Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.Cl[C:28]([O:30][C@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)=[O:29].C(N(CC)CC)C>CN(C=O)C>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:28](=[O:29])[O:30][C@H:31]3[CH2:35][CH2:34][O:33][CH2:32]3)[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(Cl)O[C@H]1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Yield: 64.9 %

Procedure:
To a solution of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (175 mg, 0.5 mmol) in DMF at 0° C. were added (S)-tetrahydrofuran-3-yl chloroformate (75 mg, 0.5 mmol) and triethylamine (137 μL, 1.0 mmol) simultaneously. Ten to fifteen minutes after addition, the reaction was complete, and it was quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 98% CH2Cl2/2% MeOH gave (S)-tetrahydrofuran-3-yl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (150 mg, 54%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:30])[C:13](=[O:29])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br>CN(C)C=O.ClCCl>[Br:31][C:16]1[CH:15]=[C:14]2[C:19]([C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[C:11]([CH:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[N:12]([CH3:30])[C:13]2=[O:29])=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
An ice cold mixture of methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (187 mg, 0.459 mmol) in N,N-Dimethylformamide (DMF) (2.0 mL) was treated with a solution of bromine (0.071 mL, 1.377 mmol) in dichloromethane (DCM) (2.0 mL). The ice bath was removed and the mixture, which was excluded from light by wrapping the reaction vessel with aluminum foil, was allowed to stir at ambient temperature overnight. The mixture was quenched by adding saturated sodium bicarbonate and then extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel to afford the title compound as a thick colorless oil (123 mg, 55%) that solidified upon standing. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.63 (d, J=2.1 Hz, 1 H), 7.56 (ddd, J=2.2, 6.0, 8.6 Hz, 1 H), 7.31-7.22 (m, 1 H), 7.20-6.88 (m, 3 H), 5.20 (s, 1 H), 3.83-3.74 (m, 3 H), 3.69 (m, 3 H), 2.37 (s, 3 H), 2.31 (s, 3 H), 1.01 (m, 9 H); LC/MS (m/z) ES+=486 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.O=[C:23]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=1)[CH:3]=[C:2]2[NH:1][CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Product: CNc1nccc(-c2cc(NC3CCNC3)c3cc(OC)ccc3c2)n1

Procedure:
4-(6-methoxy-4-(pyrrolidin-3-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 148 was synthesized according to General Procedure E utilizing compound 33 and replacing tert-butyl 4-oxopiperidine-1-carboxylate with tert-butyl 3-oxopyrrolidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:36][CH2:35][C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:38])[CH3:37]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 550.1 [(M+H+]; mp 229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11])[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[CH2:10][OH:11])[CH3:7]
Reactant: COC(=O)c1ccccc1C(C)Oc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1cccc(Cl)c1)c1ccccc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of the crude methyl 2-[1-(3-chlorophenoxy)ethyl]benzoate described above (14.8 g) in THF (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (1.93 g) in THF (70 ml) cooled to 0°-5° C. Following the addition, the reaction mixture was stirred at about 0° C. for 30 minutes, then at room temperature for 2 hours. It was poured carefully into water and was extracted with ether. The extracts were washed successively with water (×2) and brine, then dried and concentrated to give 2-[1-(3-chlorophenoxy)ethyl]benzyl alcohol (11.72 g, 85% pure by GC) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:51][C:50]([O:52][C:53]3[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=3[F:60])=[CH:49][C:48]2=[O:61])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:2][O:3][C:4](=[O:16])[CH:5]([N:15]1[CH2:51][C:50]([O:52][C:53]2[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=2[F:60])=[CH:49][C:48]1=[O:61])[CH2:6][C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Reactant: COC(=O)C(N)Cc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
In a flask was placed 2-amino-3-(2,6-dichloro-phenyl)-propionic acid methyl ester hydrochloride salt (313 mg, 1.10 mmol), acetonitrile (5 mL) and N,N-diisopropylethylamine (200 μL, 1.23 mmol). This mixture was stirred at 60° C. for 1 h and then cooled to 25° C. The mixture was then treated with N,N-diisopropylethylamine (200 μL, 1.23 mmol) and heated at 80° C. and a solution of 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 321 mg, 1.00 mmol) in acetonitrile (1 mL) was added slowly. The mixture was heated at 100° C. for 16 h and then placed in a sealed microwave tube and heated at 140° C. for 1 h in the microwave. The mixture was then concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 10% ethyl acetate/hexanes to 100% ethyl acetate) afforded 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (58 mg, 12%) as a gold oil: HR-ES-MS m/z calculated for C20H15NO4Cl2F2 [M+H]+ 442.0419, observed 442.0420.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:18])([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:29]1[CH2:43][CH2:42][CH2:41][C@H:30]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl.C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:18])([C:15]([N:29]1[CH2:43][CH2:42][CH2:41][C@H:30]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a stirring solution of EtOCO-D,L-Phe(αMe)-OH (10.3 g, 41 mmol), HOBT (5.5 g, 41 mmol), Pro-OBzl.HCl (9.9 g, 41 mmol) and N,N-diisopropylethylamine (15.9 g, 123 mmol) in dimethylformamide (200 mL) at 0° C., was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (8.6 g, 45 mmol). After stirring for 16 h, the solvents were removed in vacuo and the residue was dissolved in ethyl acetate (500 mL). The organic phase was washed three times with 0.1N HCl, three times with saturated aqueous NaHCO3, and once with brine. The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 1:1 ethyl acetate:hexanes and the product containing fractions (as judged by TLC) were combined and concentrated in vacuo to give 13.5 g (75% yield) of a white foam.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[C:25]([Si:12]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: OC1CC=CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cyclopent-3-enol (500 mg, 6.0 mmol) in CH2Cl2 (30 mL) at 0° C. was added imidazole (1.06 g, 15.6 mmol) and TBDPS-Cl (2.1 g, 7.8 mmol). The reaction was gradually warmed to room temperature and stirred for 16 hours. The reaction was then diluted with water (40 mL) and extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 5% EtOAc/Hexanes afforded tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane, which was then dissolved in CH2Cl2 (30 mL). 70% m-CPBA (830 mg, 6.9 mmol) was added at 0° C. The reaction was gradually warmed to room temperature while stirring for 16 hours. The reaction was then diluted with a saturated aqueous solution of NaHCO3 (40 mL) and extracted using CH2Cl2 (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 20% EtOAc/Hexanes afforded (6-oxabicyclo[3.1.0]hexan-3-yloxy)(tert-butyl)diphenylsilane.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:14])=O.CN(C=O)C>>[Cl:14][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ccc2nc(S)oc2c1
Solvent: CN(C)C=O
Product: Oc1ccc2nc(Cl)oc2c1
Temperature: 80 °C
Yield: 68 %

