Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([C:8]2[S:9][CH2:10][C:11](=[NH:13])[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=N)[NH:16]1>CO>[ClH:1].[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[C:10]2[S:9][C:8]([N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[N:12][C:11]2=[NH:13])[NH:16]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(N2CCCCC2)=N1
Agent: Cl
Solvent: CO
Product: N=C1N=C(N2CCCCC2)SC1=C1NC(=N)c2ccccc21
Temperature: 0 °C

Procedure:
To a solution of 21.9 parts of 2-piperidino-4-imino-2-thiazoline hydrochloride in 240 parts of methyl alcohol there was added 14.5 parts of 1,3-diiminoisoindoline. The resultant mixture was heated at reflux for six hours, then chilled to 0° C and filtered. The collected solid was washed with methyl alcohol and dried at 50° C to obtain 27 parts of 1-imino-3-(2-piperidino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride melting at 320°-321° C (dec). The assigned chemical structure was completely corroborated by a concordant nuclear magnetic resonance spectrum. The hydrochloride salt is readily converted to the free base, a colorless solid melting at 226°-227° C, by treatment with dilute ammonium hydroxide. This compound, which corresponds to Formula VIII wherein R, R1, R2 and R3 are each hydrogen and N=B is piperidino, was found on testing in vitro by standard serial dilution procedures to be bacteriostatic versus: Staphylococcus aureus 209 at a minimal concentration of 6.3 parts per million; Esherichia coli at 62.5 parts per million; Pseudomonas aeruginosa 211 at 125 parts per million; and fungicidal versus Tricophyton mentogrophytes at 62.5 parts per million; Aspergillus niger at >125 parts per million; and Candida albicans at 125 parts per million.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[N:12]2[C:26](=[O:45])[C@@H:27]([CH2:33][N:34]([CH:43]=[O:44])[O:35]CC2C=CC=CC=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[N:6][CH:7]=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][NH:13][N:12]2[C:26](=[O:45])[C@@H:27]([CH2:33][N:34]([CH:43]=[O:44])[OH:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[N:6][CH:7]=1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)cn2)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](CN(O)C=O)C(=O)N1NCC[C@H]1C(=O)Nc1ccc(F)cn1
Reaction time: 1.33 h

Procedure:
To a 100 mL round-bottomed flask was added phenylmethyl (3S)-3-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl) heptanoyl]-1-pyrazolidinecarboxylate (696 mg, 1.123 mmol) in methanol (15 ml), followed by Pearlman's catalyst (120 mg). The mixture was stirred under a balloon of H2 for 80 min. The catalyst was filtered off, and the filtrate was concentrated to dryness to provide (3S)—N-(5-fluoro-2-pyridinyl)-2-((2R)-2-{[formyl(hydroxy)amino]methyl}heptanoyl)-3-pyrazolidinecarboxamide as a colorless oil. (420 mg, 94%). LCMS: (M+H)+: 396.0. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.75-1.00 (m, 3H) 1.16-1.39 (m, 6H) 1.47 (dd, J=8.59, 5.56 Hz, 1H) 1.52-1.68 (m, 1H) 2.02-2.31 (m, 1H) 2.49 (ddd, J=12.06, 6.25, 2.65 Hz, 1H) 2.86 (td, J=10.48, 6.06 Hz, 1H) 3.36 (br. s., 1H) 3.39-3.55 (m, 1H) 3.59-3.89 (m, 2H) 4.54-4.72 (m, 1H) 7.53 (ddd, J=9.16, 7.89, 3.16 Hz, 1H) 7.83 (s, 1H) 8.03-8.20 (m, 2H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].C([O-])([O-])=O.[K+].[K+].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O.[BH4-].[Na+]>CO>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:28][C:24]1[O:23][CH:27]=[CH:26][CH:25]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccco1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: Clc1c(OCCNCc2ccco2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 2-[(1-chloronaphthalen-2-yl)oxy]ethanaminium chloride (100 mg, 0.39 mmol) in 10 mL of MeOH, K2CO3 (65 mg, 0.47 mmol) was added. After 10 min, 48 μL (0.58 mmol) of furan-2-carbaldehyde were added. The resulting solution was stirred for 1 h at room temperature, added with sodium borohydride (15 mg, 0.39 mmol) and the reaction was allowed to stir for further 2 h at room temperature. The solvent was evaporated under vacuum; the mixture was diluted with 10 mL CH2Cl2 and transferred to a separatory funnel. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 95:5) to afford 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine as a brown oil (63% yield). The oil was left to stir with a 4M HCl dioxane solution for 1 h. The reaction mixture was concentrated under reduce pressure to afford 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanaminium chloride as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].[CH2:13]=[O:14]>CC(C)=O>[F:12][C:2]([F:1])([C:7]1[CH:11]=[CH:10][N:9]([CH2:13][OH:14])[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)c1cc[nH]n1
