Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2Cl)nc1-c1ccc(C)cc1
Yield: 81.5 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 2-chlorophenylboronic acid (141 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 40 min. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 100 mg (81%) of the title compound. ESI/APCI(+): 409 (M+H).
Reaction SMILES: [CH2:1](N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:13]=[CH:12]2.Cl.C[O:25][C:26](=[O:29])[CH2:27][NH2:28]>C(Cl)Cl>[CH3:1][N:28]([S:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([Cl:8])[CH:10]=2)[CH:15]=1)(=[O:21])=[O:20])[CH2:27][C:26]([OH:25])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CCN(CC)CC
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Product: CN(CC(=O)O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.278 ml) was added to a stirred mixture of 6-chloronaphth-2-ylsulphonyl chloride (0.522 g), glycine methyl ester hydrochloride (0.251 g) and methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was recrystallised from methanol to give methyl N-(6-chloronaphth-2-ylsulphonyl)glycine (0.46 g).
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]#[CH:3])=[CH:10][CH:9]=1)[CH2:12][CH3:13]
Reactant: CCCc1ccc(C#CC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1ccc(CCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
33 g of 3-methyl-1-(4'-propylphenyl)-1-butyn-3-ol was dissolved in 320 ml of toluene in nitrogen atmosphere, and 2 g of sodium hydride (60% in paraffin liquid) was added thereto. This was stirred for 6 hours at 60° C. The reaction solution was poured into 300 ml of water, extracted with chloroform and washed three times with water. Toluene and chloroform were removed by distillation, and the residue was distilled under reduced pressure (b.p. 60° to 63° C./4 mmHg) to obtain 16 g of 4-propylphenylacetylene.
Reaction SMILES: [O:1]([C:8]1[C:13]2=[C:14]([CH3:18])[C:15]([OH:17])=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22]Br.C([O-])([O-])=O.[K+].[K+].[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>CN(C=O)C.ClCCl>[CH3:18][C:14]1[C:15]([O:17][CH2:20][CH2:21][CH2:22][NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:16][N:12]2[C:13]=1[C:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N:9][CH:10]=[N:11]2
Reactant: Cc1c(O)cn2ncnc(Oc3ccccc3)c12
Reactant: CS(N)(=O)=O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(OCCCNS(C)(=O)=O)cn2ncnc(Oc3ccccc3)c12
Yield: 67.2 %

Procedure:
A solution of 4-phenoxy-5-methyl-6-hydroxypyrrolo-[2,1-f][1,2,4]triazine (1.05 g, 4.35 mmol), 1,3-dibromopropane (4.0 g, 20 mmol), and K2CO3 (3 g, 22 mmol) was heated at 70° C. for 2 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, eluting from dichloromethane to 20% ethyl acetate/dichloromethane) to afford the crude intermediate (1.35 g, 86% yield). This intermediate (1.3 g, 3.59 mmol) was heated with methanesulfonamide (2.0 g, 21 mmol) and K2CO3 (4 g, 29 mmol) in DMF (15 mL) for 2 h. The mixture was cooled, diluted with dichloromethane, washed twice with 5% Na2CO3 solution, dried and concentrated. The residue was purified by flash column chromatography (silica gel, 20% ethyl acetate/dichloromethane) to afford N-[3-(5-methyl-4-phenoxy-pyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propyl]-methanesulfonamide (1.1 g, 81%) as a white solid. MS: (M+H)+=377.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:38])[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]4=[N:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:5]1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C:4]1([CH3:38])[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:5]1
Reactant: COCC1(C)CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1
Solvent: CO
Solvent: ClCCl
Product: COCC1(C)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Yield: 50 %

Procedure:
1-{2-[3-(3-Methoxymethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared following the same procedure using 1-[2-[3-(3-Methoxymethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as starting material. The product was obtained in 50% yield by SiO2 chromatography (DCM/MeOH 0-5% MeOH).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:15]=[CH:16][CH:17]=2)[N:4]([CH3:30])[N:3]=1.O.NN.C(O)C>>[CH3:30][N:4]1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=2)=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1nc(N)nc1NCCCOc1cccc(CN)c1
Yield: 71.7 %

