Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])(=[O:4])=[O:3].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43]12[CH2:50][CH2:49][N:46]([CH2:47][CH2:48]1)[CH2:45][CH2:44]2>C(#N)C>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43]12[CH2:50][CH2:49][N+:46]([CH2:6][CH2:7][CH:8]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[C:11]3[C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])([CH2:45][CH2:44]1)[CH2:47][CH2:48]2
Reactant: c1ccc2cc(C34CCN(CC3)CC4)ccc2c1
Reactant: COc1ccccc1C(=O)c1nccn1CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: COc1ccccc1C(=O)c1nccn1CC(CC[N+]12CCC(c3ccc4ccccc4c3)(CC1)CC2)c1ccc(Cl)c(Cl)c1
Product: CS(=O)(=O)[O-]
Yield: 80 %

Procedure:
1-Methanesulphonyloxy-3-(3,4-dichlorophenyl)-4-[2-(2-methoxybenzoyl)imidazol-1-yl]butane (0.55 g) (see Preparation 84) and 4-(2-naphthyl)quinuclidine (0.31 g) (see Preparation 7) were dissolved in acetonitrile (10 ml) and heated under reflux for 2.5 hours. The solvent was removed under reduced pressure and the resulting residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluting with a solvent gradient of 95:5 changing to 85:15, by volume, dichloromethane:methanol to give 4-(2-naphthyl)-1-(3-[3,4-dichlorophenyl]-4-[2-(2-methoxybenzoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate (0.65 g) as a white foam.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12](Cl)=[O:13].[CH3:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:16]([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13]
Reactant: CC(CC(C)(C)C)c1ccccc1N
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CC(C)(C)C)c1ccccc1NC(=O)c1c(C(F)(F)F)nn(C)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
At from 0° C. to −10° C., a solution comprising 8.1 g (42.4 mmol) of 5-fluoro-1-methyl-3-(trifluoromethyl)pyrazole-4-carbonyl chloride in 80 ml of tetrahydrofuran is added dropwise to a solution comprising 6.5 g (28.3 mmol) of 2-(1,3,3-trimethylbutyl)phenylamine and 5.7 g (56.6 mmol) of triethylamine in 200 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 1 h. For work-up, the mixture is filtered through silica gel and concentrated. Purification on silica gel (petroleum ether/ethyl acetate 3:1) gives 10.1 g (94% of theory) of [5-fluoro-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]-N-[2-(1,3,3-trimethylbutyl)phenyl]carbox-amide of log P (pH 2.3)=4.14.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[CH:20]1([NH:23][C:24]2[C:25]([NH2:31])=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[CH:20]1([N:23]2[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]=[C:15]2[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)[CH2:22][CH2:21]1
Reactant: Nc1cc(F)ccc1NC1CC1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)ccc3n2C2CC2)[nH]1
Yield: 3.5 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 645 mg of N1-cyclopropyl-4-fluorobenzene-1,2-diamine hydrochloride and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 3 ml of pyridine and 3 ml of dimethylformamide and then in 5 ml of acetic acid. After refluxing for two hours and purification by silica column chromatography, eluent: CH2Cl2/MeOH: 95/05, the residue obtained is purified by preparative HPLC/MS (method 1). After the acetonitrile has been evaporated off, the pH is brought to 8 using sodium bicarbonate (solid), then the aqueous phase is extracted with twice 25 ml of ethyl acetate, and the combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 15 mg of 2-[(1-cyclopropyl-5-fluoro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][C:6]=1Cl)[CH3:2].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)#[N:26]>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][C:6]=1[O:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1Cl
Reactant: N#Cc1ccc(O)cc1
Product: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1Oc1ccc(C#N)cc1
Yield: 62.4 %

Procedure:
2-Chloro-6-(4-trifluoromethoxy phenoxy)nicotinic acid ethyl ester (0.3 g, 0.83 mmol) and 4-cyanophenol (98.8 mg, 0.83 mmol) were coupled using the procedure of Example 17(b) to afford 0.23 g of the required product. Percentage purity (LCMS): 82.35%.
