Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=O)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.C[CH2:18][N:19](C(C)C)[CH:20](C)C.Cl.CNC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:19]([CH3:20])[CH3:18])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C1CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry flask loaded with 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (400.0 mg, 1.15 mmol) in THF (9.0 mL) was added DIEA (0.42 ml, 2.42 mmol), dimethylamine hydrochloride (0.19 g, 2.30 mmol) followed by sodium triacetoxyborohydride (539 mg, 2.42 mmol) at rt. The resulting mixture was stirred at room temperature overnight. The reaction mixture was extracted with aq. Solution of NaHCO3 (2×30 mL). The aq.—layer was back-extracted with EtOAc (2×100 mL), dried (Na2SO4) and concentrated in vacuo to a solid. The material was carried onto the next step without any further purification. MS (ES+): m/z 344.73/345.81 (100/10) [MH+]
Reaction SMILES: [N+](=C)=[N-].N(CN[C:8](N)=[O:9])=O.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]([C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=O)=[O:22]>CCOCC.O1CCOCC1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]([C:23]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:8][O:9]1)=[O:22]
Reactant: O=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Reactant: NC(=O)NCN=O
Agent: C=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1Cl)C1(c2ccc(Cl)cc2Cl)CO1
Reaction time: 16 h

Procedure:
With cooling and stirring, an ethereal diazomethane solution prepared from 3.1 g of nitrosomethylurea and aqueous sodium hydroxide solution in ether is added dropwise to a solution of 3.4 g of 2,2',4,4'-tetrachlorobenzil in 50 ml of dioxane. When the dropwise addition is complete, stirring is continued for 16 hours at room temperature, and the reaction mixture is then concentrated to dryness. The residual oil is crude 2-(2,4-dichlorobenzoyl)-2-(2,4-dichlorophenyl)oxirane which is purified by high vacuum distillation.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][C:14]1[CH:50]=[CH:49][CH:48]=[CH:47][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:46])[C@@H:28]([OH:45])[C@@H:29]([NH:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:19].C(OCC)(=O)C>C(Cl)Cl>[CH3:13][C:14]1[CH:50]=[CH:49][CH:48]=[CH:47][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:46])[C@@H:28]([OH:45])[C@@H:29]([NH:37][C:38](=[O:44])[C@@H:39]([NH:40][S:2]([CH3:1])(=[O:4])=[O:3])[CH:41]([CH3:43])[CH3:42])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:19]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NS(C)(=O)=O)C(C)C)CSC1(C)C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (25 μl) and triethylamine (46 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) in methylene chloride (3 ml) and the mixture was stirred for two hours. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography and reprecipitated from ethyl acetate/n-hexane to obtain the title compound (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)C#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].CN(C=[O:31])C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)=[O:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of (48) (7.56 g, 21.88 mmol) in anhydrous DMF (100 ml) in a water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (1.05 g, 26 mmol). After 30 min, oxygen gas was bubbled into the reaction mixture for 4 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and purified by silica gel column chromatography (eluent, ether:hexane (1:4)) to afford 5.87 g (80%) of a white solid. m.p. 119-120° C.; 1H NMR (200 MHz, CDCl3) δ: 1.19 (6H, d, J=7.1 Hz), 2.38 (3H, s), 2.80 (1H, m), 3.93 (3H, s), 4.06 (3H, s), 7.40-7.61 (3H, m).
Reaction SMILES: CN(OC)[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH2:20].[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](Br)[CH:34]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CCCCCC.C([Li])CCC>O1CCCC1.C(OCC)(=O)C.O>[NH2:20][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:3]([C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:32][NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH:38]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cc(OCCCc2ccccc2)ccc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)c2cc(OCCCc3ccccc3)ccc2N)c1
Temperature: -70 °C

Procedure:
N-Methyl-N-methyloxy-2-amino-5-(3-phenylpropyloxy)benzamide (1.0 g) and N-tert-butoxycarbonyl 3-bromobenzylamine (0.92 g) were dissolved in tetrahydrofuran (20 ml). The solution was cooled to −70° C., to which was added dropwise, while stirring, 12 ml of a hexane solution of n-butyl lithium (1.6 mol/L) over 20 minutes. To the mixture was then added water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-amino-3′-tert-butoxycarbonylaminomethyl-5-(3-phenylpropyloxy)benzophenone as a yellow oily product (0.75 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: COC(=O)CCCCCBr
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CCCCCNc1ccccc1
Temperature: 0 °C

