Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([C:8]2[N:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=23)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:21]([O:25][C:26](=[O:27])[NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31]([N:14]1[CH2:15][CH2:16][N:11]2[C:10]([C:17]([F:18])([F:20])[F:19])=[N:9][C:8]([C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])=[C:12]2[CH2:13]1)=[O:32])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)C1CCCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 72 %

Procedure:
Cyclopentyl-(3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-methanone 28b (83 mg, 0.258 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid if (0.129 g, 0.388 mmol) were dissolved in 10 mL of dichloromethane under stirring, and triethylamine (0.143 mL, 1.03 mmol) was then added to the solution. After stirring to mix well, bis(2-oxo-3-oxazolidinyl) phosphinic chloride (0.099 g, 0.388 mmol) was added. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 28c (0.11 g, yield 72%) as an orange oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([NH2:10])=[N:6][C:7]=1[CH2:8][CH3:9].O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][OH:19]>CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([NH2:10])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N)nc(N)c1O
Reactant: OCCCBr
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(N)nc(N)c1OCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-hydroxy-6-ethyl-2,4-diaminopyrimidine (6) (3 mmol) and lithium hydroxide monohydrate (6 mmol) in N,N-dimethylformamide (DMF) (10 ml) was stirred at room temperature for 2 hours under nitrogen. 3-Bromo-1-propanol (3 mmol) was added and left stirring at room temperature for 10 hours. Removal of DMF gave the crude product, further purified by crystallization with water to yield the pure 5-(3′-hydroxypropoxy)-6-ethyl-2,4-diaminopyrimidine (7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:39]([C:36]1[CH:35]=[CH:34][C:33]([S:32][CH3:31])=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(SC)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.626 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate was dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 0.593 g of 4-methylsulphanylbenzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-methoxy-phenoxy)-3-(4-methylsulphanyl-benzenesulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:31](O)(=[O:33])[CH3:32].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=[O:13])[C:10](=[C:31]([OH:33])[CH3:32])[C:9](=[O:14])[CH2:8]1
Reactant: O=C1CC(=O)CC(c2cc(Cl)sc2Cl)C1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)=C1C(=O)CC(c2cc(Cl)sc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 70.2 %

Procedure:
To a solution of 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (3.07 g), 4-dimethylaminopyridine (2.14 g) and dicyclohexylcarbodiimide (3.13 g) in dimethylformamide (10 ml) was added acetic acid (1.26 g), and the mixture was stirred at room temperature for 13 hours. To the mixture were added water (30 ml) and 2N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was extracted with 0.5N sodium hydroxide solution, and to the aqueous layer was added 2N hydrochloric acid to make the solution acidic. The solution was extracted with ethyl acetate, and the organic layer was washed with water. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 5-(2,5-dichlorothiophen-3-yl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (2.5 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[NH2:28]O.[C:30]([O-:33])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]3[N:28]=[CH:30][O:33][N:25]=3)=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CCO
Product: Clc1ccc(Sc2oc(-c3ccccc3)nc2-c2ccc(-c3ncon3)cc2)cc1
Temperature: 120 °C
Yield: 37 %

Procedure:
To 3-(4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}benzonitrile (30 mg, 0.075 mmol) in 2 mL EtOH was added 0.25 mL of 50% aqueous NH2OH and catalytic amount of K2CO3. The reaction was heated at 120° C. for 1 h via microwave irradiation. The reaction mixture was concentrated to dryness and the residue was dissolved in 5 mL triethylorthoformate. A catalytic amount of TFA was added, and the reaction was heated at 130° C. for 3 h. The volatiles were removed and the residue was purified by reverse phase HPLC to afford 12 mg (37% yield) of the title compound: m/z 432.1 (M+H)+. 1H NMR (500 MHz, CDCl3: δ 8.8 (1H, s), 8.39 (2H, d), 8.21 (2H, d), 8.19 (1H, m), 7.59 (4H, br), 7.24 (4H, br).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]=1[O:15][CH3:16])[N:4]=[C:3]([CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[N:4]=3)[CH2:21][CH2:20]1)[CH:12]=[CH:11]2
Reactant: C1CNCCNC1
Reactant: COc1cc2ccc(CCl)nc2c(OC)c1OC
Product: COc1cc2ccc(CN3CCCN(Cc4ccc5cc(OC)c(OC)c(OC)c5n4)CC3)nc2c(OC)c1OC