Procedure:
A solution of 2-[[3-[3-[(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)amino]propoxy]phenyl]methyl]-1H-isoindole-1,3-(2H)-dione (1.62 g) and hydrazine hydrate (0.22 g) in ethanol (10 mol) was heated at reflux for 1.5 h. The solvent was evaporated and the residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was basified with sodium carbonate, evaporated to dryness and extracted with hot isopropanol to give an oil which was purified by column chromatography using methanol/0.88 ammonia 79:1 an eluant to give the title compound as a crystalline solid (0.79 g) TLC silica, methanol/0.88 ammonia 79:1 Rf 0.5 NMR (d4MeOH) 2.77 t (1H); 3.0-3.3 m (3H); 5.95 t (2H); 6.30 s (2H); 6.57 q (2H); 6.65 s (3H); 7.95 m (2H).
Reaction SMILES: CO.[CH3:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17]C(=O)[CH2:15][CH2:14]1.[BH3-][C:21]#N.[Na+]>CO.C(O)(=O)C.C(O)(=O)C>[CH3:21][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][NH:4][CH:3]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[CH:7][CH:8]=1
Reactant: [BH3-]C#N
Reactant: CN1CCC(=O)CC1
Reactant: CNCc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CNC2CCN(C)CC2)cc1

Procedure:
Methanol (50 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. Methylbenzylamine (1.0 g, 8.8 mmol) and 1-Methyl-4-piperidone (1.1 g, 8.8 mmol) were added to a 100 ml round-bottomed flask and dissolved in the methanol/acetic acid (40 ml) solution previously made. The reaction mixture was stirred for 5 min and NaCNBH3 (0.83 g, 13.2 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a separatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of Na2CO3. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO4. Concentration afforded the title compound. Yield (crude): 98%. UV/MS 89/88 (M+ 353), tr (A, MS) 3.982.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][CH3:19].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].[H-].[Na+]>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:18][CH3:19])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 58.6 %

Procedure:
1-([1,1′-Biphenyl]-2-ylmethyl)-2-ethyl-4-hydroxy-1H-indole (911 mg, 2.8 mmol) was alkylated by treating with 0.26 mL (2.8 mmol) of methyl bromoacetate and 111 mg (2.8 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 655 mg (59% yield) of [[1-([1,1′-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([C:24](=[O:37])[N:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[CH:26]4[CH2:28][CH2:27]4)[CH2:21][C@@H:20]([NH:38]C(OC(C)(C)C)=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([C:24](=[O:37])[N:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[CH:26]4[CH2:27][CH2:28]4)[CH2:21][C@@H:20]([NH2:38])[CH2:19]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N(Cc2ccccc2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: Cl
Product: N[C@@H]1C[C@H](C(=O)N(Cc2ccccc2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R*,5S*)-3-tert-butoxycarbonylamino-5-[(2-chloro-benzyl)-cyclopropylcarbamoyl]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (186 mg, 0.295 mmol) and HCl (5M in 2-propanol, 2 mL, 10 mmol) is stirred for 2 h at RT. The mixture is evaporated and the residue dried to afford the title compound as a beige amorphous solid. MS: 530.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 6.02 min.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][C:9]1=[O:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]2[NH:8][C:9](=[O:26])[CH2:10][CH2:11]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reaction time: 1.5 h