Procedure:
Aniline (2.79 g, 2.73 ml), 6.27 g of methyl 6-bromohexanoate and 12.24 g (0.09 mole) of sodium acetate trihydrate are heated at 80°-100° overnight in 15 ml of absolute ethanol. After cooling, the mixture is poured into 75 ml of ice-water and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate and evaporated in vacuo to give N-(5-methoxycarbonylpentyl)aniline.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:30][S-:31].[Na+].O>CS(C)=O>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([S:31][CH3:30])[CH:3]=[C:4]([NH:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: C[S-]
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(Cl)nn23)ccc1C(=O)NC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(NCC(C)(C)O)c2ncc(-c3ccc(C(=O)NC4CC4)c(C)c3)n2n1
Temperature: 70 °C
Yield: 54.6 %

Procedure:
To a solution of 83 mg (201 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a in 1.0 mL dimethyl sulfoxide were added 70 mg sodium methanethiolate and the mixture was heated under microwave irradiation at 70° C. for 1 hour. The mixture was poured into water and extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by recrystallisation to give 46.7 mg (55%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])/[CH:22]=[CH:23]/[C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[C:29](=[N:33][O:34][CH3:35])[CH2:28][CH2:27]4)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:37]1[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[CH:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[CH2:22][CH:23]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[C:29](=[N:33][O:34][CH3:35])[CH2:28][CH2:27]4)[C:43](=[O:44])[C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc21
Reactant: O=Cc1ccncc1
Product: CON=C1CCc2cc(C(CC(=O)c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)C(=O)c3ccncc3)ccc21
Yield: 88 %

