Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Product: Nc1cc(N2CCCC2)ccc1[N+](=O)[O-]
Yield: 93 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.73 g, 10 mmol) and pyrrolidine (1.42 g, 20 mmole) was refluxed in a pressure vessel for 6 h. Solvent was evaporated and the residue was diluted with ethyl acetate. The resulting mixture was washed with aqueous NaHCO3 (5%) and distilled water, dried over MgSO4, and concentrated to afford 2-nitro-5-(pyrrolidin-1-yl)benzenamine as a solid (93% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.80 (d, J=8 Hz, 1H, 3-H), 7.22 (s, 2H, NH2), 6.05 (dd, J=8, 2 Hz, 1H, 4-H), 5.81 (d, J=2 Hz, 1H, 6-H), 3.30-3.27 (m, 4H, 2′,5′-H), 1.97-1.91 (m, 4H, 3′,4′-H). 13C NMR (100 MHz, CDCl3-d1) δ (ppm): 151.9, 148.3, 127.4, 122.1, 104.7, 94.5, 47.3, 47.3, 24.8, 24.8; EIMS: m/z 207 (M+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][N:15]=2)[CH2:9]1)C1C=CC=CC=1.[Cl:25]C(OCCCl)=O>ClCCCl>[ClH:25].[C:19]1([C:17]2[O:16][N:15]=[C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[N:18]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCOC(c3noc(-c4ccccc4)n3)C2)cc1
Reactant: O=C(Cl)OCCCl
Solvent: ClCCCl
Product: Cl
Product: c1ccc(-c2nc(C3CNCCO3)no2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-benzyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)morpholine (intermediate 27, 900 mg, 2.80 mmol) in 1,2-dichloroethane (2.0 ml) was added chloroethyl chloroformate (0.46 ml, 4.20 mmol), and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was concentrated in vacuo. After removal of the solvent, the residue was dissolved in methanol (2.0 ml), and the solution was stirred under reflux for one hour. When the reaction was complete (checked by thin layer chromatography), the reaction mixture was concentrated in vacuo. The resulting 2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholine hydrochloride (intermediate 28) was used for next reaction without further purification.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][O:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:18]([N:20]([CH3:22])[CH3:21])=O.N1C=CC=CC=1.[OH-].[Na+]>O>[CH3:15][O:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:18]([N:20]([CH3:22])[CH3:21])=[S:2]
Reactant: COC(C(=O)N(C)C)c1ccccn1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: COC(C(=S)N(C)C)c1ccccn1

Procedure:
Phosphorus pentasulfide (4 g.) is added to 9.7 g. of 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide in 25 ml. of pyridine. The mixture is heated on a steam bath for 2 hours, then 250 ml. of water and 10 ml. of 5% aqueous sodium hydroxide solution are added. The mixture is extracted with chloroform and the extracts are dried and concentrated and the residue is recrystallized to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: C(OC)(=O)C.[Cl:6][C:7]1[S:11][C:10]([S:12]([NH:15]C2C3CCC2(C(O)=O)CC2C=CC=CC=2C3)(=[O:14])=[O:13])=[CH:9][CH:8]=1.C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1.CN(C=O)C>[Cl:6][C:7]1[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:8]=1
Reactant: O=C(O)C12CCC(Cc3ccccc3C1)C2NS(=O)(=O)c1ccc(Cl)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: COC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 2 h
Yield: 112.5 %

Procedure:
To a suspension of (6R/S,9R/S,11S/R)-11-{[(5-chlorothien-2-yl)sulfonyl]amino}-7,8,9,10-tetrahydro-6,9-methanobenzo[α][8]annulene-6(5H)-carboxylic acid (example 3, Step (1)) (100 mg) in benzene (3 ml) were added oxalyl chloride (74 μl) and DMF (1 drop) at room temperature and the mixture stirred for 2 hrs. After concentration in vacuo, the residue was redissolved in benzene (3 ml) and added dropwise to a refluxing suspension of N-hydroxypyridin-2-thione sodium salt (43 mg) in CBrCl3 (4 ml) whilst irradiating with a 250 W lamp for 1 hr. Concentration and purification using HPLC gave N-[(6R/S,9R/S,11S/R)-6-bromo-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[α][8]annulen-11-yl]-5-chlorothiophene-2-sulfonamide as a white solid (54 mg, 50%).
Reaction SMILES: [C:1]1([C@@H:7]([CH2:9]O)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](=[S:13])=[S:12]>[OH-].[K+].O>[C:1]1([C@H:7]2[CH2:9][S:13][C:11](=[S:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=S
Reactant: N[C@H](CO)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: S=C1N[C@@H](c2ccccc2)CS1
Temperature: 110 °C
Yield: 8.7 %

Procedure:
To a solution of (S)-(+)-2-Phenylglycinol(1.40 g, 10 mmol) in 1N KOH/H2O (10 ml) at room temperature, was added carbon disulfide (3 ml, 50 mmol). The resulting solution was heated by a pre-heated oil-bath (110° C.) to reflux for 20 h after which the reaction mixture was cooled to room temperature and extracted with CH2Cl2 (3×30 ml), dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/CH2Cl2 followed by CH2Cl2 as the eluting system (Rf =0.09, CH2Cl2 :hexane=7:3) to obtain 4(S)-phenyl-thiazolidine-2-thione (170 mg, 9%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1.[CH3:21][Zn]C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[CH3:21][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)n3nccc3n2)cc1
Reactant: C[Zn]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2ccnn12
Yield: 84.4 %

