Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16]CC(C)=C)[C:3]=1[C:4]([O:6][CH2:7][C:8]([CH3:10])=[CH2:9])=[O:5]>CN1C(=O)CCC1>[F:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([CH2:4][C:3]([CH3:11])=[CH2:2])=[C:11]([OH:16])[C:3]=1[C:4]([O:6][CH2:7][C:8]([CH3:10])=[CH2:9])=[O:5]
Reactant: C=C(C)COC(=O)c1c(OCC(=C)C)ccc(F)c1F
Solvent: CN1CCCC1=O
Product: C=C(C)COC(=O)c1c(O)c(CC(=C)C)cc(F)c1F
Yield: 200 %

Procedure:
A solution of 2-methylallyl 2,3-difluoro-6-(2-methylallyloxy)benzoate (733) (1.53 g, 5.42 mmol) in NMP (3.5 mL) was heated in the microwave at 200° C. for 6 h. The solvent was removed in vacuo to provide 2-methylallyl 2,3-difluoro-6-hydroxy-5-(2-methylallyl)benzoate (734) (1.53 g) which was directly used in the next step reaction without further purification.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:18])[C@H:6]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:5]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:3])[CH3:2].O([CH2:40][CH2:41][O:42][CH3:43])S(C(F)(F)F)(=O)=O.[H-].[Na+]>ClCCl.CN1CCCC1=O>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:40][CH2:41][O:42][CH3:43])[C@H:6]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:5]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3cc(C)nc23)[C@@H](O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Reactant: COCCOS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COCCO[C@@H]1c2ccn3cc(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz,[D6] DMSO): δ=1.19 (s, 9H), 2.15 (s, 3H), 2.38 (s, 3H), 3.27 (s, 3H), 3.45-3.57 (m, 2H), 3.83-3.93 (m, 2H), 4.60 (d, 1H), 5.31 (t, 1H), 5.79 (d, 1H), 6.94 (s, 1H), 7,20 (s, 5H), 7.74 (s, 1H), 8.43 (d, 1H).
Reaction SMILES: [S:1]1[C:5]([C:6]([C:8]2[N:9]=[CH:10][N:11]3[CH:15]=[CH:14][S:13][C:12]=23)=[O:7])=[CH:4][N:3]=[CH:2]1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[S:1]1[C:5]([C:6]([C:8]2[N:9]=[CH:10][N:11]3[CH:15]=[C:14]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[S:13][C:12]=23)=[O:7])=[CH:4][N:3]=[CH:2]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C(c1cncs1)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncs3)c2s1

Procedure:
The title compound (260 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 187 mg of 7-(thiazol-5-yl)carbonylimidazo[5,1-b]thiazole, 0.235 ml of tri-n-butylstannyl chloride, and 1.2 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[O:8])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7]([C:5]1[S:6][C:2]([C:26]2[C:18]([CH3:17])=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH:25]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: Cc1cc2scnc2cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccccc1Cl)c1ccc(Br)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1cc2scnc2cc1-c1ccc(C(=O)Nc2ccccc2Cl)s1
Temperature: 110 °C
Yield: 83.9 %

Procedure:
A mixture of (5-bromo(2-thienyl))-N-(2-chlorophenyl)carboxamide (7, 21 mg, 0.07 mmol), 6-methyl-5-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))benzothiazole (14) (19 mg, 0.07 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 8 mg) and sodium carbonate (22 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to prep HPLC chromatography to furnish 22.6 mg of N-(2-chlorophenyl)[5-(6-methylbenzothiazol-5-yl)(2-thienyl)]carboxamide (17) as yellow solid (yield: 83.9%; purity>95%). LC-MS: calcd. for C19H13ClN2OS2: 385 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl.[F:15][CH:16]([F:33])[CH2:17][N:18]1[CH2:22][CH2:21][C:20]([C:25]2[CH:30]=[C:29](F)[CH:28]=[C:27]([F:32])[CH:26]=2)([O:23][CH3:24])[CH2:19]1>>[F:32][C:27]1[CH:28]=[C:29]([S:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]3)[CH:30]=[C:25]([C:20]2([O:23][CH3:24])[CH2:21][CH2:22][N:18]([CH2:17][CH:16]([F:15])[F:33])[CH2:19]2)[CH:26]=1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Reactant: COC1(c2cc(F)cc(F)c2)CCN(CC(F)F)C1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)CCC(=O)N4C)c2)CCN(CC(F)F)C1
Yield: 51 %

