Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[CH2:20]Br)=[O:4].[CH3:22][O:23][C:24](=[O:37])[CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[CH2:20][N:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccccc2)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1Cc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.6 %

Procedure:
A mixture of 1-benzyl-5-bromo-2-bromomethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.87 g, 6.92 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.68 g, 6.92 mmol), sodium iodide (1.96 g, 13.8 mmol) and potassium carbonate (1.91 g, 13.8 mmol) in DMF (50 mL) was stirred at r.t. for 3 days. Brine (50 mL) was added and the mixture was extracted several times with EtOAc. The organic layers were combined, washed with water, and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes) to give 2.1 g of the title compound as a yellow oil. MS: (+) m/z 576.95, 578.89 (M+1, 79/81Br).
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][N:7]([CH2:16][CH:17](O)[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].C(N(CC)CC)C>ClCCCl>[CH3:6][N:7]([CH2:16][CH:17]([Cl:5])[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: Cc1cccc(C)c1N(C)CC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(C)c1N(C)CC(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3.1 ml (4.6 g, 40 mmoles) of methanesulfonyl chloride are added dropwise, at a temperature not exceeding 20° C., to a solution of 7.0 g (36.2 mmoles) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-propanol and 5.45 ml (4.0 g, 40 mmoles) of triethyl amine in 50 ml of 1,2-dichloroethane, and the resulting mixture is stirred at room temperature for 3 hours. The mixture is washed then thrice with 30 ml of water, each, dried over anhydrous magnesium sulfate, the solvent is evaporated, and the oily residue is distilled under reduced pressure. 6.9 g (90.2%) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-chloro-propane are obtained; b.p.: 116°-118° C./133 Pa.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl[CH2:19][C:20]([N:22]1[C:28](=[O:29])[CH:27]2[CH:23]1[CH2:24][CH2:25][CH2:26]2)=[O:21]>[I-].[K+].O.C(OCC)(=O)C>[C:12]([O:17][CH2:19][C:20]([N:22]1[C:28](=[O:29])[CH:27]2[CH:23]1[CH2:24][CH2:25][CH2:26]2)=[O:21])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: O=C(CCl)N1C(=O)C2CCCC21
Reactant: C=C(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(=O)N1C(=O)C2CCCC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
In a four-necked flask with a volume of 500 mL, which was equipped with a thermometer, a stirrer, a dropping funnel, and a nitrogen introducing tube, 9.7 g (70 mmol) of potassium carbonate, 0.7 g (4 mmol) of potassium iodide, 100 mL of dimethylformamide, 25.8 g (300 mmol) of methacrylic acid, and 18.8 g (100 mmol) of 6-chloroacetyl-6-azabicyclo[3.2.0]heptan-7-one obtained in Synthesis Example 3 were charged, and the mixture was stirred at an internal temperature of 25° C. for 5 hours. To the reaction mixture, 100 mL of ethyl acetate and 50 mL of water were added, and a liquid separation operation was then carried out. The obtained organic layer was concentrated under reduced pressure and then purified by means of silica gel column chromatography, thereby obtaining 17.1 g (72 mmol) of 6-methacryloyloxyacetyl-6-azabicyclo[3.2.0]heptan-7-one having the following properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH:11](C(OC)=O)[C:12]([O:14][CH3:15])=[O:13])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[Cl-].[Li+]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]

