Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12]C)=[CH:7][CH:6]=2.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=1)=[C:3]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(OCC(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(OCC(=O)O)cc2)c1-c1ccccc1
Reaction time: 2 h
Yield: 19.4 %

Procedure:
To a cold (5° C.) solution of ([(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)oxy]acetic acid (235) (0.150 g, 0.36 mmol) in CH2Cl2 (5 mL) was added BBr3 (0.1 mL, 1.1 mmol) slowly. The reaction mixture was stirred between 5° C. and 20° C. for 2 h and poured into 10% aqueous NaHCO3 (60 mL) slowly. The reaction mixture was extracted with EtOAc (3×75 mL). The combined organic layer was washed with brine (1×50 mL), dried (Na2SO4), and concentrated to afford the crude product. Purification by flash column chromatography using CHCl3 and MeOH as an eluent gave 0.028 g (19%) of the title compound (236) as an off-white solid. A 0.058 g of 5-[(4-hydroxyphenyl)oxy]-7-methyl-6-phenyl-2-naphthalenol was also isolated. 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.26-7.18 (m, 3H), 7.12-7.09 (m, 2H), 6.92 and 6.90 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 6.65 (d, J=9.2 Hz, 2H), 6.50 (d, J=8.8 Hz, 2H), 4.29 (s, 2H), 2.17 (s, 3H). LCMS (ESI) m/z 401.35 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([O:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[N:48]=[CH:47][C:46]([C:49](OC)=[O:50])=[CH:45][N:44]=2)[CH2:39][CH2:38]1.[NH4+].[Cl-]>C1COCC1.O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][O:24][C:14]2[NH:15][N:16]=[C:12]([NH:11][C:49]([C:46]3[CH:47]=[N:48][C:43]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[N:44][CH:45]=3)=[O:50])[CH:13]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)nc1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4CCN(C)CC4)nc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
NaHMDS (1M solution in THF, 0.39 ml, 0.386 mmol, 1.5 eq) was added dropwise to a stirred solution of tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (90 mg, 0.258 mmol, 1 eq) and methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (74 mg, 0.309 mmol, 1.2 eq) in dry THF (5 ml) under nitrogen. The solution was stirred at room temperature for 1 h, then neutralised with satd. aq. NH4Cl, diluted with water (15 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over MgSO4, filtered and evaporated to give an orange gum. The gum was purified by silica column chromatography, eluting with a gradient of 0-2.5% MeOH in DCM. The crude material, containing starting methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate, was re-dissolved in THF (5 ml) under nitrogen. tert-Butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (50 mg, 0.143 mmol) was added followed by dropwise addition of NaHMDS (1M solution in THF, 0.32 ml, 0.32 mmol). The solution was stirred at room temperature for 45 mins, neutralised with satd. aq. NH4Cl, diluted with water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried over MgSO4, filtered and evaporated. The gummy residue was purified by silica column chromatography, eluting with a gradient of 0-8% MeOH in DCM, to afford the title compound as a pale brown solid (16 mg, 14% yield); 1H NMR (399.9 MHz, DMSO-d6+d4-AcOD) δ 2.42 (3H, s), 2.67-2.70 (4H, m), 3.75 (6H, s), 3.91-3.94 (4H, m), 5.08 (2H, s), 5.75 (1H, s), 6.45 (1H, t), 6.59 (2H, d), 8.90 (2H, s). MS: m/z 454 (MH+)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH2:24][CH3:25])[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH2:26](OC1N=C(C(O)=O)C=NC=1N1CCCC1)CCC.N[C@@H](CC(C)C)CO>>[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Reactant: CCCCOc1nc(C(=O)O)cnc1N1CCCC1
Agent: CC(C)C[C@H](N)CO
Product: CCCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-butoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid and (S)-2-amino-4-methyl-pentan-1-ol (commercially available). m/z (ES+): 365.5 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]([CH2:37][CH3:38])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:30])[CH:29]=2)[CH:22]=[CH:23][CH:24]=1>>[CH2:37]([N:26]1[C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[CH:29][C:28](=[O:30])[N:27]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:38]
Reactant: CCn1c(-c2cccc(N)c2)cc(=O)n1-c1ccccc1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: CCn1c(-c2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)cc(=O)n1-c1ccccc1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-(3-aminophenyl)-2-ethyl-1-phenyl-3-pyrazolin-5-one (54 mg, 0.193 mmol) similar to Example 58 and isolated as a dark yellow solid (52 mg, 54%). 1H NMR (DMSO-d6): 10.61 (s, 1H), 9.52 (s, 1H), 8.83-8.81 (m, 1H), 8.65 (dd, J=1.2, 7.5 Hz, 1H), 8.38 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.68-7.48 (m, 7H), 7.37-7.33 (m, 1H), 7.22 (s, 1H), 5.97 (s, 1H), 3.63 (q, J=6.6 Hz, 2H), 0.634 (t, J=6.6 Hz, 3H).
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[C:2]([O:6][C:7](=[O:8])[NH:9][C@H:10]([C:15]([N:62]1[CH2:61][CH2:60][N:59]([CH:58]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[C:55]2[CH:54]=[CH:53][C:52]([F:51])=[CH:57][CH:56]=2)[CH2:64][CH2:63]1)=[O:17])[CH2:11][CH:12]([CH3:13])[CH3:14])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 94.8 %

