Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:22])[CH2:19][CH2:18][N:17]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].C(N)(N)=[O:45].OO.C1(=O)C2C=CC=CC=2C(=O)O1>CCOC(C)=O>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=2[O-:45])=[O:22])[CH2:19][CH2:18][N:17]1[C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: NC(N)=O
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccccn2)CCN1C(=O)OCc1ccccc1
Agent: O=C1OC(=O)c2ccccc21
Agent: OO
Solvent: CCOC(C)=O
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2cccc[n+]2[O-])CCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 118.7 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-2-({formyl [(phenylmethyl)oxy]amino}methyl)hexanoyl]-3-[(2-pyridinylamino)carbonyl]-1-pyrazolidinecarboxylate (70 mg, 0.12 mmol) in EtOAc (6 mL) was added per carbamide (45 mg, 0.48 mmol) and 2-benzofuran-1,3-dione (71 mg, 0.48 mmol). The mixture was stirred overnight until TLC showed the completion of the reaction. The mixture was washed with aq. Na2CO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to provide the titled compound (86 mg, 85%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1COCC1>[CH2:21]([O:20][C:18]([NH:1][C@H:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@H]1CCCNC(=O)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)CCCN1
Temperature: 5 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
(3S)-3-Amino-ε-caprolactam (25 g) and triethylamine (19.7 g) were dissolved in THF (200 ml) and cooled to 5° C. Benzyl chloroformate (33 g) in THF (50ml) was added dropwise over 30 minutes. The reaction mixture was stirred at ambient temperature for 18 hours and then poured into water (500 ml). The reaction mixture was extracted with ethyl acetate (3×100 ml). The combined extracts were dried (MgSO4) and evaporated. The residue was triturated with ether (40 ml) and filtered to give 20 g of (S)-3-benzyloxycarbonylamino-ε-caprolactam as a white solid; NMR (d6-DMSO): 1.1-2(m, 6H), 2.9-3.2(m, 2H), 4.1-4.25 (m, 1H), 5.0 (s, 2H), 7.25-7.4 (m, 5H), 7.75 (t, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:12][C:13]1[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:22]=[C:21]([N:23]([CH2:2][CH2:3][O:4][CH3:5])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN(c1ccc(C(=O)OC)c(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate 10′ solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:19](=[O:23])[NH:18][C:17]([NH2:24])=[N:16][C:15]1=2)([O:6]CC)=[O:5])C.Br[Si](C)(C)C>CN(C)C=O>[P:4]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:19](=[O:23])[NH:18][C:17]([NH2:24])=[N:16][C:15]1=2)([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CCCCOn1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OCCCCP(=O)(O)O)c(=O)[nH]1
Temperature: 23 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
9-[4-(Diethoxyphosphoryl)butoxy]guanine (0.12 g, 0.33 mmol) and bromotrimethylsilane (0.43 ml, 3.3 mmol) were dissolved in dimethylformamide (5 ml) and the reaction mixture was stirred at 23° C. for 3 hr. The solvent was evaporated under vacuum and the residue dissolved in methanol:water solution (9:1). The pH of the resulting solution was adjusted to 7.0 with diluted aq. ammonia and the solvents were evaporated to dryness. The product was purified by reversed phase chromatography (eluted with water) to give the title compound (65 mg, 64%) m.p. 208° C. (water), as its ammonium salt. 1H NMR: δH ((CD3)2, SO+D2O) 1.40 (2H, m, CH2P), 1.68 (4H, br.s, CH2CH2), 4.21 (2H, m, NOCH2), 7.89 (1H, s, H-8).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:14])=[CH:6][C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[CH3:15][CH2:16][CH:17]([OH:20])[CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([CH:17]([O:20][C:4]1[C:5]([CH3:14])=[CH:6][C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)[CH2:18][CH3:19])[CH3:15]
