Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18]C(OC)=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC(=O)OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)N1c2cc(OC)c(O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 83.7 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-6-methoxycarbonyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (500 mg, 0.80 mmol) and potassium carbonate (222 mg, 1.6 mmol) in methanol (5 mL) was stirred at room temperature overnight. A small amount of water was added, and the methanol was removed in vacuo. Additional water (20 mL) was added and the aqueous mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with a saturated sodium bicarbonate solution (10 mL), brine (10 mL), and then dried over sodium sulfate, filtered and concentrated in vacuo to give 412 mg crude product. Purification by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded 378 mg of the title compound (84%): MS m/z 565 (M++1), 582 (M++18); 1H NMR (CDCl3) δ7.08 (C8, s, 1H), 6.52 (C5, s, 1H), 1.15 (C2-Me, d, 3H, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[F:11][CH:12]([F:16])[C:13](O)=O.CCOCC>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([C:13]([CH:12]([F:16])[F:11])=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(O)C(F)F
Reactant: Cc1cc(Cl)nnc1NN
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(Cl)nn2c(C(F)F)nnc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a beige suspension of 6-chloro-3-hydrazinyl-4-methylpyridazine (step 195.1) (22.44 g, 127 mmol) in dioxane (250 mL) was added difluoroacetic acid (Aldrich) (9.40 mL, 146 mmol) and the reaction mixture was stirred at rt for 5 min, then heated-up to 120° C. for 2.5 hr. With heating the suspension turned into a red-orange solution. The reaction mixture was cooled to rt. Et2O (80 mL) was added and the suspension was stirred for 2 hours at 0° C. Precipitated solids were isolated by filtration, suspended in hexanes and filtered again. After repeated washings with hexanes the tittle compound was obtained as an orange solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CC(=O)N(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 46E (0.020 g, 0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.023 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.82 (s, 9 H), 0.87 (s, 9 H), 1.32 (m, 1 H), 1.53 (t, J=11.40 Hz, 1 H), 2.41 (s, 3 H), 2.63 (m, 3 H), 2.85 (m, 1 H), 3.16 (d, J=18.02 Hz, 1 H), 3.60 (m, 5 H), 3.90 (m, 3 H), 4.19 (m, 1 H), 4.35 (s, 1 H), 4.68 (m, 2 H), 6.90 (d, J=9.93 Hz, 1 H), 7.03 (m, 6 H), 7.16 (d, J=7.72 Hz, 1 H), 7.25 (d, J=8.09 Hz, 2 H), 7.34 (m, 1 H), 7.69 (t, J=7.72 Hz, 1 H), 7.93 (m, 6 H), 8.65 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[O:18])[CH2:6][C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)C.OS(O)(=O)=O>CO>[CH3:1][O:3][C:4](=[O:19])[C:5](=[O:18])[CH2:6][C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1

Procedure:
A solution of (E)-6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (4; 33.39 g, 0.12 mol) and conc H2SO4 (0.5 mL) was stirred at reflux for 6 h in methyl alcohol (MeOH, 400 mL). Upon cooling and solvent concentration, (E)-6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoic acid methyl ester (6; 22.7 g, 71%) was collected as yellow crystals: mp 135-136° C.; 1H NMR (400 MHz, CDCl3) δ 14.74 (s, 1H), 7.67 (d, J=15.9 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 6.61 (d, J=15.9 Hz, 1H), 6.53 (s, 1H), 3.92 (s, 3H); HRMS-ESI (m/z): calcd for C13H1ClO4, 266.034. found, 266.034.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][N:49]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:48]1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 60% yield. LCMS for C31H32ClN8O2 (M+H)+: m/z=583.1.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1>[O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:15]3=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]3[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)nc3)C2=N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of 6′-phenoxy-3,3′-bipyridin-2-amine (350 mg) in THF (dry) (15 ml) was added to a mixture of NaH (60%, 266 mg) and 2-chloroethanesulfonyl chloride (542 mg) in THF (dry) (15.0 ml) at room temperature. The mixture was stirred at 50° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (419 mg) as a pale yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].Br[CH2:14][C:15](=O)[CH2:16][CH3:17]>C(O)C>[NH2:3][C:1]1[N:4]([N:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:14]=[C:15]([CH2:16][CH3:17])[N:2]=1
Reactant: CCC(=O)CBr
Reactant: N=C(N)NN=Cc1ccccc1
Solvent: CCO
Product: CCc1cn(N=Cc2ccccc2)c(N)n1

