Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[C:34]([O:45][CH3:46])(=[O:44])[C:35]1[CH:43]=[CH:42][CH:41]=[C:37]([C:38]([O-])=[O:39])[CH:36]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([C:34]([O:45][CH3:46])=[O:44])[CH:36]=3)=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(=O)Oc2ccc(-c3ccc4c(c3COc3cc(F)ccc3C)N(C)C(=O)C(C)(C)N4)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25.3 mg, 0.0562 mmol), monomethyl isophthalate (20.5 mg, 0.114 mmol), N,N-diisopropylethylamine (38.8 μL, 0.223 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (43.4 mg, 0.114 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (15 mL). The mixture was washed with water (15 mL) and saturated brine (15 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.0 mg) as a colorless solid. (Yield 64%)
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:12][C@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH:12][C@H:13]([CH3:29])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=3)=[N:16]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1nc(C(=O)O)cs1
Product: CC(=O)c1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 24.22 %

Procedure:
(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-acetylthiazole-4-carboxylic acid (0.597 g, 3.07 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.8 g, 3.07 mmol). The product was triturated using diethyl ether, isopropanol and DCM, respectively. Yield 24.22%. 1H-NMR (400 MHz; DMSO-d6): δ 1.19 (d, 3H), 2.30 (s, 3H), 4.37 (dd, 1H), 4.44 (dd, 1H), 4.47-4.56 (m, 1H), 6.96 (d, 1H), 7.87 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 7.04 (d, 1H), 8.49 (d, 1H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-33.5°±2.5° (c=0.5% in chloroform).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(Cl)[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)(Cl)C(Cl)=O)C=CC=CC=1.N1CCOCC1.[NH:46]1[CH:50]=[CH:49][N:48]=[CH:47]1>C(#N)C>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:47]2[NH:46][CH:50]=[CH:49][N:48]=2)[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N1CCOCC1)C(Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C(Cl)C(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: C1COCCN1
Product: O=C(N1CCOCC1)C(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
A mixture of 15.5 g of diphenylchloroacetic acid morpholide, m.p. 113° C (prepared from diphenylchloroacetyl chloride and morpholine in accordance with the procedure described in Ber. 41, 3593) and 11g of imidazole in 100 ml of acetonitrile is heated at reflux for 18 hours. The solvent is removed by distillation in vacuo and, after addition of 70 ml of water, the residue is extracted with methylene chloride. The extracts are dried and the solvent is removed by distillation to yield diphenyl-imidazolylacetic acid morpholide which is further purified by recrystallization from methanol. The hydrochloride salt, m.p. 118° C, is obtained by treating an ethyl acetate solution of the free base with an ethereal solution of hydrogen chloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[C-:12]#[N:13].[Na+]>CN1CCCC1=O.[Ni](Br)Br>[O:10]=[C:8]1[NH:7][C:6]2[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=[CH:4][C:5]=2[S:9]1
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2sc(=O)[nH]c2c1
Reaction time: 1 h
Yield: 36.3 %

Procedure:
Heat a mixture of 5-chloro-3H-benzothiazol-2-one (9.3 g, 50 mmol), nickel(II) bromide (10.9 g, 50 mmol) and sodium cyanide (4.91 g, 100 mmol) in 1-methyl-pyrrolidinone (100 mL) in a microwave reactor to 200° C. over 15 min and hold 1 h. Filter the cooled mixture through a glass frit, add diethyl ether and brine and filter again. Wash the organic phase with brine three times and concentrate in vacuo. Pass the residue through a plug of silica gel eluting with hexane/EtOAc (2:1) and then dichloromethane/methanol (9:1) to obtain the desired intermediate (3.2 g, 36%). MS (ES+) m/z: 177 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: COc1cccc(CNC2CC2)c1
Product: COc1cccc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[N:44]1[NH:45][N:46]=[N:47][C:48]=1[C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1.B(O)O>>[N:44]1[NH:45][N:46]=[N:47][C:48]=1[C:49]1[CH:50]=[C:51]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:52]=[CH:53][CH:54]=1
Reactant: OB(O)c1cccc(-c2nn[nH]n2)c1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cccc(-c7nn[nH]n7)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 3-(2H-tetrazol-5-yl)phenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (4.56 mg, 26%). LCMS: m/e 581.53 (M−H)−, 4.12 min (method 3). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.95 (d, J=4.10 Hz, 6H), 0.99 (s, 3H), 1.01 (s, 6H), 1.03-1.76 (m, 17H), 1.69 (s, 3H), 1.81-1.93 (m, 2H), 2.07-2.23 (m, 2H), 2.34 (dd, J=13.47, 2.34 Hz, 1H), 2.95-3.06 (m, 1H), 4.58 (s, 1H), 4.72 (s, 1H), 5.32 (d, J=4.39 Hz, 1H), 7.22 (d, J=6.44 Hz, 1H), 7.38-7.51 (m, 1H), 7.81 (s, 1H), 7.92 (d, J=7.32 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (213.6 mg, 0.599 mmol) in tetrahydrofuran (3.0 mL) was added cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 898 μL, 0.898 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The starting material wasn't consumed completely. To the mixture was added cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 449 μL, 0.449 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (231.2 mg, 0.580 mmol, 97%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:28]=[CH:27]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+].Cl.S1C(N)=NC=N1>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:2](=[O:1])[CH2:7]1)=[O:36])[CH:28]=[CH:27]2
Reactant: O=C(O)CCn1ccc2cc(Cl)ccc21
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(CCn1ccc2cc(Cl)ccc21)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1
Yield: 34.5 %

