Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1C.F[C:20]1C=CC([N+]([O-])=O)=CC=1.C[C@H]1CNC[C@@H](C)N1>>[CH3:17][C@H:15]1[NH:14][C@@H:13]([CH3:20])[CH2:12][N:11]([C:3]2[CH:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][CH:4]=2)[CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Yield: 95 %

Procedure:
Crude cis-3,5-Dimethyl-1-(4-nitrophenyl)piperazine (4.91 g, 95% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine by treatment of 1-fluoro-4-nitrobenzene (3.08 g, 21.8 mmol) with cis-2,6-dimethylpiperazine (2.50 g, 21.8 mmol). The crude product is used in the next step without chromatographic purification. LCMS-ESI (m/z): calcd for C12H17N3O2, 235; [M+H]+ found, 236.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:18]([NH:17][CH:14]([CH3:16])[CH3:15])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(F)cc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Solvent: CCOC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(F)c(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chloro-5-fluorobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 282-285° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.17 (d, 6H, CH(CH3)2), 3.92 (m, 1H, CH(CH3)2), 7.34 (br., 1H, NH), 7.45 (d, 1H, ArH), 7.76 (d, 1H, ArH), 10.44 (br.s, 1H, NH); MS: m/e 291/293 (M+); (C10H11N3Cl1F1O2S1) calc. C, 41.17; H, 3.80; N, 14.40; found C, 41.3; H, 3.8; N, 14.4.
Reaction SMILES: C([O:8][C:9]1[CH:43]=[CH:42][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH2:29][C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:27]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.C(Cl)Cl>[OH:8][C:9]1[CH:43]=[CH:42][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH2:29][C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH:27]=3)[CH2:20][CH2:21]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOc3ccc(OCc4ccccc4)cc3)CC2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOc3ccc(O)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A mixture of 3-[4-[2-[4-(benzyloxy)phenoxy]ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (300 mg, 0.51 mmol) and palladium on carbon (60 mg) in MeOH/CH2Cl2 (20/7 mL) was stirred at room temperature overnight under H2. TLC analysis of the reaction mixture indicated that the starting material had disappeared. The solids were filtered off, and the filtrate was concentrated under vacuum to provide the title compound (260 mg, 92%) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.88 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 6.97 (s, 1H), 6.75 (d, 2H, J=8.7 Hz), 6.66 (d, 2H, J=9.0 Hz), 4.05-4.01 (m, 3H), 3.92-3.90 (m, 2H), 3.77 (m, 2H), 3.32 (m, 2H), 2.74-2.71 (m, 2H), 1.99-1.65 (m, 7H), 1.40 (s, 9H), 1.38-1.18 (m, 4H). LC-MS (ESI) m/z 498 (M+H+).
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[OH:5][CH2:6][CH:7]([CH2:9]O)[OH:8].[CH2:11]([N:15]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][OH:18])[CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH2:11]([N:15]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][OH:18])[CH2:12][CH2:13][CH3:14].[B:1]([O:4][CH2:9][CH:7]([CH2:6][OH:5])[OH:8])([OH:3])[OH:2]
Reactant: OCC(O)CO
Reactant: OB(O)O
Agent: CCCCN(CCO)CCCC
Solvent: Cc1ccccc1
Product: OCC(O)COB(O)O
Reaction time: 8 h

Procedure:
N,N-dibutylethanolamine/glycerol borate was prepared as follows. Boric acid (10.3 grams), glycerol (15.3 grams), and N,N-dibutylethanolamine (28.9 grams) were added to a 250 milliliter flask. One hundred fifty milliliters of toluene was then added. The reaction was allowed to proceed overnight at 110° C., and the byproduct water (˜9 grams) was continuously removed from the reaction by azeotropic distillation. The final solution was evaporated to remove toluene under vacuum, and a brownish viscous liquid product (˜45 grams) of N,N-dibutylethanolamine/glycerol borate was obtained.
Reaction SMILES: [CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH:15]=[C:14]([O:21]C)[CH2:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2].Cl>O.CO>[CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21C
Agent: Cl
Solvent: O
Solvent: CO
Product: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 47.1 %