Reactant: CCC(O)CC
Reactant: Cc1cc2nnc(N)n2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(N)nnc2cc1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Pentanol (30 ml) was initially charged under argon, admixed with sodium hydride (1.48 g) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.005, 1.88 g), dissolved in 3-pentanol (130 ml) and DMF (60 ml), was slowly added dropwise within 1 h. After stirring for 1 h, the mixture was concentrated, and the residue was admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using an 80 g silica gel cartridge (0-10% dichloromethane-methanol gradient in 40 min). The clean product fractions were combined and dried. 1.25 g of the title compound were obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[NH:13].C(N(CC)CC)C>C1COCC1>[C:2]1([C:1]2[O:8][N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]4[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=N)NO)CC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3noc(-c4ccccc4)n3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
0.019 mL (0.16 mmol) Benzoyl chloride are added to a mixture of 45.7 mg (0.15 mmol) (S)—N-(1-{4-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (XXVII.2) and 0.063 mL (0.45 mmol) triethylamine in 4 mL THF. The mixture is stirred for 12 h at 80° C. and is subsequently purified by HPLC (RP C18 Sunfire; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].C1(C2[O:24]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([S:14]([CH3:15])=[O:24])[N:6]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc(C(N)=O)c(NC(C)C)n1
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1nc(S(C)=O)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a stirring solution of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxamide (170 g, 0.751 mol) in chloroform (22 L) was added portion-wise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (235.6 g, 0.902 mol) and the resulting solution was stirred at ambient temperature overnight. An additional amount of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (19.6 g, 0.075 mol) was added and the mixture was then stirred overnight at ambient temperature. The reaction solution was concentrated under reduced pressure to give the crude product as a white solid. The solids were triturated with ethyl acetate (1.5 L) at ambient temperature for 1 h, filtered, washed with ethyl acetate (250 mL), and dried in a vacuum oven overnight at 45° C. to afford 4-(isopropylamino)-2-(methylsulfinyl)pyrimidine-5-carboxamide (167.7 g, 92% yield) as white solid. MS (ESI) m/z 243.2 [M+1]+.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][CH:10]=[N:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C1COCC1.CO>[C:1]1([N:7]2[CH:12]=[CH:11][CH2:10][NH:9][C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ncccn1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCC=CN1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenylpyrimidin-2(1H)-one (250 mg, 1.45 mmol) in dry THF (20 mL) was added a solution of NaBH4 (58 mg, 1.5 mmol) in 20 mL MeOH by dropwise at 0° C. The reaction mixture was stirred at rt for 1 h. The mixture was concentrated to remove DCM, the residue was purified by SFC to give 1-phenyl-3,4-dihydropyrimidin-2(1H)-one and Compound 365 (74.8 mg, 30% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.41-7.33 (m, 4H), 7.23-7.21 (m, 1H), 6.53 (brs, 1H), 6.14-6.11 (m, 1H), 4.88-4.84 (m, 1H), 4.32-4.31 (m, 2H). MS (ESI) m/z [M+H]+ 174.9.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[N:6]=1.O.C(OCC)(=O)C>CN(C)C=O>[CH3:12][O:11][C:7]1[N:6]=[C:5]([C:2]#[N:3])[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(Br)n1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C#N)n1
Temperature: 165 °C
Reaction time: 15 h