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][C:15]3[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=3)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH2:3]1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][C:15]3[N:16]([CH3:29])[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=3)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH2:3]1
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)[nH]3)C21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)n3C)C21

Procedure:
To a stirred solution of 77 mg (0.2 mmol) 2-methyl-butyric acid 3,7-dimethyl-8-[2-(6-oxo-1,6-dihydro-pyridin-2-yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml DMF are added 0.1 g (0.8 mmol) potassium carbonate and 0.1 g (0.8 mmol) methyl iodide. After 2 hours at room temperature the mixture is poured on water. The aqueous phase is separated and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated in vacuo. The residue is chromatographed over silica gel eluting with hexane/acetone 1/1 to afford the title compound as white powder.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:45]([N:48]([CH2:54][S:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:57])=[O:56])[C:49](=[O:53])[C@@H:50]1[O:52][CH2:51]1)[CH:46]=[CH2:47]>O1CCCC1>[CH2:45]([N:48]1[C@H:54]([S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)(=[O:57])=[O:56])[C@@H:50]([CH2:51][OH:52])[C:49]1=[O:53])[CH:46]=[CH2:47]
Reactant: C=CCN(CS(=O)(=O)c1ccccc1)C(=O)[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1C(=O)[C@H](CO)[C@H]1S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
8 ml of a tetra-n-butylammonium fluoride/THF solution which has been prepared from 5 g of tetra-n-butylammonium fluoride trihydrate by drying at 60°/0.1 torr and making up to 20.0 ml with tetrahydrofuran is added to a solution of 201 mg (0.757 mmol) of N-allyl-N-phenylsulphonylmethyl-(R)-glycidic acid amide in 1 ml of tetrahydrofuran. The resulting reaction mixture is stirred for 2 hours at 0° and then partitioned between methylene chloride and phosphate buffer solution having a pH of 8.0. The crude product isolated from the organic layer by means of concentration by evaporation is chromatographed over preparative silica gel plates in ethyl acetate/hexane (2:1) and the title compound is obtained in the form of a colourless oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 10 h
Yield: 13 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 6 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stifling at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 18.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])[CH:4]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)OC(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
4-(trifluoromethyl)pyridin-2-amine (1.0 g, 6.17 mmol) was dissolved in THF (20 mL) and treated with pyridine (600 μL, 7.4 mmol) and isopropenyl chloroformate (596 μL, 6.17 mmol). The reaction was stirred at rt for 6 h. The reaction was then concentrated and triturated with EtOAc. The crude residue was purified by MPLC (100% CH2Cl2) to yield a pale yellow solid (1.2 g, 79%); 1H-NMR (DMSO-d6) δ 11.0 (s, 1 H), 8.57 (d, J=5.1 Hz, 1H), 8.10 (s, 1 H), 7.45 (d, J=5.5 Hz, 1 H), 4.81 (t, J=1.1 Hz, 1H), 4.76 (s, 1 H), 1.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3([CH3:15])[CH2:14][CH2:13]3)[NH:9]2)=[CH:5][C:4]=1[CH3:16].[CH:17]([C:19]1[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=1)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3([CH3:15])[CH2:13][CH2:14]3)[NH:9]2)=[CH:5][C:4]=1[CH3:16]
Reactant: COC(=O)c1cccc(C=O)n1
Reactant: COc1cc2[nH]c(C3(C)CC3)cc2cc1C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cc2c(C3(C)CC3)[nH]c3cc(OC)c(C)cc23)n1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 6-methoxy-5-methyl-2-(1-methylcyclopropyl)-1H-indole (586 mg) and methyl 6-formylpyridine-2-carboxylate (450 mg) in dichloromethane (13.6 mL) was added triethylsilane (1.30 mL) under ice-cooling. Trifluoroacetic acid (0.313 mL) was added dropwise thereto, and the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was suspended in methanol. The precipitate was collected by filtration, washed with methanol, and then dried under reduced pressure at 40° C. to obtain the title compound (688 mg). 1H-NMR (CDCl3) δ ppm: 0.66-0.72 (2H, m), 0.80-0.86 (2H, m), 1.31 (3H, s), 2.19 (3H, s), 3.84 (3H, s), 4.05 (3H, s), 4.48 (2H, s), 6.78 (1H, s), 7.00 (1H, s), 7.04-7.10 (1H, m), 7.59 (1H, t, J=7.8 Hz), 7.79 (1H, br s), 7.91-7.97 (1H, m). ESI-MS (m/z): 365 (M+H)+
