Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:16]([C:15]3[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=3)[NH:9][C:4]=2[C:3]=1[CH3:10]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(Br)ccc(N)c1N
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Br)ccc2nc(-c3ccc(F)cc3)[nH]c12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 95 %

Procedure:
A solution of 4-bromo-3-methylbenzene-1,2-diamine (prepared according to the procedure of PCT Pat. Appl. WO 2008/021851, 400 mg, 1.989 mmol) in DCM (10 mL) was treated with TEA (0.693 mL, 4.97 mmol), then was treated dropwise with 4-fluorobenzoyl chloride (0.282 mL, 2.387 mmol). The mixture was stirred at rt for 70 min, then was concentrated. The residue was suspended in ethanol (25 mL), treated with concentrated hydrochloric acid (3 mL, 36.5 mmol) and heated at 90-95° C. After 42.5 h, the mixture was cooled to rt and the ethanol was removed under vacuum. The residual paste was suspended in water and the pH was adjusted to ca. 8 with NaHCO3 (aq). The precipitate was collected by filtration, washed with water and dried under vacuum to provide 6-bromo-2-(4-fluorophenyl)-7-methyl-1H-benzo[d]imidazole as a pale pink solid (636 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (2H, dd, J=8.9, 5.4 Hz), 7.33-7.45 (4H, m), 2.57 (3H, s). Mass spectrum m/z 305, 307 (M+H)+.
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:29][C@@:28]4([CH3:30])[C@@H:15]([CH2:16][CH2:17][C@@H:18]5[C@@H:27]4[CH2:26][CH2:25][C@@:23]4([CH3:24])[C@H:19]5[CH2:20][C@H:21]([N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C@@H:22]4[OH:31])[CH2:14][C@@H:13]3[OH:37])[CH2:8][CH2:7]2)[O:5]CC1.[OH-].[Na+]>O1CCOCC1>[O:5]=[C:6]1[CH2:11][CH2:10][N:9]([C@H:12]2[CH2:29][C@@:28]3([CH3:30])[C@@H:15]([CH2:16][CH2:17][C@@H:18]4[C@@H:27]3[CH2:26][CH2:25][C@@:23]3([CH3:24])[C@H:19]4[CH2:20][C@H:21]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[C@@H:22]3[OH:31])[CH2:14][C@@H:13]2[OH:37])[CH2:8][CH2:7]1
Reactant: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12C[C@H](N3CCC(=O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
After adding 42 ml of 10% aqueous hydrochloric acid solution to 5 g of 2β-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-16β-(1-pyrrolidinyl)-5α-androstane-3α,17β-diol dissolved in 100 ml of dioxane, the reaction mixture is boiled under reflux for 3 hours. After completion of the reaction, the solution is made alkaline by adding aqueous sodium hydroxide solution, dioxane is distilled off and the residue is diluted with water. After filtering, the precipitate is washed with water until neutral and dried. The crude product is dissolved in acetonitrile, clarified by activated carbon and after filtering off the adsorbent, two thirds of acetonitrile are distilled off. After filtering, the crystalline precipitate is dried to give the title product in a yield of 4.2 g (92.1%), m.p.: 136°-138° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].[Cl-].[NH4+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[NH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(CCCO)CC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: OCCCc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-hydroxyhexane-1,3-dione (38 g, 0.17 mol) in 150 mL ethanol and hydrazine hydrate (17.05 g, 0.34 mol) is added slowly over a 30 min period (exothermic up to 35° C.). The resulting solution is stirred for 1 h at RT then the mixture is added to aqueous ammonium chloride. Extraction with ethyl acetate and evaporation of the organic phase results in the crude product. The product is purified by trituration with 2×200 mL n-hexane and the product is obtained as solid (29 g, 77%).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)S1
Temperature: 80 °C