Procedure:
Using an analogous procedure to that described in Example 6, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 1-(2,2-difluoroethyl)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine hydrochloride to give 3-[5-fluoro-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-1-(2,2-difluoroethyl)-3-methoxypyrrolidine as a gum in 51% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 120 °C
Yield: 53.9 %

Procedure:
To a solution of N-tert-butyloxycarbonylpiperazine (5 g) in anhydrous dimethylformamide (75 ml) containing triethylamine (7.4 ml), was added 1-fluoro-4-nitrobenzene (3.81 g). The solution was heated at 120° C. for 5 h then the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous phase washed with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was triturated with ether and the resultant yellow solid filtered off. The solid was then chromatographed on silica gel, using a gradient elution of 0→1% methanol in dichloromethane to afford the title compound (4.45 g) as a yellow solid. 1H NMR (360 MHz, CDCl3) δ 1.49 (9H, s), 3.40-3.43 (4H, m), 3.59-3.62 (4H, m), 6.82 (2H, dd, J=9 and 1.8 Hz), 8.13 (2H, dd, J=9 and 1.8 Hz). MS (CI, NH3) 307 (M+).
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(N(CC)CC)C.CCOCC.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(OCC)(=O)C>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([O:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])(=[O:32])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOP(=O)(CO)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(COS(=O)(=O)c1ccccc1C(F)(F)F)OCC
Reaction time: 8 h

Procedure:
A solution of 11.1 g of diethyl P-(hydroxymethyl)phosphonate (Example 17), 11 ml of triethylamine and 30 ml of ether was added dropwise over one hour to 15.5 g of 2-(trifluoromethyl)benzenesulfonyl chloride and 50 ml of anhydrous ether. The addition was mildly exothermic and a white precipitate began to form shortly after the addition was begun. The reaction was stirred overnight, then diluted with 300 ml of ethyl acetate and washed with three 85 ml portions of water. The organic phase was dried with magnesium sulfate, filtered and concentrated. The resulting crude product was purified via flash chromatography on Merck® silica gel (230-400 mesh) eluting with hexanes and ethyl acetate to yield 10.5 g of the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]([NH:13][C:14]4C=C[CH:17]=[CH:16][N:15]=4)=[O:12])[C:7](=[O:27])[C:6]=3[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1.NC1[S:35]C=CN=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]([NH:13][C:14]4[S:35][CH:17]=[CH:16][N:15]=4)=[O:12])[C:7](=[O:27])[C:6]=3[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Reactant: Nc1nccs1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 39.2 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol) (from Example 1, Step 3), commercially available 2-aminothiazole (110 mg, 0.63 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (112 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (79 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silical gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(8-Chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-thiazol-2-yl-propionamide (113 mg, 46.3%) as a white solid. 1H NMR (DMSO-d6) δ: 12.56 (br. s., 1H), 7.50 (d, J=3.4 Hz, 3H), 7.20-7.36 (m, 10H), 7.05-7.15 (m, 3H), 5.06 (d, J=5.9 Hz, 3H), 4.40 (d, J=18.6 Hz, 3H), 4.09 (d, J=18.6 Hz, 3H), 3.76 (s, 6H), 1.52-1.91 (m, 24H), 1.04-1.32 (m, 17H), 0.90-1.03 (m, 7H), 0.79-0.88 (m, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1([C:44]2[CH:60]=[CH:59][CH:58]=[CH:57][C:45]=2[CH2:46][O:47][CH2:48][CH2:49][C:50]([CH3:56])([CH3:55])[C:51]([O:53]C)=[O:52])[CH2:10][CH2:9][N:8]([C:11]([C@:13]2([O:34][C:35]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[S:37][CH:36]=3)[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:30])[C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[C@@H:14]2[CH2:31][CH2:32][CH3:33])=[O:12])[CH2:7][CH2:6]1)#[N:4]>C1COCC1.CO>[C:3]([C:5]1([C:44]2[CH:60]=[CH:59][CH:58]=[CH:57][C:45]=2[CH2:46][O:47][CH2:48][CH2:49][C:50]([CH3:56])([CH3:55])[C:51]([OH:53])=[O:52])[CH2:10][CH2:9][N:8]([C:11]([C@:13]2([O:34][C:35]3[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[S:37][CH:36]=3)[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:30])[C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[C@@H:14]2[CH2:31][CH2:32][CH3:33])=[O:12])[CH2:7][CH2:6]1)#[N:4]
Reactant: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(C#N)(c2ccccc2COCCC(C)(C)C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(C#N)(c2ccccc2COCCC(C)(C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2 N Aqueous sodium hydroxide (5.5 mL) was added to methyl 4-(2-(4-cyano-1-((2R,3S)-2-propyl-1-(3-(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)benzyloxy)-2,2-dimethylbutanoate (312 mg, 0.37 mmol) in THF/methanol (1:3, 12 mL). The reaction was stirred for 8 h at room temperature then concentrated. The residue was diluted ethyl acetate (30 mL) and the pH adjusted to 1 with 1 N hydrochloric acid. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by C18 semi-prep HPLC to obtain A60 (300 mg, 99% yield) as a white powder after lyophilization from water/acetonitrile: 1H NMR (CDCl3, 300 MHz) δ 8.81-8.82 (d, J=3.9 Hz, 1H), 8.06-8.08 (d, J=8.1 Hz, 1H), 7.24-7.50 (m, 5H), 6.84-6.87 (d, J=8.1 Hz, 1H), 6.53-6.56 (m, 1H), 4.65-5.57 (m, 5H), 3.48-3.75 (m, 6H), 3.08-3.20 (m, 3H), 1.22 (s, 6H), 0.93-2.47 (m, 17H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2C)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(C)c2C)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[CH:14][CH:15](O)[S:16][C@H:11]12)=[O:8].P(Br)(Br)[Br:34].C(OCC)(=O)C.O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Br:34])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: BrP(Br)Br
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CC(O)S[C@H]12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Br)CS[C@H]12