Reactant: C=O
Solvent: CC(C)=O
Product: OCn1ccc(C(F)(F)C(F)(F)F)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
The mixture of 1.86 g of 3-(pentafluoroethyl)-1H-pyrazole and 0.60 g of paraformaldehyde was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 1.98 g of 3-(pentafluoroethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH2:1]1[O:42][C:4]2=[CH:5][C:6]3[C:11]4[C:12]5[C:37](=[O:38])[N:36](CO)[C:35](=[O:41])[C:13]=5[C:14]5[C:15]6[C:20]([N:21]([C@@H:23]7[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]7[OH:25])[C:22]=5[C:10]=4[NH:9][C:7]=3[CH:8]=[C:3]2[O:2]1)=[CH:19][CH:18]=[C:17]([OH:34])[CH:16]=6.[NH4+].[OH-]>CO>[CH2:1]1[O:42][C:4]2=[CH:5][C:6]3[C:11]4[C:12]5[C:37](=[O:38])[NH:36][C:35](=[O:41])[C:13]=5[C:14]5[C:15]6[C:20]([N:21]([C@@H:23]7[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]7[OH:25])[C:22]=5[C:10]=4[NH:9][C:7]=3[CH:8]=[C:3]2[O:2]1)=[CH:19][CH:18]=[C:17]([OH:34])[CH:16]=6
Reactant: O=C1c2c(c3c4cc(O)ccc4n([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c3c3[nH]c4cc5c(cc4c23)OCO5)C(=O)N1CO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)c2c1c1c3cc4c(cc3[nH]c1c1c2c2cc(O)ccc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)OCO4
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 16 (30.0 mg, 0.052 mmol) in MeOH (2.0 mL) was added NH4OH (4.0 mL). The mixture was stirred at ambient temperature for 3 hours, then concentrated in vacuo to give a crude solid. Flash silica gel column chromatography eluting with MeOH/AcOH/EtOAc (12/1/87) afforded 26.1 mg (91.1%) as a yellow solid.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35]([O:37][CH2:38][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH2:40][C:41](O)=[O:42])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.COCCOC>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:41](=[O:42])[CH2:40][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[CH2:38][O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:34])[CH3:33])[NH:30][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: COCCOC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2′,3′-dideoxy-3′-fluoroguanosine (1.35 g, 5 mmole), 3,3-bis (N-CBZ-L-valyloxymethyl)-propionic acid (3.6 g, 6 mmole), DMAP (0.061 g, 0.5 mmole) and HOBT (0.81 g, 6 mmole) was coevaporated two times with DME and reduced to about 120 ml. DCC (1.24 g, 6 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH3:15])[CH2:13][C@@:12]([OH:17])([CH3:16])[C@@H:11]2[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:19][O-:20].[Na+].O>CS(C)=O>[OH:17][C@@:12]1([CH3:16])[CH2:13][C@@H:14]([CH3:15])[N:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:20][CH3:19])[CH:9]=2)[C@H:11]1[CH3:18]
Reactant: C[C@@H]1C[C@](C)(O)[C@H](C)N1c1ccc(C#N)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2[C@H](C)C[C@](C)(O)[C@@H]2C)ccc1C#N
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 50.3 %

Procedure:
To a solution (5 mL) of 2-fluoro-4-[(2S,3S,5R)-3-hydroxy-2,3,5-trimethylpyrrolidin-1-yl]benzonitrile (47.6 mg) in DMSO was added sodium methoxide (35 mg) and the mixture was stirred at 100° C. for 3.5 hr. Sodium methoxide (130 mg) was added, and the mixture was stirred at 100° C. for 4.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3) to give the title compound as a colorless solid (yield: 25.1 mg, yield: 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6](N)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Cl.N([O-])=O.[Na+].[I-:18].