Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1cnn2CCN1CCCC1
Temperature: 60 °C

Procedure:
4-Nitroindazole (3.00 g, 18.4 mmol) and potassium carbonate (7.50 g, 54.4 mmol) in 60 mL of DMF was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (4.80 g 28.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel. The silica gel was rinsed with triethylamine/ethyl acetate (1/4), the combined filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 4H), 2.45 (m, 4H), 2.92 (t, 2H, J=6.45), 4.65 (t, 2H, J=6.45), 7.65 (m, 1H), 8.10 (m, 1H), 8.30 (m, 1H), 8.52 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccnc(-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccnc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Methyl 2-(4-fluorophenyl)isonicotinate (278 mg, 1.20 mmol) was dissolved in methanol (2 mL) and the solution was added with 2 mol/L aqueous sodium hydroxide solution (2 mL, 4.0 mmol), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure and the obtained reaction mixture was dissolved in water. The solution was washed with ethyl acetate, then was added with 1 mol/L hydrochloric acid, and the obtained crystal was collected by filtration to obtain 2-(4-fluorophenyl)isonicotinic acid (134 mg, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:13]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCNC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-2-bromoethylamine (1.0 g) in anhydrous dimethylformamide (15 ml) are added N-methylcyclohexylamine (0.64 ml), anhydrous potassium carbonate (0.9 g) and sodium iodide (2.0 g), and the mixture is stirred at room temperature for three days. Water is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with a 10% aqueous sodium hydrogencarbonate solution, water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 0.82 g (72%) of N-(t-butoxycarbonyl)-N′-cyclohexyl-N′-methylethylenediamine as oily matter.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3]1=[O:22].[OH:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3](=[O:22])[C@@H:2]([NH:1][C:32](=[O:33])[C:25]2[C:24]([OH:23])=[C:29]([O:30][CH3:31])[CH:28]=[CH:27][N:26]=2)[CH2:10][O:9][CH2:8]1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCC(C)C
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a mixture of (3S,7S,8S,9S)-3-amino-7,8-diisobutoxy-9-methyl-1,5-dioxonan-2-one (170 mg, 0.536 mmol), 3-hydroxy-4-methoxypicolinic acid (136 mg, 0.803 mmol) and HATU (336 mg, 0.857 mmol) in a vial was added CH2Cl2 (3 mL), followed by 4-methylmorpholine (0.353 mL, 3.21 mmol), and the resulting suspension was stirred at room temperature for 3 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white solid (176 mg, 70%): 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 8.68 (d, J=8.0 Hz, 1H), 8.00 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.10-5.00 (m, 1H), 4.97 (dt, J=12.6, 6.3 Hz, 1H), 4.10-4.01 (m, 1H), 3.94 (s, 3H), 3.87-3.78 (m, 2H), 3.71 (dd, J=8.4, 6.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.38-3.28 (m, 2H), 3.28-3.17 (m, 3H), 1.90-1.76 (m, 2H), 1.45 (t, J=5.8 Hz, 3H), 0.98-0.88 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 170.33, 168.95, 155.38, 148.76, 140.66, 130.23, 109.58, 84.84, 83.75, 80.60, 77.74, 75.32, 73.97, 73.23, 56.11, 52.19, 29.13, 28.89, 19.60, 19.48, 19.47, 19.39, 18.66; ESIMS m/z 469.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])OC1C=CC=CC=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.O.Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:22][CH:19]1[CH2:21][CH2:20]1)=[O:18]
Reactant: NC1CC1
Reactant: O=C(Nc1ccc(O)cc1Cl)Oc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) while cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N—HCl (55 mL) were added thereto, and the mixture was stirred. The organic layer was then separated, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were collected by filtration and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=O>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:2]([S@@:5](/[N:7]=[CH:8]/[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(/C=N/[S@@](=O)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A solution of (S)-2-methylpropane-2-sulfinamide (2.0 g, 16.50 mmol) in THF (8.0 ml) and titanium(IV) ethoxide (17.3 ml, 82.51 mmol) were added sequentially to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (3.70 g, 17.33 mmol) in THF (8.0 ml). The resulting mixture was stirred at r.t for 2 hours. The reaction mixture was poured into ice/water and the suspension filtered. The filtrate was extracted with EtOAc and the organic layer was dried with MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dried under vacuum to provide the title compound (4.45 g, yield: 85%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].N1CC[C@H]([OH:29])C1.Cl>CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][C@H:21]([OH:29])[CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10]
Reactant: O[C@H]1CCNC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CC[C@H](O)C3)C2)nc1N