Procedure:
Copper(I) cyanide (2.68 g) was added to 2-bromo-6-methoxypyridine (5.62 g) in N,N-dimethylformamide (112 mL) at room temperature, followed by stirring at 165° C. for 15 hours. The resultant mixture was cooled in air. Water and ethyl acetate was added to the mixture. The insoluble matter that was formed in the mixture was filtered by Celite. The filtrate was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid substance (1.78 g, 44%).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([C:24]#[C:25][CH2:26][N:27]=[N+]=[N-])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([C:24]#[C:25][CH2:26][NH2:27])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(C#CCN=[N+]=[N-])NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#CCN)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1

Procedure:
The title compound can be prepared by treating the title compound of Example 85 with triphenylphosphine and water in THF as described in the literature [N. Knouzi, M. Vaultier, R. Carrie Bull. of Chem. Soc. France, 815 (1985)] which can afford the title compound directly. The product can be purified by reverse phase HPLC using the conditions of Example 1 to afford the title compound. The product can be verified by C NMR.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[N:34]1([S:20]([C:16]2[CH:15]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH2:37][CH2:36][CH2:35]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: C1CNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC4)c3)n2)n1
Yield: 52.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.200 g, 0.409 mmol) by treatment with commercially available azetidine [CAS-no. 503-29-7] (0.14 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 53%) as a white solid. MS (ISP) 510.2 [(M+H)+]; mp 158° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])C>O>[CH2:15]([NH:14][CH:5](/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:11])([OH:12])=[O:10])[C:4]([OH:22])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(/C=C(\C)CP(=O)(O)O)NCc1ccccc1
Solvent: O
Product: C/C(=C\C(NCc1ccccc1)C(=O)O)CP(=O)(O)O

Procedure:
A solution of 1.00 g of E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester in 6 ml of water is stirred under reflux for 20 hours. The reaction mixture is concentrated to dryness by evaporation in vacuo. Ethanol is added to the residue, and the mixture is again concentrated by evaporation. This process is repeated twice more. The residue is dissolvedin boiling methanol. After cooling there is obtained crystalline E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 150° (decomp.).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@H:3]([OH:23])[C@@H:4]([C:20]([OH:22])=[O:21])[N:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].F[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37]>CN(C)C=O>[CH2:6]([N:5]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:4]([CH:3]([O:23][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[N+:36]([O-:38])=[O:37])[C:2]([F:24])([F:25])[F:1])[C:20]([OH:22])=[O:21])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)[C@H]([C@H](O)C(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(Oc1ccc(F)cc1[N+](=O)[O-])C(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
To 15.4 g (43.6 mmol) DL-4,4,4-trifluoro-N,N-bis(phenylmethyl)-threonine in 60 ml dimethylformamide were added in portions 4.03 g (92.4 mmol) sodium hydride (55%) at 0° C. The suspension was stirred for 2 hours and then 10.5 ml (95.9 mmol) 2,5-difluoro-nitrobenzene were added. After stirring overnight at 0° C. the mixture was poured on ice/water. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1:1 (and adding 30% methanol after the first five 250 ml fractions) yielded 11.7 g (55%) racemic (2S,3S and 2R,3R)-2-dibenzylamino-4,4,4-trifluoro-3-(4-fluoro-2-nitro-phenoxy)-butyric acid acid as yellow oil, MS m/e (%): 491.1 (M−H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](F)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.CN(C)C=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2nc(-c3ccccn3)no2)cc(-n2ccnc2)c1

Procedure:
In a screw cap vial equipped with stir bar added 3-(2-Pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (20 mg, 0.08 mmol), potassium carbonate (20.8 mg, 0.15 mmol), imidazole (7.7 mg, 0.11 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 120° C. for 2 h. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 2% methanol in dichloromethane to isolate the free base of the desired compound as a white solid. The free base was converted to it's hydrochloride salt (10.0 mg), white solid. 1H-NMR (DMSO), δ (ppm): 9.85 (s, 1H), 8.86 (m, 4H), 8.49 (s, 1H), 8.23 (d, 1H), 8.13 (t, 1H), 7.95 (s, 1H), 7.73 (dd, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20]>ClCCl.C(OCC)C>[CH3:17][N:18]([CH3:23])[S:19]([N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)(=[O:21])=[O:20]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of 3-trifluoromethylpyrazole (5.0 g, 36 mmol), triethylamine (7.0 mL, 50 mmol) in dichloromethane (40 mL) was added dimethylsulfamoyl chloride (5.5 mL, 51 mmol), and the reaction mixture was heated at reflux for 2 days. The resulting mixture was cooled to ambient temperature and filtered through a pad of silica gel using dichloromethane as eluent. The filtrate was then concentrated under reduced pressure to give an amber residue. The resulting residue was dissolved in diethyl ether. The ether solution was washed with water, dried (MgSO4), and concentrated under reduced pressure to give 8.71 g of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH3:17])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26](=[O:28])[CH3:27]>CN(C)C=O>[CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[N:12]([CH2:25][C:26](=[O:28])[CH3:27])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH3:17])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)CBr
Reactant: CCCCn1c(=S)c2[nH]cnc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=S)c2c(ncn2CC(C)=O)n(CC)c1=O
Temperature: 50 °C

