Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][CH3:8])([O:5][CH3:6])[CH3:4].O(C)[Na].[Cl:12]Cl>>[Cl:12][CH2:4][C:3]([O:7][CH3:8])([O:5][CH3:6])[O:2][CH3:1]
Reactant: COC(C)(OC)OC
Reactant: ClCl
Agent: CO[Na]
Product: COC(CCl)(OC)OC
Reaction time: 4 h
Yield: 97.6 %

Procedure:
A 500 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with a mixture of 240 g (2 mol) of 1,1,1-trimethoxyethane and 1% of NaOCH3 (30%). Within 4 hours, 110 g of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. Using a distillation apparatus having approx. 5 theoretical plates, low boilers such as methanol and methyl acetate were removed in the first stages of distillation at a reflux ratio of 5:1. In the main fraction, 234 g of 2-chloro-1,1,1-trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([N:27]1[CH2:28][CH2:29][CH2:30][C:31]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[N:24]=[CH:25][C:26]1=2)=[O:15]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(C(F)(F)F)cc1Cl)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a mixture of 2-[2-chloro-4-(trifluoromethyl)phenyl]acetic acid (59 mg, 0.23 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (50 mg, 0.23 mmol) in DMF (1 mL) was added Hunig's base (59 mg, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (96 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, and then was partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine and dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (25 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 0.8H), 7.70 (s, 1H), 7.56-7.44 (m, 4H), 7.38 (s, 0.2H), 7.18-7-14 (m, 2H), 4.14 (s, 2H), 3.82 (m, 2H), 2.85 (m, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C21H16ClF4N3O [M+H]+ 438.1, found 438.1.
Reaction SMILES: [CH3:1][N:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:15])[CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5]1.[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][CH:28]=1>ClCCCl>[CH3:1][N:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:15])[CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]1[C:33](=[O:34])[CH2:32][NH:31][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1)=[O:36]
Reactant: CN(C(=O)C1CCC(c2ccccc2)N1)c1ccccc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N(C)c3ccccc3)CCC2c2ccccc2)c1
Yield: 49.7 %

Procedure:
By proceeding in a fashion similar to that described in Example 1, but starting from 1.2 g of (2RS,5SR)-N-methyl-N-phenyl-5-phenylprolinamide, 0.94 g of 2-[3-(3-methylphenyl)ureido]acetic acid in suspension in 25 cm3 of 1,2-dichloroethane and 0.33 cm3 of sulphinyl chloride, after recrystallization in acetonitrile, 1 g of (2RS,5SR)-N-methyl-1-[3-(3-methylphenyl)ureidoacetyl]-N-phenyl-5-phenylprolinamide, melting at 210° C., is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([OH:21])[CH2:19][CH2:18][C@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:20][C@H:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C@@:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:21])[CH2:19][CH2:18]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O[C@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
In a 250 mL round-bottom flask was dissolved (6S,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diol (458 mg, 1.572 mmol) (azeotroped with dry benzene) in tetrahydrofuran (8 mL) to give a light orange solution. 4-Nitrobenzoic acid (394 mg, 2.358 mmol) and triphenylphosphine (619 mg, 2.358 mmol) were added under nitrogen. Diisopropyl azodicarboxylate (0.464 mL, 2.358 mmol) was added dropwise. The mixture was allowed to stir overnight. After 15 h, LCMS showed complete conversion, but the desired product was a minor component. It was concentrated to a light yellow oil and directly purified by FCC (5% ethyl acetate/hexanes to 100%) to afford the desired product (125 mg, 18%) as a white solid. MS(ESI)[M+H+]=441.20.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[S:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[OH:37][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([OH:25])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:13]=[CH:14][C:9]([CH:8]=[C:4]4[S:3][C:2](=[NH:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)=[CH:31][C:30]=1[NH:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: N=C1NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=N)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-one (which was obtained in Example 43) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >210° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-2.00 (m, 2H), 2.50-3.00 (m, 5H), 2.92 (s, 3 H), 3.70-3.90 (m, 2H), 4.47 (dd, J=7.9, 4.4 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.90-7.10 (m, 3 H), 7.18 (d, J=2.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H), 7.47 (s, 1H); MS (ES) m/z: 532.0 (MH+); HRMS Calcd. for C24H30N5O5S2 (MH+): 532.1688. Found: 532.1672.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O.[C:12](O)(=O)C>N1C=CC=CC=1>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:12].[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)O
Agent: COC(=O)c1cccnc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cccnc1
Reaction time: 60 h