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 1, but using (S)-pyrrolidin-3-ol instead of pyrrolidine for Step 1 and a hydrogen chloride solution in methanol (1.25 M) for Step 2. MS (ES+) (M+H) 306.1; LCMS retention time: 0.26 minutes (Method M).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH2:25]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([CH3:38])=[CH:35][CH:36]=2)[C:31](=[O:39])[C:30]1=[O:40])[CH:26]([CH3:28])[CH3:27].[CH3:41][O:42][C:43]1[N:48]=[C:47]([C:49](=[O:51])[CH3:50])[CH:46]=[CH:45][CH:44]=1>>[OH:39][C:31]1([CH2:50][C:49]([C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([O:42][CH3:41])[N:48]=2)=[O:51])[C:32]2[C:37](=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=2)[N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:30]1=[O:40]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CC(C)C
Reactant: COc1cccc(C(C)=O)n1
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: COc1cccc(C(=O)CC2(O)C(=O)N(CC(C)C)c3ccc(C)cc32)n1

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 1-isobutyl-5-methylindoline-2,3-dione and commercially available 1-(6-methoxypyridin-2-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 7.70 (m, 2H), 7.19 (d, 1H), 7.10 (d, 1H), 6.97 (dd, 1H), 6.75 (d, 1H), 5.39 (s, OH), 4.02-3.98 (m, 4H), 3.56-3.42 (m, 3H), 2.30 (s, 3H), 2.16 (m, 1H), 0.97 (dd, 6H). calculated mass for C21H24N2O4, 368.17, observed, 391.1 (M+Na).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]1[O:24][CH2:23]1)=[O:19].[C:25]([OH:44])(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C>[C:25]([O:44][CH2:23][CH:22]([CH2:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:24])(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC
Temperature: 80 °C

Procedure:
1,3-Disteroylglycerol. A mixture of 171.3 g (0.5 mole) glycidol stearate, 156.5 g (0.55 mole) stearic acid, 1.0 g (0.025 mole) sodium hydroxide, and tetrabutylammonium hydrogensulfate (8.5 g, 0.025 mole) in 400 mL ethanol is heated at reflux (80° C.) for 20 hours. The solid material is removed by passage of the reaction mixture through a short column of silica gel. After evaporation, the crude solid product is subjected to centrifugal partition chromatography using a mixture of acetonitrile-hexane. Recrystallization of the resulting powder from acetone-water gives 1,3-distearoylglycerol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:31])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:31][S:40]([C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)(=[O:42])=[O:41])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted according to general operating instructions 13 with 4-chlorobenzenesulfonic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH2:10][OH:11])([CH2:8][OH:9])[CH:6]=[CH2:7])[CH3:2].[F:13][CH2:14][C:15]([CH2:17][F:18])=O>>[CH2:1]([O:3][C:4]([C:5]1([CH:6]=[CH2:7])[CH2:8][O:9][C:15]([CH2:17][F:18])([CH2:14][F:13])[O:11][CH2:10]1)=[O:12])[CH3:2]
Reactant: C=CC(CO)(CO)C(=O)OCC
Reactant: O=C(CF)CF
Product: C=CC1(C(=O)OCC)COC(CF)(CF)OC1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A vial was loaded with 2,2-bis-hydroxymethyl-but-3-enoic acid ethyl ester (0.88 g, 5.05 mmol), 1,3-difluoroacetone (0.95 g, 10.1 mmol) and para-toluene-4-sulfonic acid monohydrate (0.96 g, 5.05 mmol). The vial was sealed and heated in a microwave reactor at 100° C. for 15 min. The resultant brown oil was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic layer was filtered through a hydrophobic frit and evaporated to give a brown oil (0.98 g). The oil was purified by silica gel chromatography using iso-hexanes/ethyl acetate 3:1 to yield the title compound (0.619 g, 74%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 3.96 (d, J=12.0 Hz, 2H), 4.27 (q, J=7.1 Hz, 2H), 4.34-4.69 (m, 6H), 5.22-5.35 (m, 2H), 5.67-5.79 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (90 mg, 99%), MS (ISP) m/z=366.4 [(M+H)+], mp 329° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([CH:6]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:44]=[C:45]([CH:57]=[CH:58][C:59]=1[F:60])[CH2:46][C:47]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48]1>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[C:1]1([CH:6]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]2)[C:7]([NH:42][C:43]2[CH:44]=[C:45]([CH:57]=[CH:58][C:59]=2[F:60])[CH2:46][C:47]2([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:48][CH2:49]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC1CCN(C(C(=O)O)C2=CCCC2)CC1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1CCN(C(C(=O)Nc2cc(CC3(C(=O)OC(C)(C)C)CC3)ccc2F)C2=CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30.9 mg (0.13 mmol) of rac-cyclopent-1-en-1-yl(4-methoxypiperidin-1-yl)acetic acid were initially charged in 0.87 ml of DMF/pyridine (3:1), 63.8 mg (0.17 mmol) of HATU were added and the mixture was stirred at RT for 30 min 34.3 mg (0.13 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were then added, and the reaction mixture was stirred at RT overnight. The mixture was then diluted with ethyl acetate, washed repeatedly with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC (RP18 column; acetonitrile/water gradient with addition of 0.1% TFA, 10:90→95:5; run time 38 min). This gave 20.7 mg (33% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:29][CH2:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: NCCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCCO)ccc21
Yield: 65.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (3-hydroxy-propyl)-amide (136 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (179 mg), 3-amino-propan-1-ol (40 mg), HBTU (209 mg), and DIEA (200 uL) in DMF (1 mL). LC/MS: m/z 415.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2].[OH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](O)=[O:32]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:31]([C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]=2[OH:20])=[O:32])[CH2:8][N:7]1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1C(=O)C1CCCCC1
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1C(=O)C1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexanecarbonyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]pyrrolidine-2-carboxylic acid ethyl ester was prepared (2S,4S)-4-amino-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H31N2O5 [(M+H)+] 439.0, obsd. 439.4.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1
Yield: 99.4 %

