2-bromo-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene (1.5 g), toluene (20 mL), tetrakis-triphenylphosphine palladium (470 mg), and 2M sodium carbonate solution (6.1 mL). The resulting mixture was heated to reflux and held there for 24 hours. The solution was cooled, diluted with ethyl acetate, and the layers separated. The organic layer was washed with saturated ammonium chloride, dried over magnesium sulfate, filtered, and concentrated to afford a green oil. This was purified by flash chromatography on silica using hexane/ethyl acetate (9:1). The resulting fractions were concentrated under vacuum to afford 1-Benzyloxy-2-(4-fluorophenyl)-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene (1.1 g) as a clear oil. NMR (CDCl3): 1.18, t (3H); 2.15, m (2H); 2.59, m (4H); 4.06, t (2H); 5.00, s (2H); 6.53, s (1H); 7.06, t (2H); 7.09, s (1H); 7.30, m (5H); 7.49, d of d (2H).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[CH3:13][CH2:14]O>>[ClH:12].[CH2:13]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([OH:11])=[O:10])[CH3:14]
Reactant: O=C(O)CNc1ccccc1
Reactant: CCO
Agent: Cl
Product: CCN(CC(=O)O)c1ccccc1

Procedure:
To a mixture of phenylglycine (15.00 gram (hereinafter g.), 0.1 mole (hereinafter mol)) in EtOH (100 miliLiters (hereinafter mL)) was added 20% ethanolic HCl (30 mL). The mixture was heated at reflux for about 20 hours (hereinafter h.), then allowed to cool. The solvent was removed in vacuo, and the residue was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:35])([F:34])[F:33])[CH:4]=1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[OH:38][N:37]=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:33])([F:35])[F:34])[CH:4]=1)[NH2:2]
Reactant: Cc1ccc(-c2cn3nc(-c4ccc(C#N)cc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cn3nc(-c4ccc(C(N)=NO)cc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A 500-mL flask is charged with N-(5-(6-(4-cyano-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (7.496 g, 0.0157 mol), hydroxylamine hydrochloride (6.55 g, 0.0942 mol), Et3N (15.32 mL, 0.1099 mol), ethanol (82.5 mL) and the resulting mixture is stirred for 2 hours at 80° C. The mixture is concentrated onto celite and purified by silica gel chromatography (eluted by 0 to 100% of 10:1 EtOAc:MeOH in CH2Cl2). The isolated solid material (over 20 g) contains triethylamine and hydroxylamine salts, and the salts stay even after attempted recrystallization with isopropanol. This solid product is then added to a stirred mixture of saturated aqueous NaHCO3 and EtOAc. Solid suspension is collected by filtration. The liquid portion is back extracted with EtOAc and the organic layers are combined, dried with Na2SO4, concentrated to afford additional solid product. The combined solid product is dried on a lyophilizer overnight, recrystallized from hot Isopropanol to afford the desired title product (6.56 g). LCMS (m/z)=511.6 [M+H]+, tR=2.49 min.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH:9]([Cl:13])[C:10](Cl)=[O:11].[Cl:14][C:15]([Cl:22])([Cl:21])[CH:16]1[NH:20][CH2:19][CH2:18][S:17]1>CCOCC>[Cl:14][C:15]([Cl:22])([Cl:21])[CH:16]1[N:20]([C:10](=[O:11])[CH:9]([Cl:13])[Cl:8])[CH2:19][CH2:18][S:17]1
Reactant: ClC(Cl)(Cl)C1NCCS1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCSC1C(Cl)(Cl)Cl
Yield: 83.5 %

Procedure:
40 g of triethylamine (0.4 mole), then 43 g of dichloroacetyl chloride (0.3 mole) are added successively, while maintaining the temperature of the reaction mixture at about 0° C. to 41 g of 2-trichloromethyl-1,3-thiazolidine (0.2 mole), dissolved in 300 ml of ether. After the removal of the triethylamine hydrochloride formed in the reaction and washing the organic phase with water, the organic layer is concentrated by stripping part of the ether. By crystallization and filtration, 53 g (yield 82%) of 2-trichloromethyl-3-dichloroacetyl-1,3-thiazolidine of melting point 124° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[NH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N+:7]([O-:20])[CH:6]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(N)(=O)=O)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(N)(=O)=O)c[n+]1[O-]