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@H:41]([N:46]([C:48]([C@H:50]2[N:54]([C:55]([CH:57]([OH:59])[CH3:58])=[O:56])[CH2:53][CH2:52][CH2:51]2)=[O:49])[CH3:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[C@@H:33]([CH3:60])[O:32][C:30](=[O:31])[C@H:29]([CH2:61][C:62]2[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[OH:79])[CH3:4].[C:80](OC(=O)C)(=[O:82])[CH3:81].[CH3:87][CH2:88][O:89]CC>N1C=CC=CC=1>[CH3:1][CH2:2][CH:3]([C@@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@@H:41]([N:46]([C:48]([C@H:50]2[N:54]([C:55]([CH:57]([O:59][C:80]([CH3:81])=[O:82])[CH3:58])=[O:56])[CH2:53][CH2:52][CH2:51]2)=[O:49])[CH3:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[C@H:33]([CH3:60])[O:32][C:30](=[O:31])[CH:29]([CH2:61][C:62]2[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[O:79][C:88]([CH3:87])=[O:89])[CH3:4]
Reactant: CCOCC
Reactant: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)C(C)O)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(C)[C@@H]1NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)C(C)OC(C)=O)[C@H](C)OC(=O)C(Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A sample of didemnin B (1.0 mg) was dissolved in 1 ml of pyridine and 0.5 ml of acetic anhydride was added. The solution was stirred at room temperature for 18 hours and evaporated to dryness. The residue obtained was dissolved in 3 ml of ether and extracted with water (4×1.5 ml). Evaporation of the dried (Na2SO4) organic phase afforded 0.90 mg (84% yield) of diacetyldidemnin B as a white, amorphous solid, mp 128°-131° C.; Rf 0.65; HPLC retention time (84:16 methanol:water) 9.1 min; EIMS (70 eV) major ions at m/z 70 (100% of base peak), 86 (12), 100 (13), 121 (45), 154 (18), 184 (15), 212 (20), 224 (4), 268 (9), 339 (9), 422 (3); HREIMS gave a molecular ion at m/z 1195.6604 which corresponds to the expected molecular formula C61H93N7O17 (Δ=-2.2 mmu).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25]CC4C=CC(OC)=CC=4)=[O:24])=[C:15](OS(C)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:37].[Na+].O.CN(C)[CH:42]=[O:43]>C(N(C(C)C)CC)(C)C>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][C:1]4[CH:6]=[CH:5][C:4]([O:43][CH3:42])=[CH:3][CH:2]=4)=[O:24])=[C:15]([SH:37])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(COC(=O)C2=C(OS(C)(=O)=O)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC(=O)C2=C(S)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 34.4 g (64.5 mM) of 4-methoxybenzyl 7β-phenylacetamido-3-methanesulfonyloxy-3-cephem-4-carboxylate in 100 ml of N,N-dimethylformamide were added at -30° C. a solution of 5.68 g (71.0 mM) of 70% sodium hydrosulfide in 50 ml of N,N-dimethylformamide and 12.5 g (96.9 mM) of diisopropylethylamine, and the mixture was stirred for 30 minutes. After the reaction, 500 ml of water was added and the mixture was washed with 300 ml of ethyl acetate. The aqueous layer was adjusted to pH 2 to 3 with 0.5% hydrochloric acid and extracted with 1 l of ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution (300 ml×3) and dried over anhydrous magnesium sulfate. The solvent was evaporate and n-hexane was added to the residue for powdering to give 22.0 g of 4-methoxyphenyl 7β-phenylacetamido-3-mercapto-3-cephem-4 -carboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.O1CCOCC1>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a suspension of 11-aminoundecanoic acid (17) in 1:1 water/dioxane (160 mL total) was added K2CO3 (10.28 g, 74.51 mmol) followed by the slow addition over 30 min of benzylchloroformate (CbzCl, 4.55 mL, 32.29 mmol), and the mixture was stirred at room temperature for 2 h. The solid was then removed by filtration, washed with water (3×30 mL) and dried in a vacuum oven at 40° C. for 72 h to afford a white solid 18 (2.91 g, 35% yield): 1H NMR (500 MHz, CD3OD) δ 1.36 (m, 12H), 1.50 (m, 2H), 1.62 (m, 2H), 2.18 (m, 2H), 3.08 (m, 2H), 5.14 (s, 2H), 7.38 (m, 5H); m/z (ESI) 336 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C[N:14]([CH:16]=[O:17])[CH3:15].