Procedure:
N-tert-Butoxycarbonyl-L-leucine monohydrate (4.32 g, 17.3 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (33 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (6.04 mL, 34.7 mmol) and solid -benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.58 g, 17.4 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (5.00 g, 17.3 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 120 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×120 mL), brine (2×120 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (30% EtOAc in hexanes) to provide 8.23 g (94%) of the pure titled compound as a off-white foam: mp 59-66° C. APCI-MS m/z 502.4 (MH+).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=O)C.C([O-])(=O)C.[Na+].[C:18]([S:21][CH3:22])(=[NH:20])[NH2:19]>CN(C=O)C.ClCCl>[CH3:22][S:21][C:18]1[N:19]=[CH:4][C:5]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=2[N:20]=1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CSC(=N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ncc2c(n1)CCCC2=O
Temperature: 100 °C
Yield: 88.8 %

Procedure:
To a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (0.5 g, 2.9 mmol) in DMF (2 mL) was added sodium acetate (0.39 g, 4.7 mmol) and methyl carbamimidothioate (0.9 g, 3.5 mmol). The reaction mixture was heated at 100° C. for 5 hours. On completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL). The organic layer was separated and washed with water (2×30 mL). The solvent was then removed under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed with water (2×30 mL). The organic layer was dried using sodium sulfate and concentrated under reduced pressure to give the desired product (0.5 g, 86%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.94 (s, 1H), 3.01 (t, J=6 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.58 (s, 3H), 2.14 (quintet, J=6.2 Hz, 2H); LCSM [M+H]: 195.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[NH:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11]1[CH:18]=[CH:17][S:16][C:12]=12.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)Cl.[Cl-].[Na+].O>[CH2:23]([O:22][C:20]([N:15]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[CH:18]=[CH:17][S:16][C:12]=32)[CH2:8]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: c1cc2c(s1)C1CNCC1C2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC2Cc3ccsc3C2C1
Reaction time: 2 h

