Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11](Cl)=[C:10]([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:43][C:44]([F:58])([F:57])[C:45]1[CH:46]=[C:47]([Mg]Br)[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1.FC(F)(F)C1C=C(Br)C=C(C(F)(F)F)C=1>O.C1COCC1>[CH3:1][C:2]1[C:11]([C:47]2[CH:48]=[C:49]([C:51]([F:54])([F:52])[F:53])[CH:50]=[C:45]([C:44]([F:43])([F:58])[F:57])[CH:46]=2)=[C:10]([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(C)c1Cl
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Agent: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c(C)c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a THF solution of the obtained 2,4-dimethyl-3-chloroquinoline (0.65 g) and Ni(dpp)Cl2 (dpp: 1,3-bis(diphenylphosphino)propane) (0.1 g), 3,5-bis (trifluoromethyl)phenylmagnesium bromide prepared from Mg and 3,5-bis(trifluoromethyl)bromobenzene was dropped and the reaction solution was allowed to react for 24 hours at room temperature. Water was added to the reaction solution and the organic layer was extracted using CHCl3. The solvent was removed under reduced pressure and the residue was purified through column chromatography to obtain 2,4-dimethyl-3-[3,5-bis(trifluoromethyl)phenyl]quinoline.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([NH:34]C(=O)C(F)(F)F)[CH:28]=[CH:29][C:30]=1[NH:31][CH2:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[NH2:34][C:27]1[CH:28]=[CH:29][C:30]([NH:31][CH2:32][CH3:33])=[C:25]([N:24]=[C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12](=[O:13])[C:11](=[C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[S:15]3)[S:10]2)[CH:26]=1
Reactant: CCNc1ccc(NC(=O)C(F)(F)F)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCNc1ccc(N)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 1.6 %

Procedure:
To the product of Example 138 (0.15 g, 0.26 mmol) in MeOH (30 mL) was added H2O (6 mL) and fine mesh K2CO3 (0.30 g, 1.5 mmol), and the solution was stirred 24 h at 55° C. The reaction mixture was cooled, diluted with EtOAc (30 mL), washed with H2O (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to provide the title compound (2 mg). MS(ESI): 488(MH+).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@:2]1([CH3:9])[C:3]([OH:5])=[O:4].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:14]([O:13][C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@@:2]1([CH3:9])[C:3]([OH:5])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@]1(C(=O)O)CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@]1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To the solution prepared by dissolving 500 mg of H-α-Me-Pro-OH (commercially available from Chem-Impex International Inc.) and 693 mg of benzyl chloroformate in 10 mL of 1,4-dioxane and 5 mL of water, a 1 M aqueous sodium hydroxide solution was added at room temperature so as to keep pH 10, and the solution was stirred at room temperature for 30 minutes. To the reaction solution, 5 M HCl was added so as to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure to obtain 842 mg of 1-[(benzyloxy)carbonyl]-2-methyl-L-proline [63-1] (hereinafter, referred to as the compound [63-1]).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[Br:13]NC(=O)CCC(N)=O>ClCCl.CN(C)C=O>[NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[Br:13]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(O)c(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
To a solution of methyl 4-amino-3-hydroxybenzoate (2.5 g, 15.0 mmol) in dichloromethane (71 mL) and N,N-dimethylformamide (3.6 mL) was added N-bromosuccinamide (2.93 g, 16.5 mmol). The mixture was stirred at ambient temperature. After 15 min, the mixture was quenched with sat. sodium sulfite. Hydrochloric acid (1.0 M) was added and the mixture was extracted with dichloromethane (3×). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→100% ethyl acetate) gave the title compound (1.2 g). LC-MS [M]=246.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH3:16])[C:6]=2[CH:5]=1)[CH3:2].F[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH3:16])[C:6]=2[CH:5]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1)[CH3:2]
Reactant: CCNc1ccc2c(c1)C(C)=CCC2(C)C
Reactant: O=C(O)c1ccc(F)nc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(c1ccc2c(c1)C(C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 12 %

Procedure:
To a mixture of 1.78 g (8.3 mmol) of ethyl-(5,5,8-trimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 166) and 0.55 g (3.9 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (158 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:14][O:15][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 4.50 g of Boc-L-leucinol in 30 ml of THF were added 4.74 g of p-toluenesulfonylchloride, 7.2 ml of TEA and 0.25 g of DMAP. The reaction was stirred at rt overnight. The pH of the reaction was then adjusted to 6 by the addition of 1 M aqueous hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated to yield 6.94 g of toluene-4-sulfonic acid (S)-2-tert-butoxycarbonylamino-4-methyl-pentyl ester.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCN(CC)CCN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCNCCN(CC)CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.3 %