Procedure:
A solution of dimethyl 2-(4-fluoro-2,6-dinitrophenyl)malonate from Step A (20.5 g, 64.9 mmol) and lithium chloride (5.50 g, 130 mmol) in DMSO (120 mL) and water (2.34 mL) was heated at 90° C. for 3 h, then cooled and poured onto H2O (400 mL). The aqueous layer was extracted with Et2O (3×250 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=259 (M+1).
Reaction SMILES: [Na:1].[C:2](#[N:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:9][C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH3:8]>C(O)C>[Na:1].[C:4]([C:3]([C:2]#[N:6])=[C:13]([NH:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])[S-:14])#[N:5]
Reactant: N#CCC#N
Reactant: CCOC(=O)N=C=S
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)NC([S-])=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metal (1.01 g, 44 mmol) was dissolved in 40 mL of ethanol at ambient temperature. The resulting solution was cooled in an ice bath, and malononitrile (2.91 g, 44 mmol) was added. The ice bath was removed, and the mixture was stirred at ambient temperature for 30 minutes. After cooling to 0° C., ethoxycarbonylisothiocyanate (5.77 g, 44 mmol) was added, and the mixture was allowed to warm to ambient temperature overnight. The mixture was concentrated in vacuo, and the residue solidified upon repeated dilution with hexane and concentration in vacuo. The resulting yellow solids were collected and dried in vacuo, affording 10.74 g (100%) or sodium, 2,2-dicyano-1-ethoxycarbonylamino-ethenethiolate as a light yellow solid that contained 0.5 molar equiv. of ethanol as indicated by 1H NMR spectroscopy. 1H NMR (300 MHz, DMSO-d6) δ 4.36 (t, 0.5H, J=5.0 Hz (EtOH)), 4.03 (q, 2H, J=7.1 Hz), 3.43 (dq, 1H J=5.0, 6.7 Hz (EtOH)), 1.26 (t, 3H, J=7.3 Hz), 1.06 (t, 1.5H, J=7.0 Hz (EtOH)) ppm; MS (APCI, m/z): 197 [M−Na]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[S:16]([N:19]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17].[Cu][C:33]#[N:34]>CN1CCCC1=O>[C:33]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[S:16]([N:19]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])#[N:34]
Reactant: N#C[Cu]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2Cl)c(C)c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2C#N)c(C)c1
Temperature: 220 °C

Procedure:
To a solution of 2-chloro-N-(2,4-dimethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (200 mg, 0.429 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was added copper(I) cyanide (77 mg, 0.858 mmol). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 220° C. for 2 hours. After cooling the reaction LCMS analysis showed some evidence of the desired product. The reaction was reheated by microwaves to 220° C. for an additional 6 hours. The reaction was slowly and carefully quenched with dilute HCl (5 mL) and DCM (5 mL). The mixture was passed through a hydrophobic frit and the organic layer collected and concentrated in vacuo to give a brown oil. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were evaporated in vacuo to give the required product, 56 mg. LCMS [LCMS2] Rt 1.47 min, m/z (ES+) 457 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)Cn1ncc2c1CCCC2NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of (4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (60 mg, 0.27 mmol) in 5% sodium carbonate (0.57 mL) and 1,4-1,4-dioxane (1 mL) was added benzyl chloroformate (58 uL, 0.40 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature slowly, and stirred overnight. The reaction mixture was partitioned between water (10 mL) and dichloromethane (20 mL×3). The combined organic layers were collected and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate in hexanes) to afford racemic (4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (94.2 mg, 98.2%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (s, 1 H), 7.49-7.35 (m, 4 H), 5.18 (s, 2 H), 5.23 (s, 2 H), 4.92-4.80 (m, 3 H), 4.23 (dd, J=7.2 Hz, 2 H), 2.52 (m, 2 H), 2.05-1.88 (m, 4 H), 1.30 (t, J=7.2 Hz, 3 H). MS calcd. for C19H23N3O4 357, obsd. (ESI+) [(M+H)+] 358. The chrial separation (Gilson instrument: column: AS-H; flow rate: 15 mL/min; gradient: 55% hexane in propan-2-ol) gave ((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (retention time 7.2 minutes) and ((S)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (retention time 8.7 minutes). The recovery for both isomers together was 70%.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].[CH3:20][Mg+].[Br-].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCCCC)CCC>[NH2:2][CH:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(c2ccccn2)C1
Reactant: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCOCCCC
Solvent: Cc1ccccc1
Product: CC(N)C1(c2ccccn2)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 3-cyano-3-pyridin-2-ylazetidine-1-carboxylate (I-2, 5.0 g, 19.3 mmol) in toluene (100 mL) at room temperature was treated with MeMgBr (55 mL of a 1.0 M solution in dibutyl ether) dropwise over 15 min. After 18 h, the reaction was cooled to 0° C. and treated with MeOH (30 mL) and NaBH4 (1.3 g, 33.2 mmol). After 10 min, the reaction was quenched with the slow addition of saturated aqueous NH4Cl (75 mL), diluted with H2O (75 mL), and extracted with EtOAc (3×150 mL). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl 3-(1-aminoethyl)-3-pyridin-2-ylazetidine-1-carboxylate (I-3). This material was fully resolved into 1R and 1S isomers (>99% ee) using a ChiralPak AD column. NOE analysis of Mosher's amides confirmed the absolute stereochemistry of each isomer. Analytical LCMS: single peak (214 nm), 2.689 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:24].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (300 mg, 0.966 mmol) in DMF (5 mL) was added iodomethane (74 μL, 1.20 mmol). The solution was cooled to 0° C., treated with NaH (36 mg, 1.49 mmol, 95% dispersion in oil), and stirred for 10 minutes. The reaction was removed from the ice bath and allowed to gradually warm to room temperature. The mixture was partitioned between EtOAc and brine, and the organic extract was dried over Na2SO4 and concentrated in vacuo. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.54-7.53 (m, 2H), 7.37-7.28 (m, 3H), 5.36 (s, 2H), 4.38-4.41 (t, 2H), 3.92 (s, 3H), 3.76-3.72 (t, 2H), 3.16 (s, 3H); ES MS (M+1)=316.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:11])[C:9]=2[CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:22](OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O)[C@@H:23]1[O:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:22][C@@H:23]1[CH2:24][O:25]1)[CH:7]=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Cc1cc2c(O)cccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Temperature: 25 °C