Procedure:
2-Mercapto-benzoxazol-6-ol (1 eq) was dissolved in thionyl chloride (10 eq). DMF (0.6 eq) was slowly added to this solution at room temperature. The mixture was heated to 80° C. and refluxed for 15 minutes. The reaction mixture was cooled to room temperature and the solvent was removed. The resulting solid was azeotroped three times with xylenes. The solid was dissolved in a 10% solution of THF in ethyl acetate and washed once with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with anhydrous sodium sulfate, filtered, and the solvent removed. The solid was triturated with acetonitrile to yield pure product with a 68% yield. MH+=170.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:18])=O.[N+](C1C([N+]([O-])=O)=C(C=CC=1)C(O)=O)([O-])=O.Cl>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([Cl:18])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 90 %

Procedure:
3,5 dinitrobenzoic acid and ethyl acetate were placed in a reaction vessel. While thionyl chloride with some drops of DMF (about double as many moles as dinitrobenzoic acid) was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and was poured into hexane and then the precipitated solid was separated by filtration. 3,5-dinitrobenzoic chloride was obtained in a 90% yield.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:34])[CH2:24][C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[N:28][NH:29]3)=[N:19][C:18]=1[CH3:35])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].C1COCC1.Cl>O>[NH:29]1[C:30]2[C:26](=[C:25]([CH2:24][C:23]([NH:22][C:20]3[S:21][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:36])=[O:2])=[O:16])=[C:18]([CH3:35])[N:19]=3)=[O:34])[CH:33]=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(NC(=O)Cc2cccc3[nH]ncc23)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of the (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (34 mg, 0.0646 mmol), lithium hydroxide monohydrate (32 mg, 0.763 mmol), THF (2 mL) and water (1 mL) was stirred at 25° C. for 1½ h. Aqueous 2N HCl was added and the reaction mixture was stirred for 2 hrs and then concentrated under reduced pressure. The resulting crude product was purified by HPLC to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (21 mg, 63.5%) as a white solid. MS m/e 513.5 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][CH:6]=[C:7]([Br:9])[N:8]=1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C1COCC1>[Br:3][C:4]1[N:5]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:6]=[C:7]([Br:9])[N:8]=1
Reactant: Brc1c[nH]c(Br)n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(Br)nc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 1.2 eq) was added portionwise to a solution of 2,4-dibromoimidazole (1 eq.) in THF at 0° C. After 1 hr, SEM-Cl (1.2 eq.) was added and the mixture was stirred at RT for 12 hr. The reaction was carefully quenched with H2O and the aqueous phase was extracted with EtOAc (3×). The combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 5-33% EtOAc/pentane yielded the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ: 7.09 (1H, s), 5.22 (2H, s), 3.54 (2H, t, J=8.1 Hz), 0.92 (2H, t, J=8.1 Hz), 0.00 (9H, s). MS (ES) C9H16Br2N2OSi requires: 354/356/358, found: 355/357/359 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=[O:6].F[C:18]1[CH:30]=[CH:29][C:21]2[S:22](=[O:28])(=[O:27])[CH2:23][CH2:24][CH2:25][O:26][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:28]=[S:22]1(=[O:27])[C:21]2[CH:29]=[CH:30][C:18]([O:1][C:2]3[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=3)[C:5]([OH:7])=[O:6])=[CH:19][C:20]=2[O:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S1(=O)CCCOc2cc(F)ccc21
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)O)c1
Temperature: 160 °C