Procedure:
A solution of 1.62 g (0.01 mol) of benzaldehyde guanylhydrazone and 0.84 g (0.005 mol) of 1-bromo-2-butanone (Aldrich, Buchs, Switzerland; tech. 90%, Cat. no. 24,329-9) in 5 ml of ethanol is stirred for one hour in an ice-water bath and for 16 hours at 20° C. The reaction mixture is then concentrated to dryness by evaporation. The residue is taken up in lethyl acetate, washed twice with water and once with dilute sodium chloride solution, and dried over MgSO4. The ethyl acetate solution is concentrated, whereupon the title compound crystallizes out, m.p. 164°-167° C., 1H-NMR (DMSO): δ=8.41 (s, 1H); 8.89 (m, 2H); 7.46 (m, 3H); 7.13 (s, 1H); 5.9 (s, 2H); 2.34 (q, 2H); 1.13 (t, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:7]([CH:11]1[N:15]=[C:14]([I:16])[C:13]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=2)([CH:17]=[O:18])[NH:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1N=C(I)C(C=O)(Cc2ccc(C(=O)OC)c3ccccc23)N1
Temperature: 70 °C
Reaction time: 15 h
Yield: 84.8 %

Procedure:
A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate, 60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde, and 65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E. A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem. 59, 2629 (1981)) in 600 ml of dimethylformamide was stirred for 5 hours under argon at 70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester was added and the suspension was stirred an additional 15 hours at 70° C. The mixture was poured into water and the solid which separated was collected by filtration, washed with water, and triturated several times with 250 ml of boiling methanol to give 86.8 g (85%) of a solid; mp 177.5°-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([O-:13])([OH:12])=[O:11].[NH2:14][NH:15][C:16]([NH2:19])=[N:17][NH2:18].[N+]([O-])(O)=O>C(O)C.O>[N+:10]([O-:13])([OH:12])=[O:11].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:18][NH:17][C:16]([NH:15][N:14]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[NH:19])=[CH:4][CH:3]=1
Reactant: NN=C(N)NN
Reactant: O=Cc1ccc(Br)cc1
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CCO
Product: N=C(NN=Cc1ccc(Br)cc1)NN=Cc1ccc(Br)cc1

Procedure:
A boiling solution of 20.0 grams of 4-bromobenzaldehyde in 250 milliliters of ethanol is stirred vigorously as a solution of 6.1 grams of 1,2-diaminoguanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 16.5 grams of product and the melting point is 178°-180°C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1cccc(F)n1
Product: Cc1cccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=309.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-6-methyl-pyridine.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][CH2:15][CH3:16])=[C:6]([C:17](OC)=[O:18])[C:5]=1[C:21](OC)=[O:22])[CH2:2][CH3:3].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O>O>[OH:18][CH2:17][C:6]1[C:5]([CH2:21][OH:22])=[C:4]([CH2:1][CH2:2][CH3:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1c(C(=O)OC)c(C(=O)OC)c(CCC)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(CO)c(CO)c(CCC)c2ccccc12
Temperature: 25 °C
Yield: 89.5 %