Procedure:
An electrically heated tubular reactor with an i. d. of 12 mm was filled with 15 ml (≈15 g) of catalyst prepared according to EP-A-0 352 674, example 1. Over a period of 60 h, a mixture of methyl nicotinate (78 g), water (149 g) and acetic acid (523 g) was metered using a precision pump to the reactor operating at 410° C. From the reaction mixture, 30.5 g of 3-acetylpyridine, 8.5 g of pyridine and 9.0 g of methyl nicotinate were obtained. This corresponded to a yield of 45% 3-acetylpyridine at a methyl nicotinate conversion of 88% (selectivity 50%). The selectivity of pyridine formation was 19%.
Reaction SMILES: C([O:8][CH:9]1[CH2:18][O:17][CH2:16][CH2:15][S:14](=[O:20])(=[O:19])[CH2:13][CH2:12][O:11][CH2:10]1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:9]1([OH:8])[CH2:10][O:11][CH2:12][CH2:13][S:14](=[O:20])(=[O:19])[CH2:15][CH2:16][O:17][CH2:18]1
Reactant: O=S1(=O)CCOCC(OCc2ccccc2)COCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=S1(=O)CCOCC(O)COCC1
Yield: 91.7 %

Procedure:
A mixture of 22 (25 mg, 0.083 mmol) and a catalytic amount of 10% Pd/C in EtOAc (3 mL) was stirred at 23° C. under a hydrogen atmosphere. After 48 h the catalyst was filtered off and the filtrate was evaporated to afford 16 mg (92%) of 81 as a colorless oil: 1H NMR (CDCl3) δ 4.08-3.95 (m, 4H), 3.67 (dd, J=4.2, 9.9 Hz, 2H), 3.61-3.59 (m, 1H), 3.51 (dd, J=5.7, 9.9 Hz, 2H), 3.38-3.23 (m, 4H); 13C NMR (CDCl3) δ 69.0, 68.3, 64.5, 52.6.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH3:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:39][CH2:38][C:27]2[N:28]=[C:29]([C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(C4(C)CCCCC4)oc3C)cc2)C(=O)O)cc1C

Procedure:
The representative parallel synthesis procedure (B) was used to prepare the title compound from 2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-(1-methylcyclohexyl)-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H, J=8.60 Hz), 6.92 (d, 1H, J=8.60 Hz), 6.73 (d, 2H, J=8.99 Hz), 6.64 (d, 1H, J=2.35 Hz), 6.57 (dd, 1H, J=8.21 Hz, J=3.13 Hz), 4.06 (t, 2H, J=6.25 Hz), 3.14 (d, 1H, J=14.08 Hz), 3.04 (d, 1H, J=14.08 Hz), 2.85 (t, 2H, J=6.25 Hz), 2.19 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.07-2.01 (m, 2H), 1.53-1.28 (m, 8H), 1.36 (s, 3H), 1.20 (s, 3H); MS (ES+) calcd for C31H40NO5: Found m/e 506.3 (M+1, 100%).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][C:4]#[C:5][C:6](=[O:8])[CH3:7].[H][H]>[Pd].C1COCC1>[CH3:1][C@H:2]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: [H][H]
Reactant: CC(=O)C#CC[C@H](C)COC1CCCCO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)CCC[C@H](C)COC1CCCCO1
Yield: 100 %

Procedure:
A 50 g solution (222.9 mmol) of (S)-6-methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hept-3-in-2-one and 5 g palladium on carbon (10% Pd/C) in 400 ml of THF is hydrogenated for one hour at 8 bar hydrogen at room temperature. The catalyst is then filtered off, rewashed with little solvent and the solvent is removed in vacuo. 50.9 g of product is obtained.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:22][C@H:21]1[CH2:34][C:35](=[O:37])[NH2:36])=[O:19])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[C:35]([CH2:34][C@@H:21]1[CH2:22][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25][N:20]1[C:18](=[O:19])[CH2:17][O:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:38])=[O:5])(=[O:37])[NH2:36]
Reactant: CC(C)(C)OC(=O)COc1cc(Cl)ccc1OCC(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1OCC(=O)O
Yield: 84.1 %

