Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:15]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:14]1=[O:37].CN1CCOCC1.Cl[S:46]([CH2:49][C:50]([O:52][CH2:53][CH:54]1[C:66]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:60]2[C:55]1=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])(=[O:48])=[O:47]>ClCCl>[CH:56]1[C:55]2[CH:54]([CH2:53][O:52][C:50](=[O:51])[CH2:49][S:46]([NH:12][N:13]3[CH2:17][CH:16]([C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:15]([CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:14]3=[O:37])(=[O:47])=[O:48])[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]=2[CH:59]=[CH:58][CH:57]=1
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C3CC3)cc2)cc1
Reactant: O=C(CS(=O)(=O)Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)OCC3c4ccccc4-c4ccccc43)CC2c2ccc(C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-amino-3-[2-(4-methoxyphenyl)ethyl]-4-(4-cyclopropylphenyl)-2-imidazolidinone p-toluenesulfonic acid salt (2.61 g, 0.0050 mol), dichloromethane (12 mL), and N-methylmorpholine (1.53 mL, 0.014 mol) is added a solution of 9H-fluoren-9-ylmethyl chlorosulfonylacetate, 14, (1.76 g, 0.0052 mol) in dichloromethane (7 mL) slowly over 7 minutes at 15° C. to 20° C. The reaction is stirred at ambient temperature for 45 minutes, and then washed twice with 0.1 N HCl and water. The organic phase is dried (sodium sulfate) and concentrated to a foamy solid. The residue is purified over silica (0%-50% ethyl acetate/hexanes gradient) to afford 2.1 g of the desired compound. 1H NMR (CDCl3) δ 7.81 (d, J=7.5 Hz, 2H), 7.69 (d, J=7.5 Hz, 2H), 7.45 (m, 2H), 7.36 (m, 2H), 7.27 (s, 1H), 7.17 (m, 2H), 7.10 (m, 2H), 7.02 (m, 2H), 6.82 (m, 2H), 4.63 (m, 2H), 4.45 (t, J=8.4 Hz, 1H), 4.35 (m, 3H), 3.94 (t, J=8.4 Hz, 1H), 3.78 (s, 3H), 3.65 (m, 1H), 3.38 (t, J=8.1 Hz, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.64 (m, 1H), 1.94 (m, 1H), 1.03 (m, 2H), 0.74 (m, 2H). MS 652 (MH+). Anal. calcd. for C37H37N3O6S¾H2O: C, 66.80; H, 5.83; N, 6.32. Found: C, 66.78; H, 5.72; N, 6.30.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][N:27]([CH3:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]([C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:29]=4)=[O:32])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(N(C)C)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(dimethylamino)benzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=O)C.[CH3:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[O:7]([C:8]1[CH:9]=[N:10][C:11]([C:32]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=2)=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)cn2)ccn1

Procedure:
By carrying out the operation analogously to example 239, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-methyl-4-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=23%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH:28]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[CH:39][CH:38]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(Oc2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C1N(c2ccc(Oc3cccnc3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Brown crystalline solid. MS (ESI): 498.2 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-(pyridin-3-yloxy)-phenylamine (synthesis: Yoneda et al; Yakugaku Zasshi; 77; 1957; 944; Chem. Abstr.; 1958; 2855).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)C(=O)NCCO2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(=O)NCCO3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 7-amino-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were converted to 2-[5-chloro-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.42 (d, 1H), 8.11 (s, 1H), 7.88 (d, 1H), 7.71 (dd, 1H), 7.54 (dd, 1H), 7.41 (td, 1H), 7.24 (td, 1H), 7.09 (d, 1H), 4.41 (t, 2H), 3.48 (t, 2H), 2.92 (s, 3H); MS (m/e) 439 (M+1).
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].CC(C)([O-])C.[K+]>CS(C)=O.C(OCC)(=O)C.Cl>[C:1]12([CH2:11][O:12][C:15]3[C:14]([Cl:13])=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Temperature: 80 °C
Yield: 42 %