Procedure:
Stir dl-17α-ethyl-3-methoxyestra-2,5(10)-dien-17-ol (1.4 g) with concentrated hydrochloric acid (2.4 ml) in water (1.6 ml) and methanol (36 ml) for 2 hours. Add water, extract with ether and wash, dry and evaporate the ethereal solution. Recrystallize the product from ethyl acetate-ether to obtain the title compound (0.63 g), m.p. 173°-174.5°; ultraviolet absorption maximum at 240 mμ (ε17,500).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C1(N(C2C=CC(B(O)O)=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:7]1[S:8][N:9]=[C:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: Brc1ccc(Br)c2nsnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2nsnc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4,7-dibromobenzo[2,1,3]thiadiazole (13.2 g, 45 mmol), 4-(N,N-diphenylamino)phenylboronic acid (30.0 g, 104 mmol), a solution of sodium carbonate (21.2 g, 200 mmol) in water (80 mL), tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol), n-butanol (800 mL), and toluene (400 mL) was stirred under argon and heated at 100° C. for 20 hours. After cooling to room temperature, the mixture was diluted with water (600 mL) and stirred for 2 hours. Finally, the reaction mixture was extracted with toluene (2 L), and the volatiles were removed under reduced pressure. The residue was chromatographed using silica gel and hexane/dichloromethane (1:1) as an eluent to give 26.96 g (43.3 mmol, 96%) of 4,7-bis[(N,N-diphenylamino)phenyl)]benzo[2,1,3]thiadiazole (Intermediate A).
Reaction SMILES: C([O:3][P:4]1(=[O:13])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5]1)C>O>[OH:13][P:4]1(=[O:3])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5]1
Reactant: CCOP1(=O)OCc2ccccc21
Solvent: O
Product: O=P1(O)OCc2ccccc21
Yield: 99.9 %

Procedure:
A mixture of 1-ethoxy-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (4.0 g, 0.02 mole) in 15 ml. of water was heated on a steam bath for 1 hour. The reaction mixture was taken to dryness under vacuum and the residue recrystallized from acetone to yield 1-hydroxy-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (3.4 g, 100% yield) as colorles crystals having a m.p. of 167° C. and the following analysis:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:11]=[CH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])C>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:17][C:14]([F:15])([F:16])[C:13](=[O:18])[CH:12]=[CH:11][C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1ccc(C=CC(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
To a solution of toluene (8, R1=p-CH3, R3=R4=H, 10 mmol) and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (10 mmol) in dichloromethane (10 mL) is added zinc chloride (0.015 g, 1.5 mol %). The reaction mixture is stirred for 3 h at 22° C. The resulting precipitate is filtered, washed with dichloromethane (2×15 mL) and dried.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)C.CC(C)=O.S(=O)(=O)(O)O>O>[F:14][C:13]([F:15])([F:16])[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(COc1cccc(C(F)(F)F)c1)OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=CCOc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethylphenoxyacetaldehyde diethyl acetal (146.3 g.; 0.527 mole), acetone (600 ml.), water (550 ml.), and concentrated sulfuric acid (3.5 ml.) is heated under reflux for 22 hours.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].C(#N)C.[C:13]1(=[O:36])[N:17]([CH:18]2[C:29](=[O:30])[N:20]3[CH:21](C(O)=O)[C:22]([CH3:25])([CH3:24])[S:23][C@H:19]23)[C:16](=[O:31])[C:15]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:14]12.N1C=CC=CC=1>CN(C)C=O>[C:16]1(=[O:31])[N:17]([CH:18]2[C:29](=[O:30])[N:20]3[CH:21]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[C:22]([CH3:25])([CH3:24])[S:23][C@H:19]23)[C:13](=[O:36])[C:14]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:15]12
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
2,2,2-Trichloroethyl 6-phthalimido-2,2-dimethyl-penam-3-carboxylate is prepared by adding a solution of 11.6 g.(0.06 mole) of 2,2,2-trichloroethylchloroformate in 50 ml. of acetonitrile dropwise over a 15-minute period of a reaction mixture of 17.2 g.(0.05 mole) of 6-phthalimido-2,2-dimethyl-penam-3-carboxylic acid in 100 ml. of dimethyl formamide and 4.8 g.(0.06 mole) of pyridine at room temperature.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O.[I-].[K+]>C1C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH2:10][Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1cc(CBr)cc(C(F)(F)F)c1