Procedure:
2-Methyl-1H-indol-4-ol (0.58 g, 3.9 mmol) and THF (20 mL) were placed in a round bottom flask and stirred at room temperature. Sodium bis(trimethylsilyl) amide (3.9 mL, [1M] in THF) was then slowly added to the reaction mixture. After fifteen minutes of stirring at room temperature (R)-glycidyl-3-nitrobenzenesulfonate was added and the reaction mixture was allowed to stir overnight. Work up of the reaction mixture was carried out with saturated sodium carbonate solution and ethyl acetate. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to yield a crude oil. The crude oil was purified by flash chromatography (20% Ethyl acetate/heptane) to yield the title compound as a crystalline solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.[N+](C1C=C(S(O[CH2:23][C@@H:24]2[CH2:26][O:25]2)(=O)=O)C=CC=1)([O-])=O>CN(C)C=O>[O:25]1[CH2:26][CH:24]1[CH2:23][O:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cncc(OCC2CO2)c1
Temperature: 25 °C
Yield: 24.7 %

Procedure:
Sodium hydride (60%, 2.16 g, 54.0 mmol) was added portionwise into N,N-dimethylformamide (50 mL) with stirring at room temperature under a nitrogen atmosphere. A solution of 3-pyridinol (4.5 g, 46.28 mmol) in N,N-dimethylformamide (50 mL) was then added dropwise to this suspension over a period of 0.5 hour. After stirring for 1 hour a solution of (2S)-oxiranylmethyl 3-nitrobenzenesulfonate (10 g, 38.57 mmol) in N,N-dimethylformamide (50 mL) was added dropwise into this mixture over a period of 15 minutes. The mixture was then stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride to pH 5 and extracted with ethyl acetate. The extracts were washed with water and dried with brine. Evaporation and purification by flash column chromatography (dichloromethane/methyl alcohol 95/5) gave a brown oil (1.44 g, 25% yield); 1H NMR (400 MHz, DMSO-d6) δ 2.71–2.73 (m, 1 H), 2.81–2.84 (m, 1 H), 3.34–3.38 (m, 1 H), 3.87–3.92 (m, 1 H), 4.40–4.43 (m, 1 H), 7.30–7.33 (m, 1 H), 7.39–7.41 (m, 1 H), 8.71–8.19 (m, 1 H), 8.31 (s, 1 H); MS (ES) m/z: 152 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:14]([C:15](O)=[O:16])=[CH:13][C:12]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)=[N:11]2)=[CH:7][CH:6]=1)=[O:4].[C:29]([CH:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:32])([CH3:31])[CH3:30].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[C:29]([C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:15]([C:14]2[N:10]([CH2:9][C:8]3[CH:27]=[CH:28][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[N:11]=[C:12]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)[CH:13]=2)=[O:16])[CH2:37][CH2:38]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)N[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the intermediate from step D (0.39 g, 1.0 mmol) in DMF (2 mL) was added 4-tert-butyl cyclohexylamine (268 μL, 1.5 mmol), HOAt (0.2 g, 1.5 mmol), DIEA (0.52 mL, 3.0 mmol) and EDC (0.29 g, 1.5 mmol). The resulting solution was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate and washed with IN HCl, saturated NaHCO3, and saturated NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on Biotage Quad 3 system using 30% ethyl acetate-hexanes. The trans and cis isomers were obtained in a 3:1 ratio. Isomer A (trans isomer): 1H NMR (CDCl3, 500 MHz): 8.02 (d, J=8.4 Hz, 2H), 7.46 (dd, J=6.7, 7.9 Hz, 2H), 7.41 (d, J=8.2Hz, 