Procedure:
2-Chloromethyl-6,7,8-trimethoxyquinoline (350 mg) and homopiperazine (65 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH:17]1([C:3]2[C:2]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CN(C)CCN
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Product: CN(C)CCNc1nn2c(-c3ccccc3)nnc2cc1C1CCC1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.35 mmol) and N,N-dimethylethylenediamine were heated together in a sealed tube at 60° C. for 24 h. The mixture was cooled and the white precipitate was collected by filtration and washed with diethyl ether, then dried to give the title compound. 1H NMR (250 MHz, CDCl3) δ 1.94 (1H, m), 2.12-2.24 (3H, m), 2.29 (6H, s), 2.41-2.50 (2H, m), 2.59-2.64 (2H, m), 3.38-3.49 (3H, m), 5.51 (1H, vbs), 7.41-7.52 (3H, m), 7.62 (1H, m), 8.54-8.62 (2H, m); MS (ES+) m/e 337 [MH]+.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:13][O:14][CH:15]1[CH2:18][CH:17]([CH2:19]O)[CH2:16]1.[N-:21]=[N+:22]=[N-:23].[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH3:13][O:14][CH:15]1[CH2:18][CH:17]([CH2:19][N:21]=[N+:22]=[N-:23])[CH2:16]1
Reactant: COC1CC(CO)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC1CC(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
530 μl of triethylamine followed by 220 μl of methanesulfonylchloride were added under iced temperature to 220 mg of 1) 3-methoxy-cyclobutylmethanol obtained in the above 1). The mixture was heated to room temperature and stirred for 30 min. The reaction solution was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate water and saturated saline solution, and dried with anhydrous sodium sulfate. The residues obtained by evaportating the solvents under reduced pressure were dissolved in 4 ml of dimethylformamide. Then, 245 mg of sodium azide was added, and the mixture was stirred at 80° C. for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline solution and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents under reduced pressure were separated and purified by silicagel column chromatography (ethyl acetate:hexane=10:90) to obtain 195 mg of the above compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[N:27]([CH2:30][CH2:31][O:32][CH3:33])=[C:28]=[O:29].C(N(CC)CC)C>C1COCC1>[CH3:33][O:32][CH2:31][CH2:30][NH:27][C:28]([N:14]1[CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=2)[CH2:11][CH:12]([NH:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:24])[CH2:13]1)=[O:29]
Reactant: COCCN=C=O
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCNC(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 19 mg (0.19 mmol) of 1-isocyanato-2-methoxyethane and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (35% of theory)
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH:7](Br)[C:8](=[O:10])[CH3:9]>CC(C)=O>[Br-:6].[Br-:6].[O:10]=[C:8]([CH2:7][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)C(Br)Br
Reactant: C1CCSC1
Solvent: CC(C)=O
Product: O=C(C[S+]1CCCC1)C[S+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
Into a four-necked flask were charged 4.7 parts of tetrahydrothiophene, 5.2 parts of dibromoacetone and 47.1 parts of acetone, and they were stirred at room temperature for 24 hours. The deposited crystals were filtered and washed with acetone. The obtained filter cake was combined with ether and the mixture was stirred. After filtration, the filter cake was washed with ether and dried to give 6.4 parts of 1,1′-(2-oxo-1,3-propanediyl)bis(tetrahydrothiophenium) dibromide. Yield: 66.9%.
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Br:3])[N:11]=1
Reactant: O=P(Br)(Br)Br
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Br)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
86.0 g (0.3 mol) of phosphorus oxybromide was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 200 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 200 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 11.1 g (0.052 mol) of a pale yellow crystal of 2-amino-6-bromopurine (yield 52%). Its properties are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:33]([CH3:34])=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[CH:11][C:10]=1[CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:32]=[C:33]([CH3:34])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[C:10]([CH3:35])[CH:11]=2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of t-butyl N-[5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.71 g) in methanol (100 ml) was added 10% palladium on carbon (0.2 g). The mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 11 hours. The catalyst was filtered off and the solvent of the filtrate was evaporated to afford the desired compound (1.56 g, Rf=0.14: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=1:3 as the eluant).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([CH2:29][CH2:30][CH3:31])[CH:4]=1)#[N:2].[SH2:32].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([CH2:29][CH2:30][CH3:31])[CH:4]=1)=[S:32]
Reactant: S
Reactant: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of ethyl {(1S)-5-[3-(4-cyano-2-propylphenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (Example 143, 1.2 g, 2.9 mmol) in DMF (anhydrous, 15 mL) under argon at rt was passed H2S gas at a moderate rate for 20 min. Then, a solution of diethylamine (0.3 g, 4.3 mmol) in DMF (3 mL) was added in one portion, and the reaction mixture was stirred at 60° C. for 3 h. Upon completion, the reaction was cooled to rt and argon was passed through the reaction mixture for 1 h to remove residual H2S. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:1) to give 0.9 g (76%) of the title compound as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 0.94 (t, 3H), 1.31 (t, 3H), 1.52-1.64 (m, 2H), 1.65-1.80 (m, 1H), 2.20-2.44 (m, 4H), 2.58-2.95 (m, 5H), 3.38-3.61 (m, 1H), 4.16-4.21 (m, 4H), 4.26 (t, 2H), 6.69 (d, 1H), 6.80 (s, 1H), 6.95 (d, 1H), 7.09 (d, 1H), 7.79 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[C:4](OC)=[O:5].[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[CH2:14][N:15]1[C:19]2=[N:20][CH:21]=N[CH:23]=[C:18]2[C:17]([C:24](=[NH:27])[NH:25][NH2:26])=[N:16]1.[CH2:32](O)C>>[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:32][CH:23]=[C:18]2[C:17]([C:24]2[N:25]=[N:26][C:3]([C:2]([F:10])([F:9])[F:1])=[C:4]([OH:5])[N:27]=2)=[N:16]1
Reactant: CCO
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Product: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F

