Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:44]=[CH:43][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[C:27]([NH:29][C:30]([N:32]3[CH2:37][CH2:36][C:35]([OH:42])([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:34][CH2:33]3)=[O:31])[CH:28]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1>CO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[C:27]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][C:35]([OH:42])([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37]3)=[O:31])[CH:28]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:25])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[CH:43][CH:44]=1
Reactant: COC(=O)C(C)(C)c1ccc(Oc2cc(NC(=O)N3CCC(O)(CC(C)C)CC3)cc(Oc3ccc(F)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(Oc3ccc(C(C)(C)C(=O)O)cc3)c2)CC1
Temperature: 45 °C
Yield: 82.6 %

Procedure:
At room temperature, in a 1 L pear-shaped evaporating flask, the compound prepared in Example 8 (24.8 g) was dissolved in a mixed solution of methanol (150 mL) and THF (150 mL) and the solution was stirred. The solution was then heated to 45° C., gradually added with a 1 N sodium hydroxide aqueous solution (107 mL) and stirred overnight at 45° C. The solution was added with a 2 N sodium hydroxide aqueous solution (20 mL). After stirring for 1 hour, the solvent was distilled off under reduced pressure and the solution was further stirred for 1.5 hours at 45° C. A 2 N sodium hydroxide aqueous solution (12 mL) was further added and the solution was stirred for 45 minutes at 55° C. The solution was cooled to 0° C. and added with ice and a 5 N hydrochloric acid aqueous solution until the reaction system was acidic (pH=2). The reaction system was diluted with ethyl acetate and extracted. An organic layer was further washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=65:35→44:56→30:70) to give the titled compound (20 g) having the following physical properties.
Reaction SMILES: C(=O)=O.[CH:4](O)([CH3:6])[CH3:5].[Li].[Li].C(OCC)C.BrC(C)=C.[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1[CH:28]=[O:29].[Cl-].[NH4+]>C(OCC)C>[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:26])([CH3:27])[C:21]=1[CH:28]([C:4]([CH3:6])=[CH2:5])[OH:29]
Reactant: CC(C)O
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: C=C(C)Br
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOCC
Product: C=C(C)C(O)C1=C(C)CCCC1(C)C
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
Into a 500 ml flask equipped with immersion thermometer, mechanical stirrer, 250 ml addition funnel, Friedrich's condenser, dry-ice/isopropyl alcohol bath and gas bubbler is placed 1.9 grams (44.7 cm in length) (0.28 gram atoms) of cut up lithium wire and 100 ml anhydrous diethyl ether. The lithium/diethyl ether mixture is cooled to -10° C. 15.7 Grams (0.13 moles) of 2-bromo-1-propene (dissolved in approximately 40 ml anhydrous diethyl ether) is added drop-wise to the reaction mass keeping the temperature at between -10° C. and -5° C. Following addition of the 2-bromo-1-propene, the reaction mass is stirred for a period of 30 minutes at 0° C. and for a period of 1.5 hours at room temperature (20° C.). The reaction mass is then chilled to -20° C. and 15.2 grams (0.10 moles) of beta cyclocitral (dissolved in approximately 60 ml diethyl ether) is added dropwise while keeping the reaction temperature at between -20° C. and -15° C. After addition of the beta cyclocitral, the reaction mass is stirred for a period of 15 minutes at -20° C.; and for a period of 120 minutes at +24° C. The reaction mass is then poured into a saturated aqueous ammonium chloride solution, and the resulting organic phase is separated from the aqueous phase. The aqueous phase is washed with anhydrous diethyl ether. The organic phase is washed with saturated brine. The organic phase and the ether extracts are combined and the resulting material is dried and concentrated to yield 19.98 grams of crude material. This material is distilled under vacuum to 5 fractions as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 77 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 77%). 1H NMR (200 MHz, CDCl3): δ 2.95 (s, 3H), 2.99-3.02 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 7.01-7.05 (m, 2H), 7.17-7.42 (m, 5H), 7.81-7.84 (m, 1H).
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2F)[N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+]>O1CCCC1>[F:23][C:20]1[CH:21]=[C:22]2[C:17]([C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[N:8][N:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][CH:19]=1
Reactant: CN1CCN(C(=NNc2ccccc2)c2ccc(F)cc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution, under nitrogen, 17.0 g of 1-[(phenylhydrazono)(2,4-difluorophenyl)methyl]-4-methylpiperazine in 200 ml of tetrahydrofuran was added dropwise a solution of 7.1 g of potassium t-butoxide in 75 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to yield 6-fluoro-1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole as an oil. The oil was dissolved in ethanol-diethyl ether and treated with ethereal hydrogen chloride to precipitate the hydrochloride salt. Recrystallization from methanol yielded 9.0 g, (45%) of 6-fluoro-1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole hydrochloride, m.p. 298°-300° (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:14][CH:15]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24]C2C=CC=CC=2)=[CH:19][CH:18]=1)[CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:49])=[N-]>C(OCC)C>[C:35]([O:34][C:32]([NH:31][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:14][N:11]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:49])=[CH:42][CH:41]=1)[CH2:12][CH3:13])=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: C=[N+]=[N-]
Reactant: CCN(CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CCN(CC(Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 77 %