Procedure:
8.9 g of (S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1-a, R1=BOC) (25.3 mmol) is dissolved in 90 ml methylene chloride. Then 5 ml CF3COOH are added. This mixture is stirred at it for 1.5 h. The reaction mixture is concentrated. Heptane fraction is then added to the residue. The product is crystallized. The obtained product is dissolved in toluene and then it is washed with NaHCO3 (aq) solution. The organic layer is evaporated to yield (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)]. Spectroscopic data as in Example 3.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.C(N)C.[C:43](N1C=CN=C1)([N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1)=[O:44]>C1COCC1.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:43]([N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[O:44])[CH2:34][CH2:33]3)=[O:31])=[CH:38][CH:39]=2)=[N:16]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
A solution of dihydrochloride of Compound 18 (400 mg, 1.09 mmol) in THF (20 mL) was added with ethylamine (177 mg, 2.18 mmol) and 1,1′-carbonyldiimidazole (352 mg, 2.18 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by preparative thin-layer chromatography (chloroform/acetone=1/1) to obtain Compound 48 (350 mg, 44%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH2:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:25](OC)([N:27](C)C)[CH3:26].O.[NH2:33]N.C(OCC)(=O)C>O1CCOCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]3[NH:27][C:25]([CH3:26])=[N:33][N:21]=3)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(N)=O
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc(-c2sc(N3CCN(Cc4ccccc4)C3=O)nc2C)[nH]1
Temperature: 90 °C
Yield: 65 %

Procedure:
To a solution of 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide (0.20 g, 0.63 mmol) in 1,4 dioxane (10 mL) was added N,N-dimethylacetamide dimethyl acetal (1.0 mL, 6.80 mmol). The reaction mixture was heated to reflux for 5 hours and concentrated in vacuo. The residue was dissolved in acetic acid (10 mL) and hydrazine monohydrate (0.1 mL, 2.0 mmol) was added. The reaction mixture was heated for 3 hours at 90° C. and concentrated in vacuo. The residue was dissolved in saturated sodium bicarbonate (10 mL) and extracted with chloroform. The organic solution was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was triturated with ethyl acetate to afford the title in 65% yield (0.15 g): mp 284-287° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 13.6 (br s, 1H), 7.33-7.26 (m, 5H), 4.40 (s, 2H), 3.99-3.94 (m, 2H), 3.44-3.39 (m, 2H), 2.52 (s, 3H), 2.33 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 156.9, 155.7, 153.6, 145.6, 136.9, 129.1, 128.2, 127.9, 47.4, 42.4, 42.1, 17.1, 12.1; MS (ES+) m/z 355.2 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:10](Cl)=[O:11])=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:20][CH:21]1[C:34](=[O:35])[N:23]2[CH:24]([C:29]3[NH:33][N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:19]([C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]([NH:20][CH:21]1[C:34](=[O:35])[N:23]2[CH:24]([C:29]3[NH:30][N:31]=[N:32][N:33]=3)[C:25]([CH3:27])([CH3:28])[S:26][C@H:22]12)=[O:11])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=C(C(=O)Cl)c1ccccc1
Reactant: Oc1ccccc1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.33 h

Procedure:
A stirred solution of 1.80 g. of phenyl chlorocarbonyl ketene (U.S. Pat. No. 3,679,801) in 20 ml. of chloroform is cooled to -40° C., and then 0.94 g of phenol is added. Stirring is continued at -40° C. for a further 20 minutes, and then a solution of 2.40 g. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 1.40 ml of triethylamine in 50 ml. of chloroform is added dropwise. The cooling bath is removed, and the mixture is stirred for a further 30 minutes. The mixture is filtered, and the chloroform is evaporated in vacuo to give crude 6-(2-phenoxycarbonyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, as its triethylamine salt.
Reaction SMILES: [OH:1][C:2]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([N:6](C(OC(C)(C)C)=O)[NH2:7])=[O:5].C(OCC)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C1(OC)C=CC=CC=1>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[OH:1][C:2]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][NH2:7])=[O:5]
Reactant: CC(C)(C)OC(=O)N(N)C(=O)c1cccc(O)c1O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NNC(=O)c1cccc(O)c1O
Reaction time: 0.5 h