Procedure:
A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 7-8 h at 80° C. The crystalls were filtered and washed with ethanol. Yield 1.0 g (72%), mp 295°-298° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(Oc3ccccc3)nc2c1O
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)nc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-hydroxy-6-phenoxy-1,5-naphthyridine-3-carboxylate (3.0 g) and phosphorus oxychloride (25 ml) was heated at 50° C. for 1 hour and then worked up as described in Example B1 to give ethyl 4-chloro-6-phenoxy-1,5-naphthyridine-3-carboxylate, m.p. 133°-137° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH:21]([OH:23])[CH3:22]>>[OH:23][CH:21]([CH3:22])[CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Reactant: CC(O)CBr
Agent: Cl
Product: CC(O)CN1CCC(c2cc3ccccc3c(=O)[nH]2)CC1
Yield: 16.1 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (500 mg) and 1-bromo-2-propanol (394 mg), 3-[1-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (87 mg) was obtained.
Reaction SMILES: [CH:1]([N:4]([CH:14]([CH3:16])[CH3:15])[C:5](=[O:13])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[C:25]([O:35][CH3:36])(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH:14]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:13])[CH:6]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][C:25]([O:35][CH3:36])=[O:34])([CH3:16])[CH3:15]
Reactant: CC(C)N(C(=O)Cc1cccnc1)C(C)C
Reactant: COC(=O)C=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(c1ccccc1)C(C(=O)N(C(C)C)C(C)C)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of N,N-diisopropyl-2-pyridin-3-ylacetamide (740 mg, 3.36 mmol) in dry THF (30 mL) was added a solution of LDA (1.5 M) in THF (4.5 mL, 6.72 mmol). The reaction mixture was stirred at 0° C. for 30 min and then cooled to −78° C. Solid methyl cinnamate (654 mg, 4.031 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. After 1.5 h, the reaction was quenched by adding a saturated aqueous solution of NH4Cl and partitioned between CH2Cl2 and saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The resulting red viscous liquid was purified by flash chromatography using a linear gradient of 0% to 5% MeOH—NH3 (90:10 v/v) in CH2Cl2. Yellow solid, single diastereomer.
Reaction SMILES: [ClH:1].C(OC([N:12]([CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:28])[C:25]=2[OH:27])[CH2:20][CH2:19][NH:18]1)[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:1].[ClH:1].[CH:13]([NH:12][CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:28])[C:25]=2[OH:27])[CH2:20][CH2:19][NH:18]1)([CH3:15])[CH3:14]
Reactant: CC(C)N(CC1NCCc2ccc(O)c(O)c21)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)NCC1NCCc2ccc(O)c(O)c21

Procedure:
A mixture of 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.1 g), acetic acid (11 ml) and conc. hydrochloric acid (11 ml) was refluxed for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with acetone, followed by recrystallization from a mixture of methanol and ether to give 1-(N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride, colorless crystals, mp 255° to 258° C.
Reaction SMILES: [OH-].[Na+].CC(O)C.[CH:7]1([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>C(OCC)(=O)C>[CH:7]1([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(OC2CCCCC2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C(O)c1ccc(OC2CCCCC2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
10% Sodium hydroxide aqueous solution 0.25 mL was added to a suspension of 2-propanol 2.0 mL of methyl 4-(cyclohexyloxy)-2-(4-fluoroanilino)benzoate 40 mg at room temperature, and it was heated and refluxed for 5 hours. After the reaction mixture was cooled to room temperature,1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and solid matter was filtrated to give 4-(cyclohexyloxy)-2-(4-fluoroanilino)benzoic acid 8 mg of white solid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH:6]=[CH:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10]>C(O)C.[Pd]>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[C:2](=[O:10])[CH2:3][C:4]2=[O:9]
Reactant: O=C1CC(=O)C2C=CC1O2
Agent: [Pd]
Solvent: CCO
Product: O=C1CC(=O)C2CCC1O2
Reaction time: 6 h

Procedure:
To a stirred solution of 8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione (5.1 g) in ethanol (100 ml) was added palladium on charcoal (0.51 g, 5% by wt. catalyst) and the mixture hydrogenated at ambient temperature and pressure over 6 hours. The catalyst was removed by filtration and the solvent evaporated under reduced pressure to afford the required product containing some ethyl enolether of the required product.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.[CH3:18][C:19]1[C:24]([Cl:25])=[C:23](Cl)[N:22]2[N:27]=[CH:28][N:29]=[C:21]2[N:20]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:25][C:24]1[C:19]([CH3:18])=[N:20][C:21]2[N:22]([N:27]=[CH:28][N:29]=2)[C:23]=1[NH:17][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:16]
Reactant: Cc1nc2ncnn2c(Cl)c1Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nc2ncnn2c(N[C@@H](C)c2ccc(F)cc2)c1Cl