[K+]>O.CCO>[I:18][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [I-]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(I)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A mixture of 4-methoxy-2-nitroaniline (20 g, 0.12 mol) and concentrated HCl (30 mL) in water (30 mL) is refluxed for 15 min. The reaction mixture is cooled down to 0° C. in an ice bath. A solution of sodium nitrite (10 g, 0.14 mol) in water (30 mL) is added dropwise over 30 min. The resulting solution is stirred at 0° C. for 30 min then added dropwise to a cold solution of potassium iodide (30 g, 0.18 mol) in water (30 mL). The reaction mixture is heated to reflux for 2 h, cooled down to room temperature and diluted with EtOH (200 mL). The organic phase is washed with 3 N (100 mL) then water and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product is purified by column chromatography using hexane as eluent affording 16 g (88%) of the title compound as a yellow crystalline 1H NMR (DMSO-d6, 400 MHz) δ 7.93-7.91 (m, 1H), 7.54 (s, 1H), 7.04-7.01 (m, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]([O:12]CC)=[O:11]>C(OCC)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCOCC
Solvent: O
Product: CN1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Dissolve N-methylpiperazine (5.0 mL, 45.09 mmol) in diethyl ether in a stoppered flask and treat with neat ethyl bromoacetate (3.012 g, 18.036 mmol). Stir the reaction mixture at room temperature overnight, filter and wash the filter cake with diethyl ether. Combine the organic filtrates and evaporate the solvent in vacuo to give a light yellow oil. Take up in water (60 mL) and heat at 95° C. for 4 hours, allow to cool to room temperature and stir overnight. Evaporate the solvent in vacuo and dissolve the residue in acetonitrile and evaporate the solvent in vacuo (twice) to azeotrope residual water. Dissolve in a minimal amount of methanol, dilute with diethyl ether and place in the freezer. Isolate the crystals which form by decanting the supernatant and wash with diethyl ether. Obtain two more crops of crystals from the mother liquor to give 4-methylpiperazine-1-acetic acid (2.345 g, 82%); mp 158°-160° C. (lit 159.5°-161° C.), 1H NMR (D2O) δ3.98 (s, 2), 3.81-3.32 (m, 8), 2.89 (s, 3).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1([C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]O1)=[O:11]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1OCc2ccccc21
Reactant: Cc1cc(N)ccc1Br
Product: Cc1cc(N2Cc3ccccc3C2=O)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-methylaniline and phthalide using a similar procedure to Description 20, as a white solid (76%).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:4][CH2:3]1.Br>>[F:25][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:4][CH2:3]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCC(F)(F)CC1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](CC3CCC(F)(F)CC3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
(2S,4S)-Methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.787 g, 2.20 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 17.31 mL, 98.82 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-((4,4-difluorocyclohexyl)methyl)-piperidin-4-yl)isoxazol-3(2H)-one (424 mg, 64%). 1H NMR (600 MHz, DMSO) δ 0.98-1.41 (m, 5H), 1.51-2.61 (m, 12H), 2.66-2.75 (m, 1H), 2.95-3.04 (m, 1H), 5.59-5.67 (m, 1H). HRMS Calculated for [C15H22F2N2O2+H]+: 301.1728. Found: 301.1713
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[C:12]2[CH3:28])([CH3:7])[CH3:6])[CH3:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:37](=[O:39])[CH3:38])=[CH:25][CH:26]=1)=[C:12]2[CH3:28])([CH3:6])[CH3:7])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCn1c(-c2ccc(N)cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCn1c(-c2ccc(NC(C)=O)cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
One gram (2.53 m mole) of 2-[2-(4-amino-phenyl)-3-methyl-1-propyl-1H-indole-5-yloxy]-2-methyl-propanoic acid ethylester and 0.25 g (2.5 m mole) of triethylamine were dissolved in 15 ml of chloroform and 0.2 g (2.55 m mole) of acetyl chloride were added dropwise while ice-cooling. After a few hours at room temperature the reaction mixture was mixed with water and extracted with chloroform. The chloroform extracts were dried and evaporated, and the residue was purified by chromatography on silicagel (solvent: toluene/acetone (5:1)).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].Cl.[Cl:28][CH2:29][C:30]#[C:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(#N)C.C(OCC)(=O)C>[ClH:2].[ClH:28].[Cl:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:29][C:30]#[C:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Reactant: ClCC#CCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3)CCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