Procedure:
The product from Example 19A (21 mg, 38 mmol) was treated with diazomethane in diethyl ether (˜0.4 M, 1 mL) at ambient temperature. After stirring for 2 days, the solvent was removed under reduced pressure. The residue was dissolved in fresh diazomethane solution and stirred at ambient temperature for an additional 2 days. This process was repeated until TLC (CHCl3:methanol, 19:1) indicated the reaction was complete. The residue was purified by column chromatography on silica gel (CH2Cl2:methanol, 99:1) to provide the title compound as a colorless amorphous solid (17 mg, 77%). 1H NMR (CDCl3) δ 7.09 (d, J=8.9 Hz, 4H), 6.82 (d, J=8.5 Hz, 4H), 4.70 (br s, 1.3 H), 4.53 (br s, 0.7 H), 3.83-3.78 (m, 2H), 3.78 (s, 6H), 2.85-2.68 (m, 4H), 2.60-2.27 (m, 6H), 1.41 (s, 12H), 1.38 (s, 6H), 0.94-0.84 (m, 3H); MS (APCI+) m/z 572 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>CN(C)C=O.C(N(CC)CC)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:23]1[CH2:28][CH2:27][N:26]([S:5]([CH2:4][CH2:3][O:2][CH3:1])(=[O:7])=[O:6])[CH2:25][CH2:24]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Reactant: COCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 3 h
Yield: 82.1 %