Procedure:
0.300 g (3.0 mmol) Triethylamine, a spatula tip of tetrabutylammonium iodide and 0.514 g (3.7 mmol) of (S)-1-(4-fluorophenyl)-ethylamine were added successively to a solution of 0.500 g (2.5 mmol) of 5-methyl-6,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine in 10 ml of toluene under stirring. The reaction mixture was heated at reflux for 5 hours and then stirred for another 12 hours at room temperature. The solvent was evaporated under reduced pressure and dichloromethane was added to the resulting residue. The resulting reaction mixture was washed with 2N hydrochloric acid and with water. The organic phase was separated, dried and the solvent was evaporated under reduced pressure. Treatment of the resulting residue with hexane yielded 0.520 g (1.7 mmol, 68% of theory) of the title compound having a melting point of 103-104° C.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH2:7][Br:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)csc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1c(Br)csc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of 2,4-dibromo-3-methylthiophene (0.92 g, 3.6 mmol) in carbon tetrachloride was added N-bromosuccinimide (0.64 g, 3.6 mmol) and AlBN (5 mg). The mixture was heated under reflux for 1 h and then for another 4 h in the presence of light. The solution was then cooled to 0° C. and the succinimide was filtered. The residue was washed with carbon tetrachloride. The solvent was removed and the product recrystalized from EtOH to yield 2,4-dibromo-3-(bromomethyl)thiophene (1.08 g, 91%). mp 89-90° C.; 1H NMR (500 MHz, DMSO-d6) δ: 4.53 (s, 2H), 7.89 (s, 1H). MS (EI) m/z 332/334/336 (M+.). Anal. Calcd for C5H3Br3S: C, 17.93; H, 0.90; N, 0.00. Found: C, 18.02; H, 0.86; N, 0.00.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:23]([C:29]2[N:33](COCC[Si](C)(C)C)[C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)(O)[C:24]([F:27])([F:26])[F:25])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(O)C(F)(F)F)=C2C(=C(C)C=1)[N:55](S(C1C=CC(C)=CC=1)(=O)=O)[CH:54]=C2)C.CN>CO.C(O)C>[CH2:1]([C:3]1[C:4]([C:23]([C:29]2[NH:33][C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)([NH:55][CH3:54])[C:24]([F:25])([F:27])[F:26])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:14])=[O:15])[CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CN
Solvent: CCO
Solvent: CO
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(NC)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F

Procedure:
The title compound was synthesized from a mixture of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 105-A, methylamine in MeOH was used instead of ammonia in ethanol. MS (ESI+) m/z 566.79 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[CH:3]=1.[CH3:11][CH:12]1[NH:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1>>[CH3:18][CH:16]1[NH:17][CH:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=2)[CH2:15]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CC1CNCC(C)N1
Product: CC1CN(c2cccc(N)c2)CC(C)N1

Procedure:
Using the procedure outlined in Example 37 (A), the title compound was prepared from 1-fluoro-3-nitrobenzene (1 g, 7 mmol) and 3,5-dimethyl-piperazine (1.14 g, 10 mmol). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.00 (t, J=8.0 Hz, 1H), 6.33 (d, J=8.2 Hz, 1H), 6.21 (m, 1H), 6.15 (d, J=8.2 Hz, 1H), 3.60 (br, 2H), 3.45 (d, J=9.8 Hz, 2H), 2.98 (m, 1H), 2.22 (t, J=11.3 Hz, 2H), 1.10 (s, 3H), 1.08 (s, 3H).
Reaction SMILES: Cl.[C:2]1([P:8]2(=[O:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[O:14]=[P:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: O=P1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(CCN2CCP(=O)(c3ccccc3)CC2)cc1

Procedure:
4-Phenyl-1,4-azaphosphinane 4-oxide hydrochloride (200 mg, 0.863 mmol), tert-butyl 4-(2-bromoethyl)benzoate (246 mg, 0.863 mmol), and K2CO3 (358 mg, 2.59 mmol) were combined in MeCN (10 mL) and stirred at reflux overnight. The reaction was cooled, diluted with EtOAc, washed with water and brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded the title compound as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.88 (d, J=8.4 Hz, 2H), 7.76-7.71 (m, 2H), 7.54-7.45 (m, 3H), 7.21 (d, J=8.2 Hz, 2H), 3.09-2.99 (m, 4H), 2.85-2.80 (m, 2H), 2.77-2.73 (m, 2H), 2.19-2.11 (m, 2H), 2.08-1.98 (m, 2H), 1.55 (s, 9H). MS: cal'd 400 (MH+), exp 400 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13]C(=O)C)=[CH:6][C:5]=1[O:17][CH3:18].[OH-].[Na+:21]>>[CH3:18][O:17][C:5]1[CH:6]=[C:7]([NH2:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([O-:19])=[O:2].[Na+:21]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)[O-]