Procedure:
Dimethyl 1,4-dipropylnaphthalene-2,3-dicarboxylate (0.295 g, 0.898 mmol) was added to a 5 ml THF solution of LiAlH4 (0.075 g, 1.98 mmol) at 0° C. After stirring at room temperature for an hour, water was added to effect hydrolysis. The mixture was treated with 2N H2SO4 followed by extraction with diethyl ether. The extract was washed with brine and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure. The title compound (0.219 g) was obtained as a white solid. The isolation yield was 90%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH2:12][NH:13][CH2:14][CH:15]=1)([CH3:10])=[CH2:9].CO>[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)([CH3:10])[CH3:9]
Reactant: C=C(C)C1=CCNC1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)C1CCNC1
Reaction time: 3 h

Procedure:
To a solution of 3-isopropenyl-2,5-dihydro-1H-pyrrole trifluoroacetate (2.09 g, 0.00936 mol) in methanol (100.0 mL, 2.469 mol) was added 1.3 g of Pd (10% wt. on activated carbon), then the mixture was hydrogenated on par shaker at 43 psi for 3 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dried under high vacuum to afford the product as a white solid. LC-MS (M+H) 114.2 (base) [M+H) 130.1 base, for the corresponding alcohol].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.O1CCOCC1>O>[CH2:1]([N:8]([C:27]([CH:24]1[CH2:26][CH2:25]1)=[O:28])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1sc(-c2ccccc2)cc1NCc1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1sc(-c2ccccc2)cc1N(Cc1ccccc1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of sodium 3-benzylamino-5-phenyl-thiophene-2-carboxylate (41.1 mg, 0.1 mmol) was added 32 mg (0.3 mmol) of cyclopropanecarbonyl chloride, 1.5 ml of dioxane and 0.5 ml of water. The mixture was stirred overnight at room temperature and concentrated in vacuo. A 4N hydrogen chloride solution in dioxane (1 ml) was added and the mixture was stirred for one hour at room temperature. The mixture was again concentrated and the crude material was purified by reverse phase HPLC giving access to 11.9 mg (31.5%) of 3-(benzyl-cyclopropanecarbonyl-amino)-5-phenyl-thiophene-2-carboxylic acid as a pale yellow solid. NMR 1H (DMSO D6, 400 MHz): 7.56-7.54 ppm (m, 2H, Haro); 7.39-7.13 ppm (m, 10H, Haro, Hazole and COOH); 5.27 ppm (d, 1H, J=15.2 Hz); 4.48 ppm (d, 1H, J=15.2 Hz); 1.49 ppm (m, 1H); 0.77 ppm (m, 2H); 0.61 ppm (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[C:13]([CH2:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:40]([NH:41]C(=O)CC3SC=CC=3)[C:39](=[O:50])[N:21]2[C:22]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])#[N:14].CO>C(Cl)Cl>[NH2:41][C@@H:40]1[C:39](=[O:50])[N:21]2[C:22]([C:23]([O:25][CH:26]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:17]([CH2:16][CH2:15][C:13]#[N:14])[CH2:18][S:19][C@H:20]12
Reactant: N#CCCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: N#CCCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A suspension of phosphorus pentachloride (606 mg., ca 2.9 mmole) in methylene dichloride (5 ml) was warmed until most of the phosphorus pentachloride had dissolved. A solution of pyridine in methylene dichloride (4.6 ml., as a 10% v/v solution, ca 5.7 mmole) was added, and the mixture cooled to 0°. A solution of diphenylmethyl 3-(2-cyanoethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (700 mg ca 1.3 mmole) in methylene dichloride (9 ml) was added and the mixture was stirred at 0° for 30 minutes. After a further 30 minutes at 25° the solution was run into a vigorously stirred mixture of methanol (2 ml.) and methylene dichloride (10 ml). the resulting solution was washed with dilute aqueous sodium bicarbonate solution and water, and dried and evaporated in vacuo the residue was triturated with petroleum to remove traces of pyridine and the resulting solid (500 mg) dissolved in ethyl acetate. The solvent was removed in vacuo and the residue washed with ether to give the title compound (450 mg) as small needles m.p. 118° to 122° (decomp) [α]D25 49.1° (c 1.3, CHCl3) λmax. (CHCl3) 258.5 nm (ε 5,950) νmax. (CHBr3) 3450 and 3380 (NH2), 1780 (β-lactam) 1728 CO2R) and 758 and 740 (CHPh2) cm.-1 τ (CDCl3) 2.62 (Ph), 3.05 (CHPh2) 5.06 and 5.23 (C6 and C7 --H, two doublets J 5 Hz.) 6.48 and 6.65 (C2 --CH2AB-quartet, J 18 Hz.) 7.1 to 7.6 (CH2CH2CN complex) 7.5 (NH2). The compound ran to the cathode on electrophoresis at pH 1.9
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:33]=[CH:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCOc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3c(OCc4ccccc4)cccc32)cc1
Yield: 98.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-benzyloxychroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.51 g) as starting materials, 8-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (1 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH3:31])=[C:21]([CH:23]5[CH2:25][CH:24]5C(OCC)=O)[N:22]=4)[CH:19]=3)[C:10](=[O:32])[CH:9]=2)=[CH:4][CH:3]=1.C[Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH3:31])=[C:21]([CH:23]5[CH2:25][CH:24]5[C:8]([OH:7])([CH3:13])[CH3:9])[N:22]=4)[CH:19]=3)[C:10](=[O:32])[CH:9]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cn2c1C
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.8 %