Procedure:
A solution of 5-trifluoromethyl-m-xylene (3.4 g) and dibenzoyl peroxide (0.25 g) in 100 ml of benzene at reflux is treated with N-bromosuccinimide (4.4 g) in portions. The mixture is heated until a negative potassium iodide test is obtained. The reaction mixture is cooled and concentrated in vacuo. The residue is triturated with n-hexane and the solids are removed by filtration. The filtrate is evaporated to give the oily crude benzyl bromide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=O)[CH2:11]1>>[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:11]1
Reactant: C#Cc1ccccn1
Reactant: CC1CC(=O)CC(C)C1
Product: CC1C=C(C#Cc2ccccn2)CC(C)C1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), 3,5-dimethylcyclohexanone (6.0 mmol, 0.85 mL); yields 2-[(3,5-dimethyl-1-cyclohexen-1-yl)ethynyl]pyridine as a transparent yellow oil (500 mg, 39% overall yield) as a mixture of diastereomers. 1H NMR (CDCl3, 300 MHz) 67 8.57 (m, 1H), 7.62 (m, 1H), 7.40 (m, 1H), 7.19 (m, 1H), 6.15 (br s, 1H), 2.29 (m, 2H), 1.80 (br m, (2H), 1.00 (m, 6H), 0.88 (br m, 2H). MS (EI ionization) 211 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>C(#N)CCC>[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=3)=[CH:14][CH:15]=2)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Product: CC(=O)Oc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
2.35 g of anhydrous potassium carbonate are added to a solution of 2.80 g of 4-biphenylmethyl bromide and 1.72 g of 4-hydroxyphenyl acetate in 75 ml of butyronitrile, and the reaction mixture is stirred at 120° C. overnight. It is filtered with suction, washed with acetonitrile, and concentrated. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over sodium sulphate and filtered, and the solvent is removed in a rotary evaporator. This is followed by stirring with ethyl acetate, filtration with suction and washing of the resulting crystals several times with ethyl acetate. 1.36 g of product are obtained. A further 0.36 g of product can be isolated from the mother liquor after concentration and chromatography on silica gel with dichloromethane.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:11])=[CH:6][N:5]=1.[F:12][C:13]1([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:26][C:13]2([F:12])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[C:7]([I:11])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(F)(CNc2cc(Cl)ncc2I)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
Sodium hydride (60% by wt) (32.7 mg, 0.817 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (160 mg, 0.629 mmol) in DMF (3930 μL) at room temperature and the mixture was stirred for 10 min. The temperature was raised to 80° C. and tert-butyl 4-fluoro-4-(tosyloxymethyl)piperidine-1-carboxylate (244 mg, 0.629 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 80° C. for 2 hr before further NaH (1.3 eq.) was added after first cooling the reaction to room temperature again. The reaction mixture was heated at 120° C. for 10 hr. After cooling, the solution was partitioned between EtOAc (150 mL) and 1M aqueous NaHCO3. The organic layer was washed with 1M NaHCO3 aq., sat. NaHCO3 and brine, then dried (MgSO4) and concentrated. The residue was dissolved in dichloromethane/hexane and loaded onto a 25+M Biotage silica column. Chromatography, eluting with 1% MeOH in dichloromethane gave partial purification. Further purification by preparative thin layer chromatography, eluting with 16% EtOAc in dichloromethane, gave tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (39 mg, 0.083 mmol, 13%) as a colourless solid.
Reaction SMILES: [Na].[OH:2][CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=[O:6].O1CCOCC1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>O>[C:23]([OH:26])(=[O:25])[CH3:24].[OH:2][CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1)=[O:6]
Reactant: CC(=O)OC(C)=O
Agent: O=C(C=CO)c1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)O