Procedure:
Under nitrogen, 2-(methyloxy)ethanesulfonyl chloride (43.8 g) was added dropwise over 30 minutes to a cooled, 10° C., suspension of 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide hydrochloride (Intermediate 1, 66 g) in N,N-dimethylformamide (DMF) (350 mL) and triethylamine (77 mL). The reaction mixture was stirred for 3 hours. The reaction mixture was poured into water (2000 mL) and stirred for 1 hour. The resultant solid was collected by filtration and washed with water. The solid was dried in vacuo at 40° C. to give the title compound (67.1 g) as a cream solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:36]3[CH:37]=[N:38][CH:39]=[C:40]([C:41]#[N:42])[CH:43]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 182.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=486.3 [M+H]+, m/z=488.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=6.97 Hz, 3H) 3.15 (q, J=7.09 Hz, 2H) 3.37 (t, J=5.99 Hz, 2H) 3.44-3.55 (m, 2H) 4.62 (br. s, 1H) 7.36 (d, J=9.29 Hz, 2H) 7.82-7.90 (m, 2H) 8.11 (d, J=2.45 Hz, 1H) 8.54 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 9.04 (dd, J=5.62, 1.96 Hz, 2H) 10.26 (s, 1H).
Reaction SMILES: [O:1]=O.[C:3]([C:6]12[CH2:15][C:10]3([C:16]([OH:18])=[O:17])[CH2:11][CH:12]([CH2:14][C:8]([C:19]([OH:21])=[O:20])([CH2:9]3)[CH2:7]1)[CH2:13]2)([OH:5])=[O:4]>C(O)(=O)C>[C:16]([C:10]12[CH2:15][C:6]3([C:3]([OH:5])=[O:4])[CH2:13][C:12]([OH:1])([CH2:14][C:8]([C:19]([OH:21])=[O:20])([CH2:7]3)[CH2:9]1)[CH2:11]2)([OH:18])=[O:17]
Reactant: O=C(O)C12CC3CC(C(=O)O)(C1)CC(C(=O)O)(C3)C2
Reactant: O=O
Solvent: CC(=O)O
Product: O=C(O)C12CC3(O)CC(C(=O)O)(C1)CC(C(=O)O)(C3)C2
Temperature: 75 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
In an atmosphere of oxygen, to 25 mL of acetic acid was added 10 mmole of the 1,3,5-tricarboxyadamantane, 1 mmole of NHPI and 0.005 mmole of Co(AA)2 and the mixture was stirred for 6 hours at 75° C. As a result,the conversion was 76% and 1,3,5-tricarboxy-7-adamantanol was obtained in a 70% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22](=[O:23])[C:11]2=[CH:12][C:13]([CH:20]=O)=[C:14]3[N:19]([C:10]2=[N:9]1)[CH:18]=[CH:17][CH:16]=[CH:15]3.[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2([C:37]#[N:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22](=[O:23])[C:11]2=[CH:12][C:13]([CH2:20][N:34]3[CH2:35][CH2:36][C:31]([C:27]4[CH:26]=[C:25]([CH3:24])[CH:30]=[CH:29][N:28]=4)([C:37]#[N:38])[CH2:32][CH2:33]3)=[C:14]3[N:19]([C:10]2=[N:9]1)[CH:18]=[CH:17][CH:16]=[CH:15]3
Reactant: Cc1ccnc(C2(C#N)CCNCC2)c1
Reactant: O=Cc1cc2c(=O)n(-c3ccccc3F)nc-2n2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccnc(C2(C#N)CCN(Cc3cc4c(=O)n(-c5ccccc5F)nc-4n4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
2-(2-Fluorophenyl)-3-oxo-2,3-dihydropyrazolo[4,3-c]quinolizine-5-carbaldehyde (0.025 g, 0.081 mmol) was suspended in a mixture of 1,2-dichloroethane (2 mL) and acetonitrile (4 mL) containing powdered 4 Å molecular sieves and treated with 4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile (0.018 g, 0.094 mmol. 1.2 equiv), acetic acid (0.028 mL, 0.49 mmol, 6.0 equiv), and sodium triacetoxyborohydride (0.034 g, 0.16 mmol, 2.0 equiv). After stirring at ambient temperature for 60 hours, the mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[N:36]#[N:37]>O1CCOCC1.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:2]5[CH:3]=[CH:4][N:37]([CH2:11][C:10]6[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=6)[N:36]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1Cc2ccc(-c3ccn(Cc4cccnc4)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
The residue was dissolved in 1,4-dioxane (0.50 mL) and water (0.10 mL), to this solution was added 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.018 g, 0.043 mmol, Peak 1, Example 49, Step 7), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.76 mg, 0.00216 mmol), potassium carbonate (11.9 mg, 0.0862 mmol) and the mixture was vacuumed and refilled with N2 for 3 times. The reaction was stirred at 110° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=496.3.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][CH:20]([F:29])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:29][CH:20]([F:19])[C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(C(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(C(F)F)c1
Yield: 71.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 1.1 g of 3-(difluoromethyl)-4-fluoroaniline (stage 2) and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 260 mg of N-[3-(difluoromethyl)-4-fluorophenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Cl:8].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[Cl:8][C:4]1[N:3]([O:2][C:15]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:16])[CH:7]=[CH:6][N:5]=1
Reactant: On1ccnc1Cl
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Product: O=C(On1ccnc1Cl)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (54%, oil).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:25][O:26][CH3:27])[C:9]([NH:11][CH:12]2[C:23](=[O:24])[N:14]3[C:15]([C:20]([OH:22])=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.[Na].[C:29]([O:36][CH2:37]I)(=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>O.CN(C)C=O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:25][O:26][CH3:27])[C:9]([NH:11][CH:12]2[C:23](=[O:24])[N:14]3[C:15]([C:20]([O:22][CH2:37][O:36][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: CCCCCC(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Yield: 55.5 %