Procedure:
A mixture of 1-adamantylmethanol (5.32 g, 32.00 mmol), 5,6-dichloronicotinic acid (6.14 g, 32.00 mmol) and potassium tert-butoxide (8.3 g, 73.60 mmol) in anhydrous dimethyl sulfoxide (100 mL) was heated to 80° C. under nitrogen for 1 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (500 mL) and 1.0 M aqueous hydrochloric acid (300 mL). The layers were separated and the organic layer was washed with 1.0 M aqueous hydrochloric acid (100 mL), brine (2×100 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford the title compound as a white solid (4.32 g, 42%); 1H NMR (300 MHz, DMSO-d6) 13.23 (br s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 3.95 (s, 1H), 2.00-1.88 (m, 3H), 1.71-1.50 (m, 12H); MS (ES−) m/z: 320.3, 322.3 (M−1).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:16]=[CH:15][C:14]=2[F:25])[N:5]=1)(=O)[CH3:2].[CH3:26]C(O)=O.[C:30]1([NH:36][NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COC(OC)N(C)C.Cl>[F:25][C:14]1[CH:15]=[CH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1]2[N:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:37]=[CH:26][CH:2]=2)=[N:5]1
Reactant: CC(=O)O
Reactant: NNc1ccccc1
Reactant: COc1cn(-c2cc(-c3cnn(C)c3)ccc2F)nc(C(C)=O)c1=O
Agent: COC(OC)N(C)C
Agent: Cl
Product: COc1cn(-c2cc(-c3cnn(C)c3)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 46 %

Procedure:
A mixture of 3-acetyl-1-[2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-methoxypyridazin-4(1H)-one (200 mg, 0.585 mmol) in N,N-dimethylformamide dimethyl acetal (2.0 mL) was heated to reflux for 3 h. The mixture was concentrated in vacuo. To the residue were added AcOH (2.0 mL) and phenylhydrazine (0.115 mL, 1.17 mmol). The mixture was heated to reflux for 3 h. The mixture was diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and by HPLC and recrystallized with EtOH/hexane to yield the title compound (118 mg, 46% yield) as a white solid: mp 93-102° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.78 (3H, s), 3.89 (3H, s), 6.91 (1H, d, J=1.9 Hz), 7.20-7.52 (7H, m), 7.63-7.71 (1H, m), 7.78 (1H, d, J=1.9 Hz), 7.83 (1H, s), 8.10 (1H, s), 8.53 (1H, d, J=1.6 Hz). Anal. Calcd for C24H19FN6O2.1.3H2O: C, 61.88; H, 4.67; N, 18.04. Found: C, 61.63; H, 4.64; N, 18.09.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:34][CH:31]5[CH2:33][CH2:32]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: NC1CC1
Agent: Cl
Product: O=C(NC1CC1)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 13.4 mg (0.23 mmol) of cyclopropylamine are reacted together by general method E. 20 mg (32.2% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CN(C=O)C>C1COCC1.O>[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: CCCCCCCCCCI
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
To a suspension of sodium hydride (80% in oil, 3.2 g, 104 mmol) in 100 ml of THF, there is slowly added a solution of 2-(1-adamantyl)-4-bromophenol (29 g, 95 mmol) in 200 ml of THF. The mixture is stirred until the evolution of gas ceases at which point 27.8 g (23 ml, 104 mmol) of 1-iododecane and 100 ml of DMF are added. The mixture is stirred for 12 hours at ambient temperature, poured into water, extracted with ether, dried and the solvents evaporated. The resulting residue is purified by passage through a silica column (eluant: heptane), yielding 40.7 g (96%) of 2-(1-adamantyl)-4-bromo-1-decyloxybenzene. Melting point: 69°-70° C.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]([CH3:50])([O:19][N:20]=[C:21]([C:25]1[N:26]=[C:27]([NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:28][CH:29]=1)[C:22](O)=[O:23])[CH3:18])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:51][CH:52]1[C:77](=[O:78])[N:54]2[C:55]([C:61]([O:63][CH:64]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:62])=[C:56]([CH2:59][Cl:60])[CH2:57][S:58][C@H:53]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[Cl:60][CH2:59][C:56]1[CH2:57][S:58][C@@H:53]2[CH:52]([NH:51][C:22](=[O:23])[C:21](=[N:20][O:19][C:17]([C:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:16])([CH3:50])[CH3:18])[C:25]3[N:26]=[C:27]([NH:30][C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[S:28][CH:29]=3)[C:77](=[O:78])[N:54]2[C:55]=1[C:61]([O:63][CH:64]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:62]
Reactant: CC(C)(ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
28 g (41 mmol) of 2-(1-benzhydryloxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 17 g (41 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-caroxylate, were dissolved in 300 ml of dry methylene chloride, and 15.6 ml (123 mmol) of N,N-dimethylaniline was added thereto. The mixture was cooled to -10° C., and 4 ml (43 mmol) of phosphorus oxychloride was dropwise added thereto. The reaction solution was stirred at room temperature for 2.5 hours, and then concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed sequentially with 1N hydrochloric acid, a 5% sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 36 g (yield: 81%) of benzhydryl 3-chloromethyl-7-[2-(1-benzhydryloxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: [CH2:1]([C:5]1(C(OC)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].C[O-:39].[Na+]>CO>[CH2:1]([C:5]1([OH:39])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:19]=3[S:18](=[O:31])(=[O:32])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4]
Reactant: C[O-]
Reactant: CCCCC1(C(=O)OC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Solvent: CO
Product: CCCCC1(O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 28.8 %