A mixture of (2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine hydrochloride (400 mg) and 4-(4-chloro-2-butynyl)morpholine hydrochloride (223 mg) in dried acetonitrile (4.0 ml) was stirred at 50° C. in the presence of is powdered potassium carbonate (534 mg) and potassium iodide (32 mg). After 3 hours, the reaction mixture was filtered and the insoluble material on the filter was washed with acetonitrile. The filtrate and the washing were combined and then concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (1.0:1) as eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(4-morpholino-2-butynyl)piperazine dihydrochloride (221 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][N:25]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([CH3:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]3)[CH:26]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(N)cn2)C1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cnn(C3CN(C(=O)OC(C)(C)C)C3)c2)nc1CCc1ccccc1CC(N)=O
Temperature: 100 °C

Procedure:
A suspension of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6) (0.150 g, 0.518 mmol), 4-amino-1-(1-Boc-azetidin-3-yl)-1H-pyrazole (0.195 g, 0.777 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), Cs2CO3 (0.506 g, 1.55 mmol) and Xantphos (11.9 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was heated under microwave irradiation at 100° C. for 1.5 hours. 4-Amino-1-(1-Boc-azetidin-3-yl)-1H-pyrazole (65.0 mg, 0.259 mmol) was added and the mixture was heated for a further 1 hour at 100° C. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 12 g SiO2 cartridge, 0-5% MeOH in DCM) to give the title compound A120 as a light pink colored foam (0.050 g, 19%); 1H NMR (300 MHz, d4-MeOH) δ 8.06 (d, J=8.8 Hz, 2H), 7.66 (s, 1H), 7.16-7.27 (m, 4H), 5.12-5.21 (m, 1H), 4.39 (t, J=8.7 Hz, 2H), 4.25-4.30 (m, 2H), 3.65 (s, 2H), 3.32 (s, 1H), 3.10-3.16 (m, 2H), 2.95-3.00 (m, 2H), 2.10 (s, 3H), 1.48 (s, 9H). LCMS-B: rt 6.184 min; m/z 492 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14](Cl)[C:15]([Br:19])([Br:18])[CH2:16][Cl:17])[C:11](=[O:21])[N:10]([CH3:22])[C:9]1=[O:23].[Br:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].C(N(CC)CC)C.Cl>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[Br:24])[C:15]([Br:19])([Br:18])[CH2:16][Cl:17])[C:11](=[O:21])[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: CN1C(=O)C(=NC(Cl)C(Br)(Br)CCl)N(c2ccccc2F)C1=O
Reactant: Nc1ccccc1Br
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1C(=O)C(=NC(Nc2ccccc2Br)C(Br)(Br)CCl)N(c2ccccc2F)C1=O
Reaction time: 0.17 h

Procedure:
In this example 0.02 mol of 1-(2-fluorophenyl)-3-methyl-5-(1,3-dichloro-2,2-dibromopropyl)imino-1,3-diazolidine-2,4-dione is dissolved in 20 ml of acetonitrile and then 0.02 of mol of 2-bromoaniline is added. After about 10 minutes, triethylamine is added to neutralize the byproduct HCl produced by the reaction. The mixture is stirred for five hours and 20 ml of ethyl ether is then added. The mixture is filtered and the filtrate evaporated under high vacuum affording 1-(2-fluorophenyl)-3-methyl-5-(1-2'-bromophenylamino-2,2,-dibromo-3-chloropropyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[Cl:12]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(#N)C>[Cl:12][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[CH2:4]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)ccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.5 %

Procedure:
A suspension of 3.0 g of 4-methyl-2-oxindole was stirred in 50 mL of acetonitrile at room temperature while 3.3 g of N-chlorosuccinimide was added in portions. Trifluoroacetic acid (1 mL) was then added. The suspension was stirred at room temperature for 3 days during which time solid was always present. The white solid was collected by vacuum filtration, washed with a small amount of cold acetone and dried overnight in a vacuum oven at 40° C. to give 2.5 g (68%) of 5-chloro-4-methyl-2-oxindole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[NH2:9])=[CH:4][CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a solution of 4-fluorobenzenecarboximidamide (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1.5 hours. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.82 g (84.7%) of the desired product as a solid.