Procedure:
Triethylamine (741 mg, 7.32 mmol) was added to a solution of the product from step h) (493 mg, 2.44 mmol) in 12 mL of CH2Cl2 at ° C. followed by the addition of ethyl chloroformate (529 mg, 4.88 mmol). The reaction was allowed to come to room temperature and was stirred for two hours. The reaction mixture was diluted with brine (15 mL) and extracted with dichloromethane (3×15 mL). The combined organic extracts were dried with MgSO4 and the solvent was evaporated in vacuo give the crude product that was purified by column chromatography (SiO2) using a 0-30% ethyl acetate-hexane gradient to give the subtitle compound. MS calculated for C12H15NO2S +H: 238, observed: 238.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16]O)[O:11][C:10]([CH3:22])([CH3:21])[N:9]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]1(=[O:59])[NH:53][C:52](=[O:54])[C:51]2=[CH:55][CH:56]=[CH:57][CH:58]=[C:50]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@@H:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16][N:53]3[C:49](=[O:59])[C:50]4=[CH:58][CH:57]=[CH:56][CH:55]=[C:51]4[C:52]3=[O:54])[O:11][C:10]([CH3:21])([CH3:22])[N:9]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C(CCO)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[C@@H](CCN1C(=O)c2ccccc2C1=O)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
5.0 g (12.15 mmol) of t-butyl 4-(cyclohexylmethyl)-5-(4-hydroxy-2-isopropylbutyl)-2,2-dimethyl-3-oxazolidinecarboxylate, 4.68 g (17.8 mmol) of triphenylphosphine and 2.48 g (17 mmol) of phthalimide are dissolved in 70 ml of tetrahydrofuran and cooled to 10°. Then, a solution of 2.8 ml (17.8 mmol) of diethyl azodicarboxylate in 15 ml of tetrahydrofuran is added dropwise within 10 minutes and the reaction mixture is stirred at room temperature for 4 hours. Then, the reaction mixture is evaporated under reduced pressure and the residue is chromatographed on 160 g of silica gel with a mixture of methylene chloride and hexane as the eluting agent, whereby there are obtained 5.4 g of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-isopropyl-4-phthalimidobutyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil, MS: 525 (M-CH3)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:30][CH2:29]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:35])[N:18]3[C:31]([O:33][CH3:34])=[O:32])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:35])[N:18]3[C:31]([O:33][CH3:34])=[O:32])[CH2:11]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CN(C(=O)OC(C)(C)C)C3)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C

Procedure:
(S)-Methyl 5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was prepared by treating a solution of (S)-methyl 5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate in dichloromethane with trifluoroacetic acid according to the procedure outlined in Example 5-1, Step 3. 1H NMR (300 MHz, CD3OD) δ ppm 1.01-1.15 (m, 7H), 1.40-1.58 (m, 1H), 2.15-2.25 (m, 1H), 2.35-2.50 (m, 1H), 2.80-2.92 (m, 1H), 3.40-3.59 (m, 2H), 3.60-3.81 (m, 6H), 4.43-4.62 (m, 2H), 7.21-7.32 (m, 2H), 7.75 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 383 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[Cl:19][C:20]1[CH:29]=[C:28](I)[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[Cl:19][C:20]1[CH:29]=[C:28]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1Cl
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1Cl
Yield: 82.7 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.2 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.6 g (5 mmol) of methyl 2-chloro-4-iodobenzoate, 1.7 g (83%) of the expected ester was obtained in the form of a brown oil.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1ccc(F)cc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(F)cc1-c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5′-Amino-5,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 ml), 48% aqueous hydrobromic acid (40 ml) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 ml) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 ml). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 ml), water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography [silica gel, 2-6% EtOAc/isohexane (containing 0.5% methanol)] gave the title compound as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 7.13 (1H, dd, J 9, 9 Hz), 7.19-7.23 (2H, m), 7.52-7.60 (2H, m), 7.81 (1H, dd, J 8, 5 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH2:9][CH2:10]C.[CH3:14]C(C)/C=C/C(=O)C>>[NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH:9]([CH3:10])[CH3:14]
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(=O)/C=C/C(C)C
Product: Cc1cc(C(C)C)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 5) using (3E)-5-methyl-3-hexen-2-one (20 g, 137 mmol). LCMS E-S(M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.9 (br s, 1H), 7.86-7.96 (br s, 3H), 6.10 (s, 1H), 3.82-3.86 (m, 2H), 3.02-3.09 (m, 1H), 2.17 (s, 3H), 1.08 (d, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:37])[C:23](=[N:30][O:31]C(=O)C(Cl)Cl)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:38])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:37])[CH:23]([NH:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:38])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(NO)c3ccccc3)[C@H]2SC1