Procedure:
A solution of (2-{2-[(2R)-2-carbamoylmethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-5-chloro-phenoxy)-acetic acid tert-butyl ester (0.070 g, 0.13 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.10 mL) was stirred for 3.5 h and then concentrated. The resulting residue was diluted with dichloromethane and the excess trifluoroacetic acid was quenched with saturated aqueous sodium carbonate. The aqueous layer was neutralized with 0.1N hydrochloric acid and extracted one time with dichloromethane/methanol (1:1) and twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound (0.054 g, LRMS: 492.4, 494.4).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]([CH3:19])([CH3:18])[C:10](=N)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O.[OH:21]S(O)(=O)=O>>[OH:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]([CH3:19])([CH3:18])[C:10](=[O:21])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=N
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
To a mixture of ethyl 5-hydroxy-7-imino-8,8-dimethyl-7,8-dihydroquinoline-6-carboxylate (100 mg, 384 μmol) and water (3 mL, 166525 μmol), was added H2SO4 (0.02 mL, 384 μmol). The resulting mixture was then heated to 80° C. After 30 minutes, 0.1 mL of H2SO4 was added. After 90 minutes, the reaction was cooled to room temperature and extracted with EtOAc. The organic phase was washed with water and then with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give a light-yellow solid. The aqueous layer was concentrated in vacuo to give a white solid/yellow liquid. The solid was washed with EtOH and a white solid was filtered away. The filtrate was concentrated in vacuo to give a yellow solid. The solid was washed with DCM and the supernatant was decanted off. The solid was dissolved in MeOH and concentrated in vacuo to give a light-yellow solid which was washed once more with DCM and the supernatant was decanted away. The solid was placed under high-vacuum to leave a light-yellow solid which was purified by silica flash chromatography (0-10% MeOH/DCM) to give the title compound as a white crystalline solid (24 mg, 24%). MS (m/z)=262 (M+H)+. Calculated for C14H15NO4 261.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH:10]=NO)=[C:4]([CH2:14][CH3:15])[CH:3]=1.C(N)(=[O:18])C>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH2:14][CH3:15])[CH:3]=1)[NH:8][C:9](=[O:13])[C:10]2=[O:18]
Reactant: CCc1cc(Br)ccc1NC(=O)C=NO
Reactant: CC(N)=O
Product: CCc1cc(Br)cc2c1NC(=O)C2=O

Procedure:
Following the procedure of example 36.B. except using N-(4-Bromo-2-ethyl-phenyl)-2-hydroxyimino-acetamide as the acetamide component afforded the title compound as a solid. ESI (−) MS m/e=252 (MH−).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12].[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:1]1([CH:9]([OH:13])[CH:10]=[CH:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C/C=C/C=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC=CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
To a cooled (0-55° C.) 927 mL of 1 M solution of phenyl magnesium bromide in tetrahydrofuran was added dropwise a solution of crotonaldehyde (65.0 g) in 130 mL of anhydrous ether over a period of 2 hours and 45 minutes. The reaction was stirred for an additional 45 minutes and then warmed to room temperature. After four more hours of stirring, saturated ammonium chloride aqueous solution (750 mL) was added to the reaction. The mixture was extracted with 750 mL of ether twice. The combined extract was dried over anhydrous potassium carbonate and filtered. The solvent was evaporated to give 135.88 g (99.9%) of the desired 1-phenyl-2-buten-1-ol as an oil which was used in the next step without further purification.
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([O:9][C:10]([CH2:12][O:13][N:14]=[C:15]([C:37]1[N:38]=[CH:39][S:40][CH:41]=1)[C:16]([NH:18][CH:19]1[C:35](=[O:36])[N:21]2[C:22]([C:32]([OH:34])=[O:33])=[C:23]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][S:25](=O)[C@H:20]12)=[O:17])=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>CN(C)C=O>[C:5]([O:9][C:10]([CH2:12][O:13][N:14]=[C:15]([C:37]1[N:38]=[CH:39][S:40][CH:41]=1)[C:16]([NH:18][CH:19]1[C:35](=[O:36])[N:21]2[C:22]([C:32]([OH:34])=[O:33])=[C:23]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][S:25][C@H:20]12)=[O:17])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CS(C)(=O)=O)CS(=O)[C@H]12)c1cscn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CS(C)(=O)=O)CS[C@H]12)c1cscn1
Reaction time: 0.17 h