Procedure:
A mixture of N,N-diethylethylenediamine (9.6 g, 0.0826 mol) and 8.4 g (0.0826 mol) of triethylamine in 40 ml of chloroform was added dropwise to the ice cold chloroform solution (40 ml) of octanoyl chloride (13.4 g, 0.0826 mol). After addition, the ice bath was removed and the solution was stirred for 5 hours at room temperature. The reaction mixture was stirred with aqueous sodium bicarbonate for one hour. The organic layer was then dried over magnesium sulfate leaving a yellow liquid which was concentrated in vacuo. The yellow liquid was subject to high vacuum distillation to yield 9.65 g (0.040 mol, 48.3%, b.p.0.05mm =115° C.). The above amide (9.65 g, 0.040 mol) was reduced with lithium aluminum hydride (1.7 g, 0.045 mol) to yield 6.94 g (0.030 mol, 76.1%) of the product after vacuum distillation: (b.p.0.05mm =77° C.). NMR (CDCl3) δ 2.7-2.4 (m, 10H, NCH2 and NHCH2), 1.6 (s, 1H, NH), 1.5 (m, 2H, NHCH2CH2), 1.28 (s, 10H, NHCH2CH2 (CH2)5), 1.01 (t, 6H, NCH2CH3), 0.88 (t, 3H, CH3). Elemental Analysis: Caled. for C14H32N2 (228.41): C, 73.61; H, 14.12; N, 12.26. Found: C, 73.68; H, 14.76; N, 12.12.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.[CH3:36][N:37]1[CH2:44][CH2:43][CH2:42][C@H:38]1[C:39](O)=[O:40].C(Cl)CCl>C(Cl)Cl.N1C=CC=CC=1>[C:23]([N:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:39]([C@@H:38]3[CH2:42][CH2:43][CH2:44][N:37]3[CH3:36])=[O:40])=[CH:35][CH:34]=2)=[O:11])[CH:13]([CH3:33])[CH2:14]1)(=[O:25])[CH3:24]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1CC(C)N(C(=O)c2ccc(OCCCNC(=O)[C@@H]3CCCN3C)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
(2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (100 mg, 0.204 mmol) was dissolved in methylene chloride (2 mL) and pyridine (2 mL). N-methyl proline (33 mg, 0.255 mmol) and EDC (63 mg, 0.255 mmol) were added and the reaction was stirred for 1 hour. The mixture was partitioned between methylene chloride and water; the methylene chloride layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate) to afford the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]C)=[O:17])=[CH:7]2.[OH-].[Li+].C(O)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCc1cc2c(c(Cl)c1OC)OC(C(F)(F)F)C(C(=O)OC)=C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc2c(c(Cl)c1OC)OC(C(F)(F)F)C(C(=O)O)=C2

Procedure:
To a solution of 0.14 g(0.4 mmol) of methyl 8-chloro-6-ethyl-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 5 mL of tetrahydrofuran was added a solution of 82 mg (1.95 mmol ) lithium hydroxide in 8 mL of water, followed by addition of 3 mL of ethanol. The resulting solution was heated to reflux for two h. The mixture was concd in vacuo. The residue was diluted with water and acidified to pH=1.0 with dilute hydrochloric acid. The product was extracted with ethyl acetate and the combinced organic extracts dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 86 mg (64%) of a the product as white solid: 1H NMR (CDCl3/400 MHz) 7.80(s, 1H ), 7.01(s, 1H ), 5.77(q, J=6.8 Hz, 1H), 3.89(s, 3H), 2.62(q, J=7.6 Hz, 2H), 1.21(t, J=7.2 Hz, 3H). MS (ESI+) 337.0 (M+1, 100). MS(ES−) 335.0 (M−H, 100), HRMS (ES−) m/z calcd for (C14H11ClF3O4) M−H: 335.0292, found 335.0297.
Reaction SMILES: [F:1][C:2]([F:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15](O)=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[S:10][C:11]([C:15]([NH:56][CH2:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)=[O:16])=[C:12]([CH3:14])[N:13]=2)[N:6]=[N:5]1
Reactant: Cc1nc(-c2cn(CC(F)(F)c3ccccc3)nn2)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn(CC(F)(F)c3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1-(2,2-difluoro-2-phenylethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid (0.10 g, 0.28 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.07 g, 0.34 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.51 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroxy-benzotriazole (0.10 g, 0.74 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and 3-(aminomethyl)pyridine (0.04 mL, 0.04 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, then diluted with ethyl acetate (30 mL), washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to the title compound as a white solid (0.03 g, 7%): mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.53-8.47 (m, 1H), 8.23 (s, 1H), 7.74-7.64 (m, 1H), 7.55-7.39 (m, 5H), 7.32-7.22 (m, 1H), 6.56 (t, J=5.6 Hz, 1H), 5.02-4.93 (m, 2H), 4.60 (d, J=5.6 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.8, 157.6, 157.3, 149.2, 149.1, 143.1, 135.7, 133.7, 132.8, 131.2, 129.0, 125.0, 124.6, 123.7, 122.9, 118.6, 56.1, 41.6, 17.3; MS (ES+) m/z 441.4 (M+1).
Reaction SMILES: [CH:1]1[C:6]([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]([C:13](NCC2NCCCC2)=[O:14])=[C:3]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:2]=1.OC1C=CC(O)=CC=1C(O)=O.FC(F)(S([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>>[F:27][C:25]([F:26])([F:28])[CH2:24][O:23][C:3]1[CH:2]=[CH:1][C:6]([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([O:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[O:14]
Reactant: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(O)c1cc(O)ccc1O
Product: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
Process for the synthesis of FLECAINIDE comprising the reaction between 2,5-dihydroxybenzoic acid with trifluoroethanol perfluorobutanesulphonate to give the intermediate trifluoroethanol 2,5-bis-trifluoroethoxybenzoate, the reaction of said intermediate with 2-aminomethylpiperidine to give FLECAINIDE.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][C@H:14]1[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]1.C12CC(C=C1)C(=O)N2>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:13][C@H:14]2[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]2)([NH:9][CH:10]=[O:11])[CH2:6][N:7]=1
Reactant: N[C@@H]1CC=C(CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: O=C1NC2C=CC1C2
Product: NC1=NCC(NC=O)(N[C@@H]2CC=C(CO)C2)C(Cl)=N1