Procedure:
(2,3-Dihydroxybenzoyl)hydrazine carboxylic acid, t-butyl ester (17 g) was dissolved in 50 ml of trifluoroacetic acid/anisole (4:1) at 0° C. and stirred for 30 minutes. Diethyl ether (200 ml) was added, and (2,3-dihydroxybenzoyl)hydrazine, trifluoroacetate salt crystallized from the solution. After washing with ether and drying over silica gel, 17.2 g of (2,3-dihydroxybenzoyl)hydrazine, trifluoroacetate salt were obtained as beige, fine crystals; melting point 212° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(OCC)(=O)C.[ClH:28]>C(OCC)C>[ClH:28].[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1cc(CCN2CCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Alternatively, 1-Boc-4-[2-(4-pyridinyl)ethyl]piperazine (1.0 g, 3.43 mmol) was dissolved in ethyl ether. Ethyl acetate (15 mL) saturated with HCl was added, and the mixture stirred for 30 min at room temperature. The mixture was concentrated under vacuum and provided 1-[2-(4-pyridinyl)-ethyl]piperazine hydrochloride (900 mg, 87%) as a tan solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.C(N)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].ClCC(Cl)=O.[CH2:27]([NH:34][C:35](=[O:38])[CH2:36][Cl:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]([CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1)[C:35](=[O:38])[CH2:36][Cl:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: ClCc1cscn1
Agent: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: NCc1ccccc1
Product: O=C(CCl)N(Cc1ccccc1)Cc1cscn1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
4-Chloromethylthiazole (1.33 g, 10.0 mmol) and benzylamine (2.2 mL, 20.0 mmol) were mixed together and heated to 80° C. for 24 hours and allowed to cool to room temperature. The solid mass was treated with 2M aqueous sodium carbonate and stirred until the mass was broken up and the mixture was extracted with 2 portions of ethyl ether. The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in 40 mL of dichloromethane, cooled to 0° C., and 40 mL of saturated, aqueous NaHCO3 was added. To this stirred biphasic mixture was added chloroacetyl chloride (1.8 mL, 22.0 mmol) dropwise and mixture was stirred for an additional 2 hours at 0° C. The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, 30% -50% ethyl acetate/hexanes) to provide first, 0.58 g (21%) N-benzylchloroacetamide followed by 0.76 g (27%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[H-].[Na+].[H][H].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:27][O:28][CH3:29])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: [H][H]
Reactant: COCCl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.00 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 20 ml of dimethylformamide is added to a suspension of 0.26 g of a 55% sodium hydride dispersion in 20 ml of absolute dimethylformamide and the mixture is stirred at room temperature until the hydrogen evolution has finished. Subsequently, 0.57 g of chlorodimethyl ether is added and the mixture is stirred at room temperature for 2 hours. The reaction mixture is evaporated to dryness under reduced pressure, the residue is taken up in 100 ml of ethyl acetate and the solution is washed twice with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane as the eluent. There is obtained 3-(4-chloro-2-fluoro-5 -methoxymethoxy-phenyl)-1-methyl-6-trifluoromethyl -2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 400 MHz): 7.31 ppm (d,1H), 7.12 ppm (d,1H), 6.36 ppm (s,1H), 5.22 ppm (d,1H), 5.19 ppm (d,1H), 3.55 ppm (d,3H), 3.51 ppm (s,3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1>ClCCl.CO.[Hg]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]/[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)/C=C1\CCc2ccc(F)cc21
Agent: [Hg]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)/C=C1/CCc2ccc(F)cc21
Yield: 36 %

Procedure:
A solution of (E)-2-(6-fluoro-1-indanylidene)acetamide (20 g,104.6 mmol) in dichloromethane:methanol(3:1) (1000 ml) was irradiated by an Canrad-Hanovia quartz, mercury-vapor photochemical immersion lamp, 450 wattts (Ace Glass, 7825-35) for 0.5 h. The volatiles were removed by spin evaporation in vacuo to give a beige residue. This residue was chromatographed on Silica Gel 60 using a step gradient going from ethyl acetate: hexanes(1:1) to ethyl acetate:ethanol(1:1). Fractions containing (Z)-2-(6-fluoro-1-indanylidene)acetamide were combined and concentrated by spin evaporation in vacuo. The resulting solid was slurried in hexanes to give 7.2 g (37%) of (Z)-2-(6-fluoro-1-indanylidene)acetamide as a white crystalline solid, m.p.,175°-177 ° C.;