Procedure:
Synthesized according to general procedure 14, method A. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (100 mg, 0.29 mmol), 3-(5-chloro-1H-indol-1-yl)propanoic acid (65 mg, 0.29 mmol), HATU reagent (220 mg, 0.58 mmol), sodium bicarbonate (74 mg, 0.87 mmol), and DMF/CH2Cl2-1/1 (0.50 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.58-7.53 (m, 2H), 7.49-7.44 (m, 3H), 7.26 (d, J=4.6 Hz, 1H), 7.13 (dd, J=2.1, 8.7 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 6.42-6.41 (m, 1H), 4.47-4.40 (m, 2H), 4.18 (s, 1H), 4.15 (s, 1H), 3.77-3.74 (m, 4H), 2.94-2.90 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=544.2; tR=3.00 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: CC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title ketone of Example 3 (1.0 g, 0.0032 mole) was dissolved in 10 ml of absolute ethanol and the solution cooled to about 0° C. in an ice bath and 31 mg of sodium borohydride was added. The reaction was stirred for about one hour and acetone was added. The solvents were removed in vacuo, the residue extracted twice with benzene, the organic extracts combined and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product which was chromatographed on silica to give the title compound. Analysis calc. for C18H30O2S(310.5):
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[C:14]([N:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.O>CC#N.CCOC(C)=O>[C:17]([O:16][C:14]([N:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][C:6]2[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:22]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
The mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (332 mg, 1.50 mmol), 1-Boc-3-aminomethylpyrrolidine (300 mg, 1.50 mmol) and DIEA (0.650 mL, 3.73 mmol) in CH3CN (6 mL) was stirred at room temperature for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (544 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu](I)I>[F:11][C:12]([F:21])([F:22])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 100 °C
Yield: 9.6 %

Procedure:
A solution of ethyl 4-pyrazolecarboxylate (500 mg), 4-(trifluoromethoxy)iodobenzene (1.00 g), trans-1,2-bis(methylamino)cyclohexane (100 mg), copper iodide (70 mg) and cesium carbonate (1.7 g) in dioxane (5.0 mL) was stirred while heating at 100° C. for 5 hr. The reaction mixture was filtered through Celite and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-80:20) to afford ethyl 1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-4-carboxylate (100 mg).
Reaction SMILES: [C:1]([C:4]([C:16](=[O:18])[CH3:17])=[CH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH2:14][CH3:15])(=O)[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1>C(O)(C)C>[C:16]([C:4]1[CH:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[CH2:14][CH3:15])[C:21]2[C:22](=[O:26])[NH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:1]=1[CH3:2])(=[O:18])[CH3:17]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CCc1cc(C#N)ccc1C=C(C(C)=O)C(C)=O
Solvent: CC(C)O
Product: CCc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cc[nH]c(=O)c21
Reaction time: 96 h