Procedure:
To a solution of 19 g. (40 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-2-hydroxy-3-cephem-4-carboxylate in 300 ml of dry DMF was added 15 g. (56 mmole) of phosphorus tribromide and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate and water and the organic phase was separated and washed repeatedly with water and dried over magnesium sulfate. The dried organic phase was evaporated in vacuo to dryness. The crude reaction product residue weighing about 9 g. was purified by chromatography over 500 g. of silica gel using ethyl acetate-hexane (55:45 v:v) as eluent. The eluate was evaporated to dryness under reduced pressure and the product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-bromo-3-cephem-4-carboxylate was obtained crystalline by triturating the dry residue with diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].F[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)Cc1ccccc1
Yield: 72.5 %

Procedure:
Combine benzyl-[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.7 g, 8.3 mmol), 4-fluoronitrobenzene (1.2 g, 8.3 mmol), cesium carbonate (5.4 g, 16.6 mmol), and N,N-dimethylformamide (70 mL), stir at room temperature overnight. Pour the reaction into brine then extract with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (3.5 g). The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield benzyl-{2-[4-(4-nitro-phenoxy)-phenyl]ethyl}-carbamic acid tert-butyl ester (2.7 g): 1H NMR (CDCl3, 300.00 MHz): 8.22 (d, 2H, J=9.2 Hz), 7.44-6.95 (m, 11H), 4.44 (m, 2H), 3.44 (m, 2H), 2.84 (m, 2H), 1.52 (m, 9H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:16]S(C(C)(C)C)=O)[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl.O1CCOCC1>CO>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of ethyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate (220 mg; 0.54 mmol) in MeOH (3 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.27 ml; 1.08 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 298.22 g/mol.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH:24]=[CH2:25])[CH2:16]1)C1C=CC=CC=1>ClCCCl>[CH:24]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH2:23][NH:15][CH2:16]2)=[CH2:25]
Reactant: C=Cc1cccc2c1CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: C=Cc1cccc2c1CNC2
Temperature: 5 °C
Yield: 71.2 %