Procedure:
By the method of Example 7, N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.56 g, 52.4 mmol) was reacted with (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, 52.4 mmol), available from (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (Chiroscience) by methods described in Examples 1-4 and 42 of U.S. Pat. No. 5,049,671. Crystallization from ethyl acetate--methanol gave title compound as white crystals, mp. 148-150° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6)δ: 8.97 and 8.55 (s and d with J=11.3 Hz, total 1, NHCHO), 8.12 and 7.80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7.78 (both d, J=7.4 Hz, total 1, NH), 6.60 and 6.40 (both 8, total 2, NH2), 5.48 (s, 1, =CH), 4.74 (t, J=5.5 Hz, 1, OH), 4.74-4.60 (m, 1, NCH), 4.0-3.90 (m, 2, CH2O), 2.75-2.55 and 2.40-2.15 (both m, 2 each, 2CH2); [α]58920 -4.4°, [α]57820 -5.2°, [α]54620 -4.8°, [α]43620 -20.0°, [α]36520 -60.4° (c 0.25, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:11]1)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 2,2-dimethylpropionic acid 2-[(R)-3-(2-amino-5-fluorophenylamino)piperidin-1-yl]ethyl ester (500 mg, 1.48 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (309 mg, 1.63 mmol) and HOAt (202 mg, 1.48 mmol) in DCM (30 mL) was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (341 mg, 1.78 mmol). The reaction mixture was stirred in the ice bath for 1.5 h, then diluted with DCM, washed with 2M Na2CO3 and then water. The organic fraction was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 50-100% EtOAc in cyclohexane) affording the title compound as a purple gum (quantitative). LCMS (Method B): RT 2.50 min [M+H]+ 509.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C@H:11]1[CH2:13][C@@H:12]1[CH2:14][C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:9][CH2:10][C@H:11]1[CH2:13][C@@H:12]1[CH2:14][C:15]([O:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: BrCc1ccccc1
Reactant: O=C(O)C[C@H]1C[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C[C@H]1C[C@@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
Benzyl bromide (539 μL, 4.53 mmol) was added to a mixture of 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetic acid (536 mg, 4.12 mmol), potassium carbonate (626 mg, 4.53 mmol) and DMF (8 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water (80 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 33→53% ethyl acetate/hexane) to give benzyl 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (718 mg, 3.26 mmol, 79%) as a colorless oil.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18]Cl)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1.[I-:46].[Na+].[C:48]([NH2:56])(=[O:55])[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1.C(OC(C)C)(C)C>CN(C)C=O>[I-:46].[CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18][N+:52]4[CH:53]=[CH:54][C:49]([C:48](=[O:55])[NH2:56])=[CH:50][CH:51]=4)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccncc1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: NC(=O)c1cc[n+](CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3S(=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate 1-oxide (syn isomer) (2.5 g) and sodium iodide (3.4 g) in N,N-dimethylformamide (20 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added isonicotinamide (0.91 g) under ice-cooling and the mixture was stirred for 2 hours at the same temperature. The mixture was poured into diisopropyl ether to give an oil. The oil was separated by decantation and triturated with water. The solid was dissolved in tetrahydrofuran, dried over magnesium sulfate, concentrated under reduced pressure, and triturated in diisopropyl ether to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate 1-oxide iodide (syn isomer) as a solid.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:22]1C2C[CH:28](O)[CH:24]([CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][C:7]12[CH2:28][CH:24]([CH2:23][CH2:22]1)[CH2:25][CH2:8]2)=[O:5])#[N:2]
Reactant: OC1CC2CCC1C2
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC(C(=O)OC12CCC(CC1)C2)=C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 53.9 %

Procedure:
55.4 g (0.2 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 100 g of norborneol and 4 g of Na2CO3 were reacted with one another at about 185° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 4 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with cyclohexane and dried, giving 37 g (53%) of norbornyl 2-cyano-3,3-diphenylacrylate [λmax=304 nm, E11 =386] as a colorless solid.