Procedure:
reacting methyl-2-methoxy-4-acetylamino-5-nitrobenzoate with sodium hydroxide to form sodium 2-methoxy-4-amino-5-nitrobenzoate;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:2]1.[NH2:14][CH:15]1[C:34](=[O:35])[N:17]2[C:18]([C:31]([OH:33])=[O:32])=[C:19]([C:22]([S:24][C:25]3[N:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:20][S:21][C@H:16]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH:8]([CH3:13])[CH2:9][C:10]([NH:14][CH:15]2[C:34](=[O:35])[N:17]3[C:18]([C:31]([OH:33])=[O:32])=[C:19]([C:22]([S:24][C:25]4[N:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH2:20][S:21][C@H:16]23)=[O:12])=[O:7])=[CH:2]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12
Reactant: CC(CC(=O)O)S(=O)c1ccsc1
Product: CC(CC(=O)NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12)S(=O)c1ccsc1

Procedure:
436 mg. of 3-(3-thienylsulfinyl)butyric acid and 7-amino-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 432 mg. of 7-[3-(3-thienylsulfinyl)butyramido]-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][C:3]=1[Cl:13].[CH3:14][C@@H:15]([NH2:27])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([CH:6]([OH:9])[CH2:7][N:27]([CH2:7][CH:6]([OH:9])[C:5]2[CH:4]=[C:3]([Cl:13])[C:2]([NH2:1])=[C:11]([Cl:12])[CH:10]=2)[C@H:15]([CH3:14])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[Cl:13]
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Reactant: C[C@@H](N)CCc1ccc(C(N)=O)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CCc1ccc(C(N)=O)cc1)N(CC(O)c1cc(Cl)c(N)c(Cl)c1)CC(O)c1cc(Cl)c(N)c(Cl)c1

Procedure:
A mixture of 13.6 g of 4-amino-3,5-dichlorophenacyl bromide and 4.6 g of (R)-1-methyl-3-(4-aminocarbonylphenyl)propylamine in 100 ml of chloroform was warmed to 50° for 3 hours. The mixture was evaporated in vacuo, the residue was dissolved in 200 ml of methanol was 70 ml of water and a solution of 3.0 g of sodium borohydride in 20 ml of water was added dropwise thereto while cooling with ice and stirring so that the temperature did not rise above 20°. After completion of the addition, the mixture was stirred at 5°-10° for a further 2 hours, then poured into ice-water and extracted with methylene chloride. The material isolated from the methylene chloride extract was chromatographed on silica gel. With chloroform/n-propanol/25% ammonia (1000:10:1) there was obtained pure p-[(R)-3-[bis-[(RS)-4-amino-3,5-dichloro-β-hydroxyphenethyl]amino]butyl]benzamide in amorphous form; [α]D20 =-46° (c=1.0% in methanol); ε242 =31080; ε302 =7250.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1
Reactant: COc1cccc2c(O)cc(C(F)(F)F)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc2c(Cl)cc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
4-Hydroxy-8-methoxy-2-trifluoromethylquinoline (18.77 g) is dissolved in 450 mL 8:1 CH2Cl2:DMF. POCl3 (50 mL) is added dropwise and the reaction is allowed to stir overnight. The reaction is then poured into 500 mL ice/H2O and the aqueous is extracted 2× with CH2Cl2. The organic portions are combined, washed 1× with brine, dried over MgSO4, and evaporated. The resulting oil crystallizes upon standing. The solid is recrystallized from 95% EtOH. A second crop of crystals could be obtained by concentrating down the EtOH filtrate. The total yield of product is 15.36 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][N:20]2[C:24](=[O:25])[C:23]3[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]2=[O:30])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Yield: 79 %

Procedure:
The mixture of 1-(2,3-dichlorophenyl)piperazine hydrochloride (compound 35, 10.0 g, 37.4 mmol), N-(3-bromopropyl)phthalimide (compound 34, 9.09 g, 33.9 mmol) and potassium carbonate (11.7 g, 84.8 mmol) in DMF was stirred at room temperature. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The obtained product was washed with EtOH to provide the title compound (11.2 g, 80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.[Br:20]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Br:20])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[S:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (27.0 g, 100 mmol)in 1.10 L of CHCl3 at 60° C. was added bromine (15.98 g, 100 mmol) dropwise as a solution in 200 mL of CHCl3. After the addition was complete, the reaction was cooled to room temperature, and the solvent removed in vacuo to provide 34.2 g (100%) of 6-methoxy-2-(4-methoxyphenyl)-3-bromobenzo[b]thiophene as a white solid. mp 83-85 OC. 1H NMR (DMSO-d6) δ 7.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H). FD mass spec: 349, 350. Anal. Calcd. for C16H13O2SBr: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76.