[C:18](Cl)(=[O:22])C(Cl)=O>C1COCC1>[CH2:6]([C@@H:15]1[CH2:18][O:22][C:16](=[O:17])[N:14]1[C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1)[C:5]1[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(F)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 4-fluorocinnamic acid (85 g) and DMF (2.5 mL) in THF (850 mL) was added dropwise oxalyl chloride (97.4 g) at 5° C. over 10 min, and the mixture was stirred at 5° C. for 1 hr. The mixture was concentrated under reduced pressure, and the residue was suspended in THF (300 mL). This suspension was added dropwise at 5° C. to a mixture of (4R)-4-benzyl-1,3-oxazolidin-2-one (100 g), triethylamine (259 g), lithium chloride (108 g) and THF (850 mL) over 30 min, and the mixture was stirred at room temperature for 1 hr. The mixture was poured into water (850 mL), and the mixture was extracted with ethyl acetate (500 mL), washed with saturated aqueous ammonium chloride solution (500 mL) and saturated brine (500 mL), dried and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/IPE to give (4R)-4-benzyl-3-[(2E)-3-(4-fluorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one (134 g, 80%) as a white powder.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:32](=[CH:36][CH:37]1[CH2:39][CH2:38]1)[C:33](O)=[O:34])#[N:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:33]([C:32](=[CH:36][CH:37]4[CH2:39][CH2:38]4)[C:30]#[N:31])=[O:34])[CH2:25]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@@H]1CCCNC1
Reactant: N#CC(=CC1CC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
To a mixture of (R)-5-(4-phenoxyphenyl)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.26 mmol, 1.0 eq), 2-cyano-3-cyclopropylacrylic acid (45 mg, 0.32 mmol, 1.2 eq) and DIPEA (102 mg, 0.78 mmol, 3 eq) in 10 mL DCM was added HATU (150 mg, 0.40 mmol, 1.5 eq) and the reaction mixture was stirred for 4 h at RT under N2. The reaction mixture was purified by Pre-TLC to give the title compound (60 mg, 54% in yield). LCMS: m/z (505.0) (M+H)+ 1HNMR (400 MHz, CDCl3): δ 0.826˜0.837 (m, 2H), 1.147˜1.183 (m, 6H), 1.744˜2.210 (m, 5H), 4.661˜4.699 (m, 1H), 5.212˜5.226 (m, 2H), 6.499˜6.524 (m, 1H), 6.921˜7.367 (m, 10H) and 8.223 (S, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:3][CH2:4][C:5]([NH:43][CH:40]1[CH2:41][CH2:42][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:23]3[N:22]([CH3:21])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH:32]=2)[CH2:38][CH2:39]1)=[O:7])[CH3:2]
Reactant: Cn1c(-c2cccc(N3CCC(N)CC3)c2)nc2ccccc21
Reactant: CCOCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCC(=O)NC1CCN(c2cccc(-c3nc4ccccc4n3C)c2)CC1
Temperature: 70 °C
Yield: 435 %

Procedure:
Method N—Step e To a solution of ethoxyacetic acid (0.05 mL, 0.49 mmol) in acetonitrile (3 mL) was added CDI as a stock solution (0.80 g, 0.49 mmol) and the resulting suspension was stirred at room temperature for 3 h. {1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-ylamine hydrochloride (0.13 g, 0.41 mmol) and DIPEA (0.07 mL, 0.41 mmol) were added and the resulting solution heated at 70° C. overnight. The reaction was then cooled to room temperature, the solvent removed under reduced pressure. The crude product was redissolved in dichloromethane (4 mL) and washed with saturated Na2CO3 solution (2 mL) and water (2 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: dichloromethane:MeOH, gradient from 100% dichloromethane to 95% dichloromethane:5% MeOH) to afford 0.70 g (44%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[CH:20]=[N:19][CH:18]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl.CN(C)C=O>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:26][CH2:25][CH2:24][NH:23][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([CH3:16])[N:22]=1)=[O:6]
Reactant: Cc1cncc(NCCN)n1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cncc(NCCNC(=O)/C=C/C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (70 mg, 0.5 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (42 μl, 0.5 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(6-methylpyrazin-2-yl)ethane-1,2-diamine (38 mg, 0.25 mmol) and EDIPA (175 μl, 1 mmol) in a mixture of anhydrous dichloromethane (2 ml) and anhydrous dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 19.9 mg of a solid (0.07 mmol, 14.5% yield)