Procedure:
1.098 g (7.035 mmol) of methyl 3,3,3-trifluoro-2-oxopropanoate in 10 ml of ethanol were initially introduced and heated to reflux. Then, 2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 25 ml of ethanol were added and the mixture was heated under reflux overnight. After cooling, the mixture was filtered, and the filtercake was washed with a little ethanol and purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, ratio 45:55). This gave 710 mg of the target compound (purity 93%; 24% of theory).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH:13]([CH3:17])[NH:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:10][CH:11]1[NH:12][CH:13]([CH3:17])[CH2:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1CNCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Temperature: 120 °C
Yield: 56.9 %

Procedure:
A mixture of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol), 2,6-dimethylpiperazine (2.2 g, 19.3 mmol), and K2CO3 (2.7 g, 19.3 mmol) in DMF (10 mL) was heated at 120° C. for 4 hours. Then, the reaction was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 3% to 10% MeOH/CH2Cl2 afforded 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (2.0 g, 57%).
Reaction SMILES: F[C:2]([F:15])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]1[CH:22]=C(F)[CH:20]=[CH:19][C:18]=1[C@@:24]1([NH:52][C:53]([NH:55][C:56](=[O:63])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[S:54])[C@H:28]([CH2:29]O)[C@@H:27]([CH2:31][O:32][C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(C2C=CC=CC=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][CH2:25]1>N1C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:2]([F:15])[CH:20]=[CH:19][C:18]=1[C@:24]12[CH2:25][O:26][C@H:27]([CH2:31][O:32][C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:28]1[CH2:29][S:54][C:53]([NH:55][C:56](=[O:63])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[N:52]2
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethanesulphonic acid anhydride (0.40 mL, 2.35 mmol) was added slowly to a stirred solution of N-(((3S,4R,5S)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (1.3 g, 1.96 mmol) in dry pyridine (4 mL) under nitrogen such that the internal temperature remained below −20° C. Upon complete addition, the reaction was stirred at −20° C. for a further 10 minutes and then transferred to an ice bath. After 2 hours at 0° C. the reaction was quenched with saturated aqueous NH4Cl (20 mL) and then the mixture was partitioned between EtOAc (50 mL) and water (25 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (50 mL×1). The combined extracts were washed with half saturated brine (2×50 mL) and brine (50 mL×1), then dried (Na2SO4), filtered and evaporated. The residue was azeotroped with toluene (×2) to give 1.6 g (oil). The reaction was repeated starting with 5.0 g of N-(((3S,4R,5S)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide and the crude product from the two experiments was combined for purification by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane) to give the title compound. (3.99 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.71 (dd, J=13.76, 3.97 Hz, 1 H) 3.02-3.17 (m, 1 H) 3.19-3.28 (m, 1 H) 3.31-3.35 (m, 1 H) 3.40 (dd, J=10.27, 4.28 Hz, 1 H) 4.00-4.07 (m, 1 H) 4.38-4.47 (m, 1 H) 4.54 (d, J=9.17 Hz, 1 H) 6.96-7.13 (m, 2 H) 7.17-7.39 (m, 9 H) 7.42-7.58 (m, 10 H) 8.03 (br. s., 2 H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][C:14]3=[O:25])[CH2:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([N:16]=[CH:15][C:14](=[O:25])[N:13]2[CH2:12][CH2:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[CH:18][CH:19]=1
Reactant: COc1ccc2ncc(=O)n(CCC3CCC4(CC3)OCCO4)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCC3CCC(=O)CC3)c2c1
Reaction time: 0.25 h

Procedure:
To 0.16 g of 1-(2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 1.5 mL of an 80% aqueous trifluoroacetic acid solution was added at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Thereto was added ethyl acetate under cooling with ice, and the reaction mixture was adjusted to pH 8.0 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.18 g of a brown oily substance, 7-methoxy-1-(2-(4-oxocyclohexyl)ethyl)quinoxalin-2(1H)-one.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[F:9][C:10]([F:27])([F:26])[C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([O:24][CH3:25])[C:12]=1[C:13](O)=[O:14]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:13](=[O:14])[C:12]1[C:11]([C:10]([F:26])([F:27])[F:9])=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:17][C:16]=1[O:24][CH3:25]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N

Procedure:
The title compound, yellow foam, MS: m/e=385.1 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2,4-bis(trifluoromethyl)-6-methoxybenzoic acid.