Procedure:
A solution of t-butyl 3-acetoxymethyl-7β-(2-dichloroacetoxyimino-2-phenylacetamido)-ceph-3-em-4-carboxylate (3.0 g) in trifluoroacetic acid (25 ml.) was allowed to stand at room temperature for ten minutes. The excess acid was removed under reduced pressure, and benzene evaporated from the residue, which was taken up into ethyl acetate and extracted into saturated aqueous sodium bicarbonate. The aqueous phase was washed with ethyl acetate, acidified and extracted with ethyl acetate. The extracts were combined, dried, concentrated to about 5 ml and added dropwise to petroleum (200 ml.). The solid which precipitated was filtered and dried, giving 3-acetoxymethyl-7β-(2-hydroxyamino-2-phenylacetamido)ceph-3-em-4-carboxylic acid (syn-isomer) as a white solid (1.9 g; 88%) [α]D +68° (c 0.8 DMSO), λmax. (EtOH) 254 nm (ε 17,600), νmax. (Nujol) 3380 (NH and OH) 1778 (β-lactam), 1720 (CO2H and acetate), 1666 and 1540 cm-1 (CONH), τ(DMSO-d6) values include 0.32 (doublet, J 9 Hz; NH of syn-isomer), 1.00 (doublet, J 9 Hz; NH of anti-isomer, comprising ca. 10% of the product), 2.15-2.7 (multiplet; aromatic protons), 7.8 (singlet; CH3CO).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: C1CCNCC1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCCCC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 82 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with piperidine (1 mL) in MeOH (3 mL) under reflux to give the desired product (63 mg, 82%, Z/E=1/1) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.24 & 7.22 (s, 1H), 7.21 (d, J=9.2 Hz, 1H), 7.09 & 7.06 (d, J=8.6 Hz, 2H), 7.01 & 6.99 (d, J=8.8 Hz, 1H), 6.78 & 6.69 (d, J=8.2 Hz, 2H), 6.68 & 6.66 (d, J=8.6 Hz, 2H), 6.47 & 6.45 (s, 1H), 6.42 & 6.25 (d, J=8.6 Hz, 2H), 4.10 & 3.90 (t, J=6.0 Hz, 2H), 2.81 & 2.70 (t, J=6.0 Hz, 2H), 2.48-2.57 (m, 6H), 1.47-1.68 (m, 6H), 0.89-0.93 (m, 3H); m/z=502[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:14]#[C:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12][OH:13]>CO.[Ni]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12][OH:13]
Reactant: Nc1ncnc2c1nc(C#Cc1cccnc1)n2CCO
Agent: [Ni]
Solvent: CO
Product: Nc1ncnc2c1nc(CCc1cccnc1)n2CCO
Yield: 40.3 %

Procedure:
To a suspension of 1.1 g of 2-(6-amino-8-(2-pyridin-3-yl-ethynyl)-purin-9-yl)ethanol in 400 ml methanol were added 2.0 g of Raney-nickel and the mixture was hydrogenated (4 atm) at 80° C. during 6 hours. After completion of the reaction the catalyst was removed and the solvent was evaporated. The crude product was purified by column chromatography on silica gel (CHCl3:MeOH 9:1) to give 0.45 g (41%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[C:10]([OH:14])(=[O:13])[CH:11]=[O:12].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([CH:11]([OH:12])[C:10]([OH:14])=[O:13])=[C:4]([OH:5])[C:3]=1[OH:9]
Reactant: O=CC(=O)O
Reactant: Oc1cccc(F)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)c1ccc(F)c(O)c1O
Temperature: 0 °C
Yield: 59 %

Procedure:
51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolved at 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solution in 400 ml of water were added to this solution cooled to 0° C. The mixture was heated for 4 hours at 46° C., then cooled to 0° C. and the pH was brought to 4.6 by the addition of concentrated hydrochloric acid. Extraction was carried out with ethyl ether (after evaporation 14.7 g of the starting 9-fluorocatechol were collected) and the aqueous phase was acidified with concentrated hydrochloric acid until a pH of 1.8 was obtained. Extraction was carried out with ethyl acetate and after evaporation of the solvent, 47.7 g of the desired product were obtained (mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro; 2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16.