Procedure:
A suspension of 12.0 g. of 3-hydroxy-3'-(trifluoromethyl)acrylophenone sodium salt in 75 ml. of dioxane and 10 ml. of acetic anhydride is stirred at room temperature for 2 hours and then poured into water. The precipitate is collected by filtration, dissolved in methylene chloride and then passed through a hydrous magnesium silicate column and crystallized from methylene chloride-hexane to give the desired product, m.p. 55°-57° C.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[N:26]3[N:30]=[CH:29][CH:28]=[N:27]3)=[O:17])[CH2:15][CH:10]2[CH2:9]1)C1C=CC=CC=1>CCO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:13]1[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH2:15][N:14]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[N:26]1[N:27]=[CH:28][CH:29]=[N:30]1)=[O:17]
Reactant: COc1ccc(C(=O)N2CC3CN(Cc4ccccc4)CC3C2)c(-n2nccn2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1

Procedure:
(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone in EtOH (20 mL) and AcOH (1 mL) was continuously flowed through a 20 wt % Pd(OH)2/C cartridge at a rate of 1 mL/min for 2 h at 50° C. and 50 bar using a H-cube apparatus. Then the reaction was concentrated and neutralized with 5% Na2CO3 (aq), and extracted with CH2Cl2 (3×). Combined organics and dried (Na2SO4) to give (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone as a clear oil that was used without further purification. 1H NMR (CDCl3): 7.83-7.80 (m, 2H), 7.50 (d, J=2.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.96 (dd, J=8.5, 2.5 Hz, 1H), 3.89 (s, 3H), 3.75-3.63 (m, 2H), 3.27 (s, 1H), 3.08 (dd, J=11.9, 8.1 Hz, 1H), 2.94 (dt, J=11.4, 5.7 Hz, 2H), 2.88-2.75 (m, 2H), 2.69 (dd, J=17.8, 14.3 Hz, 1H), 2.56 (dd, J=11.4, 3.9 Hz, 1H).
Reaction SMILES: C(O)(=[O:3])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:23]1([S:29][C:30]2[CH:31]([CH3:61])[C@@H:32]3[C@H:49]([C@H:50]([C:56](C)(C)C)CO[SiH](C)C)[C:48](=[O:60])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C>[C:23]1([S:29][C:30]2[CH:31]([CH3:61])[C@@H:32]3[C@@H:49]([C@H:50]([OH:3])[CH3:56])[C:48](=[O:60])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1C(Sc2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@@H](CO[SiH](C)C)C(C)(C)C)[C@@H]12
Reactant: CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1C(Sc2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 μl of acetic acid and 2.1 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran were added to a solution of 298 mg of p-nitrobenzyl (1RS,5S,6S)-2-phenylthio-6-[(1R)-1-t-butyldimethylsilyl-oxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate in 6.4 ml of tetrahydrofuran, kept at 0° to 5° C. with ice-water cooling. The mixture was kept stirred overnight at room temperature, and then for 4 hours in an oil bath at 30° C. The reaction mixture was then diluted with ethyl acetate and washed successively with saturated aqueous sodium chloride solution, 5% aqueous sodium bicarbonate solution, and again saturated aqueous sodium chloride solution. The solvent was distilled off, and the resulting residue was chromatographed on a column of silica gel using a 3/1 mixture of benzene/ethyl acetate as eluent, giving 57 mg of the title compound as pale yellow crystals.
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[S:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1.Br[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=[O:17]>C(N(CC)CC)C>[C:19]1([CH:15]([S:4][C:5]2[S:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=2)[C:16]([OH:18])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2c(s1)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Sc1nc2c(s1)CCCC2)c1ccccc1
Yield: 77 %