Yield: 48.7 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.245 g, 1.08 mmol), 8-fluoro-3,4-dihydro-2H-1,5-benzoxathiepine 5,5-dioxide (235 mg, 1.08 mmol) and potassium carbonate (299 mg, 2.17 mmol) in acetonitrile (7.8 mL) was heated in a microwave reactor at 160° C. for 5 hours. The mixture was reduced in vacuo and the residue purified by preparative HPLC (on a C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant) to give the desired compound as a beige solid (222 mg). 1H NMR δ (d6-DMSO): 1.22 (d, 3H), 2.22-2.24 (m, 2H), 3.17 (s, 3H), 3.43-3.58 (m, 4H), 4.03-4.16 (m, 1H), 4.16-4.25 (m, 2H), 4.63-4.73 (m, 1H), 6.80-6.85 (m, 1H) 6.90-7.01 (m, 2H), 7.15 (s, 1H), 7.35 (s, 1H), 7.83 (d, 1H); m/z 421 (M−H)−
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:44])=[CH:46][CH:47]=1
Reactant: NCCc1cccs1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCCc1cccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-thiopheneethylamine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2-ylethyl)benzamide was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.71 (d, J=7.9 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 7.24-7.13 (m, 3H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (dd, J=5.0, 3.5 Hz, 1H), 6.86 (d, J=3.5 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.51-6.46 (m, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 4.97 (ABq, 2H), 4.83 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.78-3.57 (m, 2H), 3.13 (t, J=6.2 Hz, 2H), 2.95 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.9, 166.8, 161.8, 161.3, 141.7, 141.1, 139.2, 134.1, 132.5, 128.7, 127.5, 127.4, 127.0, 125.4, 123.9 (2C), 123.6, 119.9 (2C), 118.7, 109.0, 93.2, 80.5, 72.3, 57.6, 43.7, 41.2, 29.8, 28.9; MS (ES+) m/z 523.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C:17](=O)[C:16](=[O:19])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[NH:21][NH2:22].Cl.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:25]([O:24][C:20]([NH:21]/[N:22]=[C:17]1/[C@H:5]2[S:4][CH2:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16]/1=[O:19])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)/C(=N\NC(=O)OC(C)(C)C)[C@H]2SC1
Yield: 25.6 %

Procedure:
In chloroform (70 ml) are dissolved 2,2,2-trichloroethyl 3-methyl-7-oxo-3-cephem-4-carboxylate (14.30 g), t-butyl carbazate (6.00 g) and pyridine hydrochloride (4.77 g) and the mixture is refluxed in a Dean-Stark trap packed with Molecular Sieve 3A for 30 minutes. The reaction mixture is washed with 1 N-HCl and water in that order, dried over magnesium sulfate and concentrated. The residual oil is subjected to silica gel (240 g) column chromatography and elution is carried out with ethyl acetate-benzene to give crystals of 2,2,2-trichloroethyl (E)-7-t-butoxycarbonylhydrazono-3-methyl-3-cephem-4-carboxylate (4.88 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([N:14]([CH3:22])[S@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](c1cc(F)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of (S)-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methyl propane-2-sulfinamide (350 mg, 1.12 mmol) in THF (10 mL) under N2 atmosphere, was dropwise added LHMDS (2.24 mL, 1 M in THF, 2.24 mmol) at −60° C. The reaction was stirred for 30 min at −60° C. followed by addition of MeI (240 mg, 1.69 mmol). The mixture was stirred at rt for another 3 h and quenched with water at 0° C. The resulting mixture was extracted with EtOAc (2×40 mL). The organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (270 mg, yield: 74%); m/z (ES+): 326 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O.O1CCOCC1>[CH2:18]([O:25][C:26]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1

Procedure:
A 1L 3-neck flask was charged with 25.09 (160 mmol) trans-4-aminomethyl-cyclohexanecarboxylic acid, 77.4 g (560 mmol) K2CO3, 250 mL dioxane and 250 mL water. The suspension was stirred, then 28.5 mL (200 mmol) benzylchloroformate was added dropwise. The reaction mixture was then stirred at room temperature for 6.5 hours then poured into 800 mL water and acidified (slowly) with 1N HCl. The resulting white precipitate was filtered and dried-45.6 g.