Procedure:
A mixture of Example 1G (0.3 g, 0.55 mmol) in 30% weight sodium methoxide in methanol (3 mL) was stirred at 25° C. for 24 h. The solution was quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic extract was concentrated in vacuo, extracted with ethyl acetate, and the organic layer was concentrated in vacuo. Column chromatography on silica (4% methanol/ethyl acetate) afforded the title compound as a white solid (0.095 g, 28.8%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.72 (m, 3H), 0.95-1.29 (m, 5H), 1.63 (m, 2H), 2.99 (s, 3H), 4.95 (s, 1H), 7.17-7.59 (m, 8H), 7.93 (d, J=7.35 Hz, 1H), 9.89 (s, 1H); MS(ESI) m/z 504.1 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[C:13]1([N:19]2[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:6])([F:7])[F:8])=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 95 °C
Yield: 61.3 %

Procedure:
A mixture of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.93 g, 16 mmol) and phenylhydrazine (1.947 g, 18 mmol) in EtOH (15 mL) was heated at 95° C. for 8 hours. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with 5-25% EtOAc/hexane as eluants to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as a yellow solid (2.23 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.51 (m, 5H), 5.87 (s, 1H), 3.93 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1.[BH4-].[Na+]>CN(C=O)C.[Co](Cl)Cl>[NH2:33][CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([C:18]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:19])=[CH:25][CH:24]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 72 h
Yield: 43.1 %