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 6-methylpyridine-3-sulfonamide (0.5 g, 3 mmol) in chloroform (40 mL) is added mCPBA (1.5 g; 8.7 mmol) and the reaction mixture is stirred overnight under nitrogen. The solvent is evaporated under reduced pressure. The residue is taken up in ACN and the precipitate is filtered off then dried under vacuum to afford 0.4 g (73%) of the title compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.53 (s, 1H), 7.74 (s, 2H), 7.69-7.64 (m, 1H), 7.59-7.52 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1>CC(CC(C)C)=O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:42][CH:39]2[CH2:41][CH2:40]2)[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: c1ccc(COC[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)CN2CC2CC2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.25 g, 0.62 mmol) was dissolved in methyl-isobutylketone (15 ml). Potassium carbonate (0.17 g, 1.2 mmol) and potassium iodide (0.03 g, 0.18 mol) was added. After stirring for 10 min at 25° C. cyclopropylmethylbromide (0.078 ml, 0.81 mmol) was added. The mixture was stirred under a N2 atmosphere at 80° C. for 24 hours and evaporated in vacuo. Water (20 ml) was added and extraction with methylene chloride (3×20 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded a yellow oil. Purification of the crude product twice on a silica gel column (1: Eluent: CH2Cl2/MeOH (19:1) and 2: Eluent: CH2Cl2/MeOH (39:1)) gave (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-cyclopropylmethylpyrrolidine (0.213 g, yield: 75%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C([O:18][CH2:19][CH2:20][CH2:21]Cl)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:21][CH2:20][CH2:19][OH:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(=O)OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCSc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
3-Bromobenzenethiol (0.40 g) and potassium carbonate (0.44 g) were suspended in N,N-dimethylformamide (4.2 mL), 3-chloropropyl acetate (0.34 mL) was added, and the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was partitioned between diethyl ether (40 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (8.5 mL), 28% sodium methoxide-methanol solution (0.08 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give the title compound (0.49 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[CH2:10][C@@H:9]([C:11]([OH:13])=[O:12])[NH:8][CH2:7][CH2:6]1.[CH3:14]O>>[ClH:3].[CH3:14][O:12][C:11]([C@@H:9]1[CH2:10][CH2:5][CH2:6][CH2:7][NH:8]1)=[O:13]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCCN1
Product: COC(=O)[C@@H]1CCCCN1
Product: Cl
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.58 ml) was added dropwise to a solution of L-pipecolinic acid (450 mg) in methanol at room temperature. The reaction mixture was stirred at 55° C. for 2 hours. The whole mixture was evaporated under reduced pressure to give (2S)-piperidine-2-carboxylic acid methyl ester hydrochloride as a colorless oil.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[C:24]4[CH:31]=[C:30]([CH2:32][OH:33])[NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:8][CH:7]=1.O1CCCC1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[C:24]4[CH:31]=[C:30]([CH:32]=[O:33])[NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:20][CH:21]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(CO)cc23)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
After adding 3 ml of chloroform and 50 mg of manganese dioxide to 18 mg of 1-(4-fluorophenyl)-3-[4-(6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea, the mixture was stirred overnight at room temperature. Tetrahydrofuran and ethyl acetate were added to the reaction system, and the mixture was filtered with celite and concentrated to dryness to obtain 16 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][NH:14][CH3:15])([CH3:3])[CH3:2].[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][N:14]([CH3:15])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:22]1[CH:23]=[N:24][C:25]2[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=2[CH:21]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1oc2ccccc2c1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a solution of (3-isopropylbenzofuran-2-yl)-N-methylmethanamine (115 mg, 0.57 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (111 mg, 0.51 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), diisopropylethylamine (289 uL, 1.54 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (109 mg, 0.57 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield the title compound as a white solid (38 mg, 17%): 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.75-7.73 (d, J=7.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.26-7.18 (m, 3H), 4.99-4.80 (rotamers, 2s, 2H), 3.40-3.35 (m, 1H), 3.32 (s, 3H), 2.91-2.89 (m, 2H), 2.55-2.53 (m, 2H), 1.37-1.36 (d, J=6.8 Hz, 6H); MS (ESI) m/e 404 (C24H25N3O3+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([N:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: O=C([C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)N1CCOCC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and morpholine. Melting point: 221°-225° C.; Rf : 0.47 (silica gel; petroleum ether/ethyl acetate/methanol=10:8:3)