Procedure:
A solution of 1-chloroethyl chloroformate (7.51 mL, 69.6 mmol) in 1,2-dichloroethane was added to a cooled (ice bath) solution of 2-benzyl-4-vinylisoindoline (58 mmol) in 1,2-dichloroethane (150 mL) over 20 minutes, maintaining the internal reaction temperature<5° C. After addition was complete, the reaction mixture was allowed to warm to RT, then heated to reflux for 45 minutes. The reaction mixture was recooled to RT, and the solvent was removed by evaporation. MeOH (200 mL) was added, and the mixture was heated to reflux for 30 minutes, then cooled to RT. The solvent was then removed by evaporation. Water (200 mL) was added, and the resulting mixture was washed with EtOAc (2×250 mL). The aqueous layer was made basic with 2N sodium hydroxide then extracted with DCM (4×250 mL). The combined organic extracts were dried over Na2SO4 and filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica (DCM/MeOH/NH4OH 97/3/0.3 to 95/5/0.5) to give the title compound as a brown oil, (6.00 g). LRMS (ESI) m/z 146 [(M+H)+; calcd for C10H12N: 146].
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]=[N+:20]=[N-:21])[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.C(OC(=O)C)C.O>[O:25]=[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]=[N+:20]=[N-:21])[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:5][CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.7 %

Procedure:
(5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one (2.3 g, 6.5 mmol) (see WO 01/81350) was dissolved in methanol/ethylacetate (1:1, 100 ml) and sodium periodate (1.75 g, 8.2 mmol), dissolved in water (20 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 7 hours at room temperature, filtered to remove most of the salts and the methanol was evaporated under vacuum. The aqueous solution thus obtained was extracted with ethyl acetate, dried over sodium sulfate and it was evaporated to dryness. The residue was subjected to chromatography on silica gel with acetone/hexane (2:1) to give 2.18 g of the product.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])#[N:2]>[Rh].N.CCO>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: N#CCCCCCCCCC(=O)O
Agent: [Rh]
Agent: N
Solvent: CCO
Product: NCCCCCCCCCC(=O)O
Yield: 69.4 %

Procedure:
A slurry of 9-cyanopelargonic acid (8.6 g, 48 mrnol), a catalytic amount 5%Rh/Al2O3, and 200 mL of 2.0N NH3 -EtOH was shaken under 50 psig of H2 pressure for 6 h, then filtered through dicalite. The filter pad was washed with 100 mL of hot 1:1 MeOH--H2O, and the combined filtrates were concentrated to give 6.1 g of 10-aminodecanoic acid. The crude product (5.7 g) was dissolved in 15.5 mL of 2N NaOH and treated simultaneously with 23 mL of 2N NaOH and 5.8 g of carbobenzoxychloride at 0° C. with vigorous stirring over 0.5 h. Water and 2N NaOH were added as needed to maintain stirring and a pH between 10-14. After stirring for 2.5 h, the reaction was diluted with 400 mL of H2O and filtered through dicalite. The filtrate was acidified (pH 2) with H2SO4, then extracted with ether. The combined ether extracts were dried (Na2SO4), filtered and concentrated. The residue was dissolved in CH3CN, filtered, and the filtrate concentrated to afford 5.3 g of 10-(N-carbobenzoxy)-aminodecanoic acid which was used without further purification: FAB-MS m/z 322 (MH+).
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[F:1][C:2]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)([F:4])[F:3]
Reactant: c1ccncc1
Reactant: FC(F)(F)I
Product: FC(F)(F)c1ccccn1
Temperature: 180 °C
Yield: 19.9 %

Procedure:
In the same reaction vessel as used in Example 1, 15.82 g of pyridine and 7.83 g of trifluoromethyl iodide were mixed. The vessel was airtightly sealed and heated at 180° C. for 24 hours. After the reaction, the reactor was cooled to room temperature. Thereafter, the reaction mixture was removed from the cooled vessel and treated by following the procedure of Example 1. Consequently, there was obtained 1.17 g (19.90% of theoretical value) of trifluoromethyl pyridine. This substance was found to be a 48:41:11 mixture of α, β and γ isomers.