Procedure:
1 g (4.14 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-ethylbenzonitrile and 0.45 g (4.14 mmol) of 4-aminopyridin-2(1H)-one [Scats, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] are dissolved in 20 ml of isopropanol and stirred at the reflux temperature under argon for 4 days. The mixture is then concentrated and the residue is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 10:1). 277 mg (20% of theory) of the title compound are obtained as a pale yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:9]=1[C:10](O)=[O:11].O.[OH-].[Na+]>C(OCC)C>[Cl:7][C:8]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A suspension of 5.5 grams (0.144 mole) of lithium aluminum hydride in 300 mL of diethyl ether was stirred, and 25.0 grams (0.111 mole) of 2,3,5-trichlorobenzoic acid in 200 mL of diethyl ether was added dropwise at a rate which maintained a gentle reflux. The complete addition required about 75 minutes. Upon completion of addition, the reaction was mixture heated at reflux for 4.5 hours. After this time the reaction mixture was stirred for about 16 hours, during which time it was allowed to cool to ambient temperature. The reaction mixture was then cooled to below 10° C., and 6 mL of water was added slowly dropwise. Upon completion of addition, 5 mL of aqueous 20% sodium hydroxide was added dropwise, followed by an additional 12 mL of water added dropwise. The reaction mixture was then stirred for 20 minutes and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to a residue. The residue was stirred into water, and the combination was extracted with ethyl acetate. The extracts were combined and washed with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 17.1 grams of 2,3,5-trichlorophenylmethanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [SH3+].[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(C)C=CC=CC=1.C(O)CC.[OH-].[Na+]>>[O:9]1[CH2:10][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: [SH3+]
Solvent: CCCO
Product: c1ccc(C2CO2)cc1
Temperature: 50 °C

Procedure:
To the sulphonium salt mixture was added benzaldehyde (13.52 g at 98%, 0.125 moles), toluene (92 g, 1 mole), and n-propanol (35.5 g, 0.59 moles) and the mixture stirred and heated to 50° C. Aqueous sodium hydroxide solution (32 g at 53%, 0.425 moles) was added and a temperature rise to 80° C. was observed (due to neutralisation of excess acid). The mixture was cooled to 70° C. and stirred at this temperature for 1 hour. The mixture was cooled, the organic layer separated, washed with water and dried over magnesium sulphate. Qualitative GC analysis showed 76% conversion to the title epoxide (by comparison with authentic sample).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:17][NH2:18])[C:4]=2[CH:3]=1
Reactant: NN
Reactant: O=C1c2ccccc2-c2ccc(F)cc21
Solvent: CCO
Solvent: O
Product: NN=C1c2ccccc2-c2ccc(F)cc21
Yield: 60 %

Procedure:
A mixture of commercially available (Aldrich Chemical, Inc.) 2-fluoro-9-fluorenone (11) (10 g, 50.5 mmoL) and hydrazine monohydrate (10 mL , 200 mmoL, 4 eq) in ethanol (250 mL ) was refluxed for 1.5 h. The solution was then reduced in volume (to about a 100 mL) and chilled. The solid that separated was collected by filtration, washing with cold ethanol to provide 6.5 g (60%) of product (12): mp 161°-165° C.; IR (KBr) 3390, 3310, 3200, 1450 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.85 (bd, 1H, J=7.3Hz), 7.69 (bd, 1H, J=7.1Hz), 7.57 (dd, 1H, J=4.8, 8.1Hz), 7.36 (m, 3H), 7.02 (ddd, 1H, J=2.5, 8.3, 9.2Hz), 6.48 (bs, 2H); MS m/z 212 (M+), 183 (base peak).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39](=[N:43][O:44][CH3:45])[C:40](O)=[O:41])[N:34]=1)=[O:31]>C(Cl)Cl>[CH:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39](=[N:43][O:44][CH3:45])[C:40]([NH:1][CH:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]4[NH:13][N:14]=[N:15][N:16]=4)[CH3:10])[CH2:7][S:8][C@H:3]23)=[O:41])[N:34]=1)=[O:31]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1nccc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nccc(NC=O)n1
Temperature: 25 °C

Procedure:
On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and trimethylsilylacetamide (11 g.) were added to methylene chloride (66 ml.) and the mixture was stirred at ambient temperature for an hour, and to this solution was added all at once the above activated solution of 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid under cooling at -20° C. with stirring, and the stirring was continued at the same temperature for an hour and at ambient temperature for additional an hour. The reaction mixture was concentrated under reduced pressure and then ethyl acetate and an aqueous solution of sodium bicarbonate were added to adjust the solution to pH 7 to 8. After the aqueous layer was separated out, a proper quantity of ethyl acetate was added thereto. The mixture was adjusted to pH 1 to 2 with dilute hydrochloric acid and then salted out. The ethyl acetate layer was separated out, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate, and then evaporated to dryness under reduced pressure. The resultant foamy substance was pulverised in ethyl ether, collected by filtration and then dried to give 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (2.9 g.). Thus obtained product (0.6 g.) was dissolved in a mixed solution of methanol and ethyl acetate (5 ml.)(2:1 by volume), and the solution was poured into ethyl ether (40 ml.) and then the mixture was allowed to stand for a while. The precipitates were collected by filtration to give purified pale-yellowish powder of 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.5 g.).