2H), 6.75 (s, 1H), 5.86 (s, 2H), 5.83 (d, J=8.2 Hz, 1H), 3.93 (s, 3H), 3.8 (m, 1H), 2.11 (bm, 2H), 1.18 (bm, 2H), 1.2-1.0 (m, 3H), 0.91 (s, 9H). LC-MS: 3.07 min; (M+H)=528.2. Isomer B (cis isomer): 1H NMR (CDCl3, 500 MHz): 8.01 (d, J=8.0 Hz, 2H), 7.48 (t, J=6.6 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.73 (s, 1H), 6.08 (d, J=7.1 Hz, 1H), 5.84 (s, 2H), 4.23 (m, 1H), 3.92 (s, 3H), 1.94 (d, J=14.2 Hz, 2H), 1.71 (d, J=11.2 Hz, 2H), 1.61 (m, 211), 1.1 (m, 2H), 0.89 (s, 9H). LC-MS: 3.07 min; (M+H)=528.2.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[CH3:6][O:7][CH2:8][C:9]([NH2:11])=[O:10]>C1(C)C=CC=CC=1>[CH3:6][O:7][CH2:8][C:9]1[O:10][C:2](=[O:3])[S:4][N:11]=1
Reactant: O=C(Cl)SCl
Reactant: COCC(N)=O
Solvent: Cc1ccccc1
Product: COCc1nsc(=O)o1
Temperature: 95 °C
Yield: 79.9 %

Procedure:
Chlorocarbonylsulfenyl chloride (7.35 g) was added to a suspension of methoxyacetamide (5 g) in toluene (30 cm3). The reaction mixture was stirred and heated at 90-100° C. for 5 hours, then cooled. The solvent was removed by evaporation under reduced pressure to give a brown gum (6.6 g). M+ =147; 1H NMR (DMSO-d6): δ3.30(3H,s); 4.30(2H,s) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:14])[N:8]([CH3:13])[C:9]=1[C:10]([OH:12])=O)=[O:4].Cl.Cl.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[CH2:29][CH2:30][NH2:31]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:14])[N:8]([CH3:13])[C:9]=1[C:10](=[O:12])[NH:31][CH2:30][CH2:29][C:19]1[N:18]([CH3:17])[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=1)=[O:4]
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Reactant: COC(=O)c1nc(C)n(C)c1C(=O)O
Agent: Cl
Product: COC(=O)c1nc(C)n(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
The product was obtained starting from 1,2-dimethyl-1H-imidazole-4,5-dicarboxylic acid 4-methyl ester (100 mg, 505 μmol; example 8, steps 1-2) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine dihydrochloride (152 mg, 555 μmol; example 7, steps 1-4) according to the method described in example 10, step 5 after stirring at 70° C. for 16 h, aqueous workup and purification as light yellow oil (111 mg, 291 μmol, 57.7%). MS: M=382.4 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13]OS(C)(=O)=O)=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1.[CH3:32][NH:33][CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13][N:33]([CH3:34])[CH3:32])=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Reactant: CNC
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 77.1 %

Procedure:
Following the procedure of Example 7, 2-(3, 4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as slightly-yellow needles (yield: 77.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:29](=[O:31])[CH3:30])[CH:25]2[CH2:26][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CC2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopropylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH2:24][CH2:25]1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: CN1CCN(CCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCN2CCN(C)CC2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
225 mg (0.844 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 159 mg (1.01 mmol) of 1-(aminopropyl)-4-methylpiperazine were dissolved in 10 ml of DMF. 243 mg (1.27 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.