Procedure:
7-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn-isomer: 1.5 g.) and sodium bicarbonte (0.56 g.) were dissolved in water (50 ml.) at room temperature with stirring and lyophilized. A solution of iodomethyl hexanoate (0.93 g.) in dimethylformamide (5 ml.) was added dropwise to a solution of the product obtained above in dimethylformamide (15 ml.) at -5° C. and stirred at the same temperature for 30 minutes. Ethyl acetate (50 ml.) and water (100 ml.) were added to the resultant solution and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml.) twice. The extracts were combined with the ethyl acetate layer, washed with a saturated aqueous solution of sodium bicarbonate three times and a saturated aqueous solution of sodium chloride three times in turn, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. After washing the concentrate with n-hexane (50 ml.), n-hexane (50 ml.) and diethylether (25 ml.) were added to the residue and allowed to stand in a refrigerator overnight. The precipitating powder was collected by filtration, washed with n-hexane and dried to give a mixture (1.0 g.) of n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn-isomer) and n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-2-cephem-4-carboxylate (syn-isomer.)
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[Li+].CC([N-]C(C)C)C.[Br:23][CH2:24][CH2:25]Br>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:25][CH2:24][Br:23])[C:12](=[O:14])[N:13]=1
Reactant: O=C1CSC(N[C@H]2C[C@@H]3CC[C@H]2C3)=N1
Reactant: BrCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCBr
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)thiazol-4(5H)-one (2.98 g, 14.2 mmol) in THF (15 ml) at −78° C. was added LDA (2.0 N, 28.4 ml). After 5 min, 1,2-dibromoethane (4.87 mL, 56.8 mmol) was added, and the reaction mixture was stirred for 3 h at −78° C. The resulting reaction mixture was poured into sat'd NaH2PO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as a white solid. MS (ES+): 317 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:10][C:11]1[C:12]([CH:16]=O)=[N:13][NH:14][CH:15]=1>>[Br:10][C:11]1[C:12]([CH2:16][N:1]2[CH2:9][CH2:8][N:7]([CH2:16][C:12]3[C:11]([Br:10])=[CH:15][NH:14][N:13]=3)[CH2:6][CH2:5][N:4]([CH2:16][C:12]3[C:11]([Br:10])=[CH:15][NH:14][N:13]=3)[CH2:3][CH2:2]2)=[N:13][NH:14][CH:15]=1
Reactant: C1CNCCNCCN1
Reactant: O=Cc1n[nH]cc1Br
Product: Brc1c[nH]nc1CN1CCN(Cc2n[nH]cc2Br)CCN(Cc2n[nH]cc2Br)CC1

Procedure:
L4: 1,4,7-tris(4-bromo-pyrazol-3-ylmethyl)-1,4,7-triazacyclononane was prepared by procedure B using TACN and 4-bromo-pyrazole-3-carboxaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][NH:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH2:26]>C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:26][CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][NH:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C(=O)OC(C)(C)C)c1ccc(C2CCC(=O)CC2)cc1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCC(C(=O)OC(C)(C)C)c1ccc([C@H]2CC[C@H](NC)CC2)cc1

Procedure:
from 4-[4-(1-tert.butoxycarbonyl-methylaminoethyl)-phenyl]-cyclohexanone and methylamine. Oil. Rf value: 0.5 (alumina, ethyl acetate/methanol=10:1, v:v).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=1)=[O:5].C(N(CC)C(C)C)(C)C.F[C:28]1[N:33]=[C:32]([F:34])[CH:31]=[CH:30][N:29]=1>ClCCl>[F:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([N:2]([CH3:1])[CH2:3][C:4]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=2)=[O:5])[N:33]=1
Reactant: Fc1ccnc(F)n1
Reactant: CCOC(=O)Cc1csc(NC(=O)CNC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(F)n2)n1

Procedure:
The product of step (i) (3.0 g) was slurried in dichloromethane (100 ml) and treated with N,N-diisopropylethylamine (4.0 ml) forming a complete solution. 2,4-Difluoropyrimidine (J. Heterocyclic Chem. 1985, 22, 149) (0.6 g) was then added quickly with stirring. After 10 minutes the solvents were evaporated under reduced pressure and the residue purified by chromatography eluting with 20% ethyl acetate in isohexane. The first and minor component of the mixture to be eluted was the subtitle compound (0.77 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][C:7]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Br)cc1OC
Solvent: ClCCl
Product: COc1cc(Br)c(S(=O)(=O)Cl)cc1OC
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a cooled (0° C.) solution of 4-bromoveratrole (15 mL, 100 mmol) in dichloromethane (100 mL) was added dropwise chlorosufonic acid (26 mL, 400 mmol). The reaction was allowed to slowly warm to ambient temperature and maintained for 3 hours, at which time it was concentrated and diluted with ether (300 mL). The resultant solution was then washed with ice cold water (2×250 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated to furnish a grayish powder (25 g, 78%).