Procedure:
10.6 g (0.071 mol) of p-tertiarybutylaniline was dissolved in 19 ml of glacial acetic acid. 8.0 g (0.078 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 3 hours. The reaction solution was then poured into 200 ml of water. The resulting crystal was filtered off, washed with water, and then dried to obtain 13.5 g (yield: 99.9%) of p-tertiarybutylacetanilide. The melting point of the crystal was from 172.5° C. to 173.5° C.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](N)=[CH:17][C:16]=1[F:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:17][C:16]=1[F:22]
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: O=S(=O)(Cl)c1ccc(Cl)c(F)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-fluoro-phenylamine.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.COC1C=CC(C[O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[CH:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH:36]=[CH:37][CH3:38])=[O:16])=CC=1.C(O)C(O)C.C1(C)C(O)=CC=CC=1>O.N1C=CC=CC=1.C(Cl)Cl>[NH2:25][CH:24]1[C:23](=[O:35])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH:36]=[CH:37][CH3:38])[CH2:19][S:20][C@H:21]12
Reactant: CC=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: Cc1ccccc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
22.8 g of phosphorous pentachloride, 150 ml of methylenechloride, and 8.88 ml of pyridine were added to a 20° C. reactor and stirred for 30 minutes. 30 g (62.6 mmol) of the 7-phenylacetamido-3-[propen-1-yl]-3-cephem-4-carboxylic acid p-methoxybenzyl ester prepared in Example 1 was dropwise added thereto, stirred for 2 hours, and cooled to −10° C. The reaction mixture was stirred for 2 hours after addition of 30 ml of 1,2-propanediol and then for 2 hours after addition of 120 ml of cresol. 200 ml of distilled water was dropwise added to the reaction solution and stirred for 1 hour. After phase separation, an aqueous layer was sent to a crystallization bath and an organic layer was extracted with 300 ml of 2N HCl and then the extract was sent to the crystallization bath. 200 ml of a 30% sodium hydroxide solution was dropwise added to the crystallization bath for crystallization and cooled to 0° C. to precipitate a solid. The solid was filtered and dried in vacuum to give 12 g (50 mmol, yield 80%, Z/E=10.1/1) of the titled compound as a beige solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:40][O:41][CH3:42])[C:14]([NH:16][CH:17]2[C:38](=[O:39])[N:19]3[C:20]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[O:26])=[C:21](O)[CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1)=[O:6].C(OCC)(=O)C.O>CN(C)C=O>[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:40][O:41][CH3:42])[C:14]([NH:16][CH:17]2[C:38](=[O:39])[N:19]3[C:20]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[O:26])=[C:21]([Cl:3])[CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 1.1 h
Yield: 19.4 %

Procedure:
Thionyl chloride (0.423 g.) was dropwise added to a stirred solution of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 1 g.) in N,N-dimethylformamide (10 ml.) under ice cooling over 2 minutes, and the solution was stirred at room temperature for 1.1 hours. Ethyl acetate (40 ml.) and water (30 ml.) were added to the resultant solution and shaken sufficiently. The aqueous layer was extracted with ethyl acetate, and the extract was combined with the ethyl acetate layer separated above. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (30 g.) and eluted with chloroform and then a mixture of chloroform and ethyl acetate (7:3). The latter eluate was concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.2 g.), mp 216° C. (dec.).