Procedure:
A methylene chloride solution of 5.13 g (0.03 m) 2-mercapto-4,5,6,7-tetrahydrobenzothiazole, α-bromophenylacetic acid and 6.0 g (0.06 m) triethylamine is heated to gentle reflux overnight. The solution is extracted twice with a dilute hydrochloric acid solution, once with water and is then dried over anhydrous MgSO4. The residual solid after solvent removal is recrystallized from acetonitrile. 7.0 g (77% yield) of title compound, melting at 118°-20° C., is obtained.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([CH3:25])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[C:18]([CH3:25])[CH:17]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CSc1ccc(C2=C(c3ccc(F)cc3C)CCC2)cc1
Yield: 88.2 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 500 mg (1.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 590 mg (3.8 mmol) of 4-fluoro-2-methylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane gave 500 mg (95%) of 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 67°-68° C.; NMR (CDCl3) d 2.00-2.11 (m, 2H), 2.05 (s, 3H), 2.41 (s, 3H), 2.69-2.77 (m, 2H), 2.86-2.95 (m, 2H), 6.80-7.07 (m, 7H) .
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[N:14]=[C:13]2[C:15](=[CH:18][C:19]#[N:20])[CH2:16][CH2:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Pd+2].[OH-].[C]>[CH2:21]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:14]=[C:13]2[CH:15]([CH2:18][C:19]#[N:20])[CH2:16][CH2:17][C:12]2=[CH:11][CH:10]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#CC=C1CCc2ccc(N(Cc3ccccc3)Cc3ccccc3)nc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N#CCC1CCc2ccc(N(Cc3ccccc3)Cc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
[2-(Dibenzylamino)-5,6-dihydro-7H-cyclopenta[b]pyridin-7-ylidene]acetonitrile (1.01 g, 2.87 mmol) was dissolved in methanol (40 mL), 20% palladium hydroxide-carbon powder (200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 60 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction of Reference Example 34 without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:15]([CH2:16][CH2:17][CH:18]2OCCCO2)[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:31]1([C:36]2[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=2)[CH:35]=[CH:34][N:33]=[CH:32]1.[OH-].[Na+]>OS(O)(=O)=O>[CH2:1]([N:8]1[CH:15]([CH2:16][C:17]2[C:40]3[C:39](=[CH:38][CH:37]=[C:36]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)[CH:41]=3)[NH:42][CH:18]=2)[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CC2CC(CCC3OCCCO3)N(Cc3ccccc3)C2C1
Reactant: NNc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)N1CC2CC(Cc3c[nH]c4ccc(-n5ccnc5)cc34)N(Cc3ccccc3)C2C1
Yield: 43.6 %

Procedure:
A mixture of (1RS,3RS,5RS)-2-benzyl-3-[2-(1,3-dioxan-2-yl)ethyl]-2,7-diazabicyclo[3.3.0]octane-7-carboxylic acid, ethyl ester (0.3081 g, 0.793 mmol) and 4-(imidazol-1-yl)phenylhydrazine, dihydrochloride (0.2055 g, 0.832 mmol) in 4% H2SO4 (aq) (10 mL) was heated at reflux under argon for 20 h whilst stirring magnetically. After cooling, the reaction mixture was made basic with 50% NaOH solution and extracted with EtOAc (4×25 mL). The combined organic extracts were dried (K2CO3) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2-4% MeOH/CH2Cl2) to give 0.1625 g (44%) of the title compound as a yellow gum. δH (250 MHz, CDCl3) 1.23-1.26 (3H, m), 1.56-1.68 (1H, m), 1.92 (1H, m), 2.56 (1H, m), 2.79 (1H, m), 3.14 (1H, dd), 3.17-3.78 (7H, m), 4.07-4.13 (3H, m), 7.10-7.34 (11H, m), 7.74 (1H, s), 8.24 (1H, br s). m/e (ES+) 470 (M+H)+.