Procedure:
A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide (200 mg, 0.442 mmol, 1.0 equiv.), cobalt chloride (86 mg, 0.664 mmol, 1.5 equiv.) and sodium borohydride (50 mg, 1.33 mmol, 3.0 equiv.) in DMF (15 mL) was stirred at 0° C. to rt for 3 days. The reaction was quenched with ice cubes, diluted with DCM (100 mL) and filtered through celite. The filtrate was washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave {4-[2-(aminomethyl)phenyl]phenyl}-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (87 mg, 43%). MS found for C26H21ClN4O2 (M+H)+: 457.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:10][O:11][C:12]1([O:21][CH3:22])[CH2:15][CH:14]([C:16](=O)[CH2:17][C:18]#[N:19])[CH2:13]1>CCO>[C:2]([N:6]1[C:18]([NH2:19])=[CH:17][C:16]([CH:14]2[CH2:15][C:12]([O:11][CH3:10])([O:21][CH3:22])[CH2:13]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: COC1(OC)CC(C(=O)CC#N)C1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC1(OC)CC(c2cc(N)n(C(C)(C)C)n2)C1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a slurry of tert-butylhydrazine hydrochloride (45.1 g, 362.0 mmol) in EtOH (1 L) was added NaOH pellets (12.4 g, 310.3 mmol). After 30 min, crude 3-(3,3-dimethoxy-cyclobutyl)-3-oxo-propionitrile in EtOH (300 mL) was added. The resulting slurry was heated to 75° C. (oil bath). After 14 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. Isopropyl ether was added to the resulting slurry. The slurry was stirred for 15 min, filtered, and concentrated to yield a viscous oil. Trituration with ether/hexanes (several crops) gave the title compound (56.2 g, 86% yield over two steps) as a colorless solid: mp 80.9° C. 500 MHz 1H NMR (CDCl3) d 5.50 (s, 1H), 3.51 (bs, 2H), 3.18 (s, 3H), 3.16 (s, 3H), 3.19-3.14 (m, 1H), 2.60-2.54 (m, 2H), 2.20-2.14 (m, 2H), 1.59 (s, 9H). LRMS m/z (APCI+) 254 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C[NH:23][CH2:24][CH2:25][C:26]#N.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN([CH:45]=[O:46])C>CN(C)C1C=CN=CC=1>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:23][CH:24]3[CH2:25][CH2:26][O:46][CH2:45]3)=[O:15])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: CNCCC#N
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NC1CCOC1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 39.3 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), tetrahydrofuran-3-amine (0.077, 6.7mg), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (7.3 mg, 39.3%). 1H NMR (400 MHz, CD3OD) δ 0.93 (d, J=6.57 Hz, 3 H) 1.04 (dd, J=6.57, 2.78 Hz, 3 H) 1.74-1.95 (m, 1 H) 2.21 (d, J=7.83 Hz, 1 H) 2.42-2.54 (m, 1 H) 3.50-3.67 (m, 1 H) 3.69-3.97 (m, 3 H) 4.37(td, J=3.85, 1.89 Hz, 1 H) 4.96-5.12 (m, 2 H) 5.36-5.52 (m, 1 H) 7.86 (s, 1 H) 8.17 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C18H21FN4O3, 361; found, 361.4.
Reaction SMILES: [H-].[Na+].[Br-].[F:4][C:5]([F:32])([F:31])[C:6]1[CH:11]=[CH:10][C:9]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1.[CH3:33][C:34]([CH3:53])([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)[CH:35]=O.O.[CH3:55]S(C)=O>>[CH3:33][C:34]([CH3:53])([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)[CH:35]=[CH:55][C:9]1[CH:8]=[CH:7][C:6]([C:5]([F:4])([F:31])[F:32])=[CH:11][CH:10]=1
Reactant: CS(C)=O
Reactant: FC(F)(F)c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C=O)COCc1cccc(Oc2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C=Cc1ccc(C(F)(F)F)cc1)COCc1cccc(Oc2ccccc2)c1

Procedure:
A suspension of sodium hydride (0.1 g) in dry dimethylsulphoxide (15 cm3) was heated to 65° C. for a period of 11/2 hours. After cooling to the ambient temperature (ca. 25° C.) 4-trifluoromethylphenyltriphenylphosphonium bromide (1.75 g) was added in portions, and the mixture was stirred for a further hour. A solution of 2,2-dimethyl-3-(3-phenoxybenzyloxy)propan-1-al in dimethylsulphoxide (15 cm3) was then added, and after stirring for 2 hours, the reaction mixture was poured into water and extracted into ethylacetate. The extracts were combined, washed with water and dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent to yield an orange oil. This was flash chromatographed on a silica gel column with dichloromethane as eluent to yield 3,3-dimethyl-1-(4-trifluoromethylphenyl)-4-(3-phenoxybenzyloxy)but-1-ene (0.7 g) as a colourless oil, identified by nmr spectroscopy as an impure mixture of the Z and E isomers (ratio 3:1).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1>CS(C)=O.O>[C:1]([CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1)#[N:2]
Reactant: BrCC1COc2ccccc2O1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3 dihydrobenzo[1,4]dioxine) (6.87 g, 30 mmol) in DMSO (90 mL) and stirred at ambient temperature for 20 h. The reaction mixture was then diluted with water (250 mL) and extracted twice with diethyl ether. The diethyl ether was washed with water, then washed twice with brine, dried (Na2SO4) and evaporated in vacuo to yield 2-cyanomethyl-(2,3 dihydrobenzo[1,4]dioxine) as a white solid.