Procedure:
The title compound (0.9 g, 88%) was prepared from the product of Step 2 and pyridine-4-carboxaldehyde using the method of Example 1 Step 4; MS(ES+) m/e 597 [M+H]+.
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>O1CCCC1.O>[N:20]1[CH:21]=[CH:22][C:17]([C:7]2[CH:6]=[CH:5][C:4]([CH:3]=[O:11])=[CH:9][CH:8]=2)=[CH:18][CH:19]=1
Reactant: Brc1ccncc1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A solution of 6.93 g of 4-bromobenzaldehyde dimethyl acetal in 40 ml of tetrahydrofuran was dropwise added to a mixture comprising 0.80 g of magnesium powder, a catalytic amount of iodine and 10 ml of tetrahydrofuran under stirring at a temperature in the bulk of 40° to 50° C. in a nitrogen atmosphere to prepare a Grignard reagent. This Grignard reagent was dropwise added to a solution of 4.46 g of 4-bromopyridine and 0.4 g of bis(1,3-diphenylphosphinopropane)nickel (II) chloride in 100 ml of tetrahydrofuran at a room temperature in a nitrogen atmosphere. The obtained mixture was refluxed for 4 hours and allowed to cool to a room temperature, followed by the addition of water. The obtained mixture was distilled to remove the tetrahydrofuran Ethyl acetate was added to the residue. The obtained mixture was extracted with dilute hydrochloric acid thrice. The extracts were combined, allowed to stand for a short time, made alkaline with concentrated aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol) to obtain 3.28 g of the title compound as a pale yellow crystal (yield: 64%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:9][CH2:8][C@H:7]1[OH:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:10][C@@H:7]1[CH2:8][CH2:9][C@@H:6]1[O:5][C:4]1[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=1[C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26]
Reactant: O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of C7 (484 mg, 2.08 mmol), triethylamine (0.87 mL, 6.3 mmol) and dichloromethane (30 mL) was cooled to 0° C. and methanesulfonyl chloride (0.32 mL, 4.2 mmol) was added drop-wise over 15 minutes. After an additional 30 minutes at 0° C., the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL), and the mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a colorless oil. Yield: 640 mg, 2.06 mmol, 99%. 1H NMR (400 MHz, CDCl3) δ 7.60 (br dd, J=7.8, 1.2 Hz, 1H), 7.45-7.51 (m, 1H), 7.06 (br dd, J=7.7, 7.6 Hz, 1H), 6.88 (br d, J=8.4 Hz, 1H), 5.26-5.32 (m, 1H), 5.01-5.06 (m, 1H), 2.95 (s, 3H), 2.53-2.63 (m, 1H), 2.37-2.46 (m, 1H), 2.18-2.30 (m, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-:18])(=O)=O)=CC=1.[C:20]([O:25][CH3:26])(=[O:24])/[CH:21]=[CH:22]/[CH3:23].O>O1CCCC1>[CH3:23][C:22]1[C:21]([C:20]([O:25][CH3:26])=[O:24])=[CH:16][NH:17][CH:18]=1
Reactant: C/C=C/C(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c[nH]cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To a suspension of potassium tert-butoxide (76.7 g) in tetrahydrofuran (900 mL) was added dropwise a solution of p-toluenesulfonylmethyl isocyanide (94.6 g) and methyl crotonate (48.5 g) in tetrahydrofuran (900 mL) over 30 min. The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a white solid (yield 16.8 g, 25%).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=O)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CCO>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[N:23][OH:24])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=NO)cccc32)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 42 (900 mg, 3 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (1.0 g, 15 mmol) and pyridine (1.0 mL). After the reaction mixture was stirred at 70° C. overnight, the solvent was removed in vacuo to afford 800 mg (85%) of 1-tosyl-1H-indole-4-carbaldehyde oxime (44) as white solid: MS (ESI) m/z=315 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH2:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:40][C:36]3[S:35][CH:39]=[CH:38][N:37]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNc1nc(-c2cccc(C(=O)Nc3nccs3)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 42.4 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added 1,3-thiazol-2-amine (3.5 mg, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (7 mg, 40%). LC-MS m/z 551 (M+H)+; 1H-NMR (MeOD) δ 2.22 (s, 6H), 2.46 (m, 2H), 3.16 (m, 2H), 4.51 (s, 2H), 7.17 (m, 3H), 7.51 (m, 2H), 7.69 (m, 1H), 7.83 (d, 1H), 8.16 (d, 1H), 8.23 (s, 1H).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[O:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:43]2[C@H:44]([CH3:67])[C@H:45]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[O:19]1[CH2:18][CH2:17][N:16]([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:43]4[C@H:44]([CH3:67])[C@@H:45]5[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]5[C:47]=4[C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[CH2:6]3)[O:10][CH:11]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)N3CCOCC3)co2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CCOCC5)co4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
To a solution of 3-acetylthio-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (260 mg, 0.835 mmol) (obtained as described in Reference Example 72) in dimethylformamide (13 ml) was added hydrazine acetate (92 mg, 1.00 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (496 mg, 0.835 mmol) in acetonitrile (25 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (582 μl, 3.34 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate:methanol (9:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (552 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:21]N1C(=O)CCC1=O.OS([O-])=O.[Na+]>C(#N)C>[Br:21][C:11]1[CH:12]=[N:13][N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:10]=1[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(-c2c(Br)cnn2C2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (10 g, 34.8 mmol) and acetonitrile (120 ml) were added into a flask and the temperature was adjusted to 0° C. with an ice bath. N-bromosuccinimide (6.80 g, 38.2 mmol) was added in small batches keeping the temperature below 5° C. The mixture was stirred at room temperature for 3 h. 10% NaHSO3 (100 ml) was added and the mixture was stirred for 15 min. The reaction mixture was extracted with DCM. The combined organic phases were dried, filtered and evaporated. The product was purified by recrystallization from ethanol. Yield 82%. 1H-NMR (400 MHz; DMSO-d6): δ 1.51-1.59 (m, 2H), 1.62-1.76 (m, 1H), 1.90-2.00 (m, 2H), 2.06-2.18 (m, 1H), 3.62-3.70 (m, 1H), 3.91-3.98 (m, 1H), 5.49 (dd, 1H), 8.02 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.38 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][N:9]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)(=O)=O.[F:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[C:7]1[CH2:8][N:9]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(OS(=O)(=O)C(F)(F)F)=CC(c3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(c3cc(F)ccc3F)=CC(c3ccccc3)C2)cc1

Procedure:
To a flame dried flask equipped with stir bar was added crude 1-[(4-nitrophenyl)sulfonyl]-5-phenyl-1,2,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate (1-5) (376 mg, 0.76 mmol), 2,5-difluorophenyl boronic acid (240 mg, 1.5 mmol), and Na2CO3 (243 mg, 2.3 mmol). The solids were dissolved in 5 mL 4:1 DME/H2O and degassed with N2. Pd(PPh3)4 (9 mg, 0.008 mmol) was added and the reaction was sealed under N2 and heated to 90 C for 2 h. Upon completion, the reaction was diluted with CH2Cl2, washed with 5% NaHCO3 and dried over MgSO4. Following filtration, the organic layer was concentrated and purified via ISCO (SiO2, 0-50% EtOAc/hexanes gradient) to provide 5-(2,5-difluorophenyl)-1-[(4-nitrophenyl)sulfonyl]-3-phenyl-1,2,3,6-tetrahydropyridine (1-6). 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.34 (in, 5H), 7.20 (m, 1H), 7.02 (m, 2H), 6.09 (s, 1H), 4.27 (m, 1H), 3.94 (m, 1H), 3.82 (m, 2H), 2.86 (dd, J=12.0, 8.0 Hz, 1H); MS 457.3 found 457.5 (M+H+) required.