Procedure:
1-n-Butyl-3-ethyl-6-thioxanthine (4 g) was dissolved in dimethyl formamide (30 ml) and a small amount of potassium carbonate was added. To this mixture, 1-bromopropan-2-one (2,7 g) was added dropwise at room temperature, with stirring. The reaction was heated at about 50° C. for two hours. The reaction mixture was then extracted with chloroform several times, the chloroform phase washed with 1N KOH and water, dried with sodium sulphate, filtered and the chloroform removed in vacuo to yield a red/brown oil which, on crystallisation in a mixture of ethylacetate/petroleum, gave 1-n-butyl-3-ethyl-7-(2-oxopropyl)-6-thioxanthine as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[CH:4][N:3]=1.N[C:9](N)=N.[CH3:12][O:13][C:14](=[NH:16])[NH2:15]>>[NH2:1][C:2]1[N:7]=[C:6]([O:13][CH3:12])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:12][O:13][C:14](=[NH:15])[NH2:16]
Reactant: Nc1ncncn1
Reactant: N=C(N)N
Agent: COC(=N)N
Product: COc1nc(C)nc(N)n1

Procedure:
According to U.S. Pat. No. 3,754,547, 2-amino-s-triazine derivatives can be prepared by reaction of N-cyanimido-esters with guanidine, O-methylisourea or amides. This process is also unsuitable on an industrial scale, since the yields produced are only about one-half of the desired yield (a maximum yield of 45% results in the case of the important compound 2-amino-4-methoxy-6-methyl-s-triazine), and the free O-methylisourea base, which is relatively unstable, must be used as the starting substance in this process.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CCOCC>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:25](=[O:27])[CH3:26])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Reaction time: 4 h

Procedure:
A solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (5 parts) in ether (85 parts) was treated with triethylamine (2.2 parts) and acetic anhydride (2.3 parts) at 10° C. and allowed to stand for 4 hours. The solution was then diluted with light petroleum (80 parts) and filtered. The filtrate was evaporated to give an oil which solidified. This was recrystallised from a mixture of chloroform and petroleum to give 2-acetoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (2.5 parts), melting point 84°-85° C.
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16])[CH:5]=[CH2:6].[CH3:17]N(C)C=O.CI>C(OCC)C>[CH3:17][CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:4][CH:5]=[CH2:6])[C:11]1=[O:16]
Reactant: CN(C)C=O
Reactant: C=CCc1cccc2c1CCC2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: C=CCc1cccc2c1CC(C)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.88 g of sodium methylate in 15 ml of ethyl ether is cooled to 0° C., a solution composed of 2.8 ml of ethyl formiate and 3 g of 4-(2-propenyl)-indanone in 6 ml of ether is introduced over 15 minutes, 5 ml of ether is added, with agitation for 15 minutes, and the suspension is allowed to rise to 20° C. 70 ml of dimethylformamide is added, with agitation for 2 hours, 2.15 ml of methyl iodide and 2 ml of ether are introduced, followed by agitation for 2 hours. The resulting mixture is then poured over 100 ml of ice water and extracted with ethyl ether, the extracts are dried and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (95-5) and 1.62 g of expected product is obtained.