Procedure:
Phosphorus trichloride (1.5 g) was added to a solution of 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-mesylmethyl-3-cephem-4-carboxylic acid-1-oxide (syn isomer (2.1 g) in N,N-dimethylformamide (20 ml) at -50° C. and the solution was stirred at -40° to -30° C. for 10 minutes. The reaction mixture was poured into a mixture of cold water (200 ml) and ethyl acetate (150 ml). The separated organic layer was washed with water (50 ml), dried over magnesium sulfate and evaporated to give 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-mesylmethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1
Reactant: COc1cccc([C@@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Solvent: C1CCOC1
Product: COc1cccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 35 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-methoxyphenyl)piperidin-1-yl]-methanone (21 mg, 0.059 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 7.0 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([C:30]1[CH:31]=[C:32]([CH3:39])[C:33]([C:36]([NH2:38])=[O:37])=[N:34][CH:35]=1)#[N:29].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CC(OC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:38][C:36]([C:33]3[C:32]([CH3:39])=[CH:31][C:30]([C:28]#[N:29])=[CH:35][N:34]=3)=[O:37])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)cnc1C(N)=O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(Br)n2)CO[C@@]1(C)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: Cc1cc(C#N)cnc1C(=O)Nc1cccc([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)n1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of [(2R,5R)-5-(6-Bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (60.00 mg, 0.133 mmol), 5-cyano-3-methylpicolinamide (23.52 mg, 0.146 mmol), Xantphos (6.91 mg, 0.012 mmol) and Cs2CO3 (60.50 mg, 0.186 mmol) in dioxane (0.611 ml) was degassed with argon for 5 min, then Pd2dba3 (3.64 mg, 3.98 μmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The reaction mixture was diluted with H2O and TBME. The phases were separated and the aq. phase was reextracted with TBME. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si 10 μM column, 150×30 mm, gradient n-heptane:EtOAc 0-1.2 min 75:25, 1.2-9 min 0:100, 9-12 min 0:100, flow: 50 ml/min, detection: 254 nm) yielded the title compound as a colourless solid. HPLC RtH4=1.37 min; ESIMS: 533 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 11.22 (s, 1H), 10.47 (s, 1H), 8.78 (d, 1H), 8.33 (d, 1H), 7.98 (d, 1H), 7.84-7.80 (m, 1H), 7.13 (d, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 2.88 (s, 3H), 1.64 (s, 3H), 1.57 (br s, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CS(C)=O>O>[CH3:10][S:11]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CS(=O)[O-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C#N)nc1
Yield: 87 %

Procedure:
5-Bromo-2-cyanopyridine (38.0 kg 1.0 mol eq, limiting reagent) and sodium methane sulfinate (29.68 kg, 1.4 mol eq) were charged followed by DMSO (228 L, 6 rel vol). The reaction was heated to 100° C.-105° C. and stirred until reaction complete as judged by HPLC analysis. After cooling, the reaction mixture was added to preheated water (356 L, 9.4 rel vol). After cooling and stirring, the product was isolated by filtration. The solid was washed with water (456 L, 12 rel vol) and dried to constant weight to yield the title compound (33 kg, 18.1 mol, 87%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]#[N:17])[CH2:15][CH2:14]1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CCCCCC.O1CCCC1>[C:19]1([CH2:18][C:13]2([C:16]#[N:17])[CH2:15][CH2:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CC1CC1
Reactant: ClCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: N#CC1(Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a mixture under nitrogen of 26.3 g (260 mmoles) of diisopropylamine and 300 ml of tetrahydrofuran cooled to -75° C., there is added dropwise 125 ml (200 mmoles) of n-butyllithium in a 1.6M hexane solution, then 13.4 g (200 mmoles) of commercial cyclopropanecarbonitrile and finally 25.3 g (200 mmoles) of benzyl chloride. The reaction mixture is stirred 2 hours at -70° C. then 2 days at 20° C. 4 ml of water is added, before washing the reaction mixture with water saturated with NaCl. The organic phase dried over Na2SO4 is concentrated to give a brown liquid, which is purified by distillation. There is obtained 16.8 g (yield=53.5%) of a colorless liquid. b.p.13 =140°-8° C.
Reaction SMILES: ClC1C=C([C@@H](O)CNC2CCCC(C3C=CC=CC=3OCC([O-])=O)C2)C=CC=1.[Na+].[Cl:30][C:31]1[CH:32]=[C:33]([C@@H:37]([OH:59])[CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH:42]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][C:54]([O:56]CC)=[O:55])[CH:47]=3)[CH2:41]2)[CH:34]=[CH:35][CH:36]=1.[OH-].[Na+]>C(O)C>[Cl:30][C:31]1[CH:32]=[C:33]([C@@H:37]([OH:59])[CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH:42]([C:46]3[CH:47]=[C:48]([CH:49]=[CH:50][CH:51]=3)[O:52][CH2:53][C:54]([OH:56])=[O:55])[CH2:41]2)[CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Agent: O=C([O-])COc1ccccc1C1CCCC(NC[C@H](O)c2cccc(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of the trans-H compound, (1R)-1-(3-chlorophenyl)-2-[3-(3-ethoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol (hydrochloride), obtained in Example 11 (220 mg) in ethanol (10 ml) there was added 1 N sodium hydroxide solution (2.5 ml), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, water (2 ml) was added, and after adding 1 N aqueous solution of hydrochloric acid (2.03 ml) while stirring and cooling on ice, the deposited crystals were filtered off and dried to give 153 mg of (2R)-(3-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy) acetic acid (trans-H) as a white crystalline powder (81% yield).