Procedure:
To a stirred solution of ethyl 2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxylate (250 mg) in THF (2 ml) was added methylmagnesium bromide (3.0 M solution in ether, 1.8 ml) at 0° C., and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then quenched with saturated NH4Cl solution, and extracted with DCM. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (7 mg) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]2[O:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].O>[Fe].CO>[N:17]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[O:10][C:9]=1[C:7]1[S:8][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2nc3ccncc3o2)s1
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 2-(5-nitrothiophen-2-yl)oxazolo[5,4-c]pyridine (170 mg, 0.69 mmol), NH4Cl (199 mg, 3.73 mmol), iron powder (328 mg, 5.87 mmol), H2O (10 mL) and methanol (40 mL) was heated to reflux for 6 hrs under N2. The mixture was concentrated in vacuo followed by addition of 100 mL of water and left overnight at 4° C. The precipitate was collected by filtration and dried to give 5-(oxazolo[5,4-c]pyridin-2-yl)thiophen-2-amine as a brown solid (52 mg, yield 35%). 1HNMR (400 MHz, DMSO-d6) δ: 8.84 (1H, s); 8.40 (1H, d, J=5.2); 7.64 (1H, d, J=4); 7.57 (1H, d, J=5.2), 7.06 (2H, s), 1.09 (1H, d, J=4.4).
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[C:11]([C:15]([C:18]([C:21](Cl)=[O:22])([F:20])[F:19])([F:17])[F:16])([F:14])([F:13])[F:12]>[Pd]>[C:18]([CH:21]=[O:22])([C:15]([C:11]([F:12])([F:13])[F:14])([F:17])[F:16])([F:20])[F:19]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Product: O=CC(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A 3-necked round bottom flask fitted with dropping funnel, dry-ice condenser, and gas inlet was charged with 10% Pd/C(0.35 g) and cooled to 0° C. Triisopropylsilane (7.29 g, 46 mmol) was added, and CF3CF2CF2C(O)Cl (9.30 g, 40 mmol) was added dropwise over a 10 min period. The reactor was connected to a cold trap (-78° C.) while the mixture was stirred for 18 hr. Transfer from the trap and reaction vessel gave a total of 5.1 g (62%) of colorless liquid. 1H NMR (CD2Cl2): 9.62 (m). 19F NMR: -81.24 (t, J=8.3 Hz), -126.4 (quartet of doublets, Jq =8.3, Jd =3.2), -127.9 (s).