Procedure:
To a solution of 7-chloro-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (1.49 g, 5.0 mmol) and tetrakis(triphenylphosphin)palladium (1.73 g, 1.5 mmol) in THF (50 mL) was added at 20° C. 2 M dimethylzinc/toluene solution (6.25 mL, 12.5 mmol) and the mixture was refluxed in an atmosphere of argon for 2 h. After the slow addition at 0° C. of sat. aqueous NH4Cl solution (12 mL), the mixture was partitioned between AcOEt and 10% sodium chloride solution. The organic layer was evaporated in vacuo and the residue was chromatographed on silica gel using AcOEt/hexane (1:3 v/v) as eluent to give the title compound (1.17 g, 84%). Pale yellow solid. MS (ISN) 276.1 [(M−H)−]; mp 89-90° C.
Reaction SMILES: [N+]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-])=O.[S-:13]C#N.[K+].[C:17]([S:25][C:26]#[N:27])(=O)C1C=CC=CC=1.CS>C(O)C.CO.C1(C)C=CC=CC=1>[C:6]([NH:27][C:26](=[S:13])[S:25][CH3:17])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:4]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: N#C[S-]
Reactant: N#CSC(=O)c1ccccc1
Agent: CS
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSC(=S)NC(=O)c1ccccc1

Procedure:
Thus, in the reaction of Equation 43a, 2-nitrobenzoyl chloride LVII is reacted with potassium thiocyanate in a solvent such as toluene or acetronitrile at reflux for 0.2 to 5 hours; the resultant benzoyl thiocyanate is then reacted with excess methanol, ethanol or methyl mercaptan at 25° to 80° C. for 0.2 to 5 hours to form an O-alkyl benzoylthiocarbamate or methyl benzoyldithiocarbamate of Formula (LVIII). In reaction 43b, LVIII is reacted with sodium methoxide and methyl iodide in methanol at 0° to 25° C. for 1 to 5 hours to form a dialkyl benzoyliminothiocarbonate or dimethyl benzoyliminodithiocarbonate of Formula (LIX). And in reaction 43c, LIX is reacted with hydroxylamine in methanol or ethanol at 0° to 25° C. for about 10 to 96 hours to form Xm'.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+]([O-])(O)=O.[Br:16]Br>C(O)(=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[Br:16][C:8]1[C:7]([CH3:11])=[C:3]([C:2]([F:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1cccc(F)c1C(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1c(Br)ccc(F)c1C(=O)O
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred solution of 2-fluoro-6-methyl-benzoic acid (1 g, 6.4 mmol, 1.0 eq) in acetic acid (32 mL) was added nitric acid (3.27 mL), water (3 mL) and bromine (0.36 mL). A solution of silver nitrate (1.43 g, 8.4 mmol 1.3 eq) in water (10 mL) was then added dropwise over a period of 15 min. After the addition was completed, stirring was continued a further 1.5 h at room temperature. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a crude product, which was triturated with hexane to give the title compound as a yellow solid (1.35 g, 90%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](O)=[C:20]([CH:24]=1)[C:21]([NH2:23])=[O:22].N1CCCC1>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:23][C:21](=[O:22])[C:20]3[CH:24]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=3[O:14]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(Br)ccc1O2
Temperature: 70 °C
Yield: 68.4 %

Procedure:
1-BOC-piperidin-3-one (4.0 g, 20 mmol) was added to a mixture of 5-bromo-2-hydroxybenzamide (2.0 g, 9.2 mmol) and pyrrolidine (0.76 ml, 9.2 mmol) in MeOH (7.5 ml), and the reaction mixture was heated to 70° C. by MW (closed vessel) for 5 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography on silica gel (eluent: DCM/EtOAc 7:3) to give (±)-6-bromo-3,4-dihydro-4-oxo-spiro-[2H-(1,3)-benzoxazine-2,3′-piperidine]-1′-carboxylic acid tert-butyl ester (2.50 g) as a yellow solid.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][N:10]([C:17]1[S:18][C:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:20][N:21]=1)[C:11](=[O:16])[CH2:12][CH2:13][S:14][CH3:15].C(N(CC)CC)C.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:9][N:10]([C:17]1[S:18][C:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:20][N:21]=1)[C:11](=[O:16])/[CH:12]=[CH:13]/[S:14][CH3:15]
Reactant: CSCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS/C=C/C(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 40.2 %

Procedure:
N-Chlorosuccinimide (100 mg, 0.75 mmol, 1.1 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (200 mg, 0.68 mmol, 1.0 equiv) in benzene (3.3 mL) at 23° C. The resulting cloudy yellow solution was stirred at 23° C. for 30 m. Triethylamine (210 μL, 1.5 mmol, 2.2 equiv) was added and the resulting bright yellow mixture was stirred at 23° C. for 24 h. The reaction mixture was directly subjected to silica gel column chromatography (ethyl acetate) to afford the title compound as a tan powder (80 mg, 40%): 1H NMR (300 MHz, DMSO-d6) δ 9.14 (br s, 1H), 8.67 (m, 1H), 8.27 (m, 1H), 8.11 (d, J=14 Hz, 1H), 7.41 (m, 1H), 6.30 (d, J=14 Hz, 1H), 3.91 (s, 3H), 2.46 (s, 3H); ESIMS m/z 293 ([M+H]+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>ClC(Cl)C>[CH3:5][CH:6]([CH2:14][CH2:15][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under ice cooling, 24.86 g of anhydrous aluminum chloride was added to a dichloroethane suspension (250 ml) containing of [2-methyl-4-phthalimidobutyl]benzene and 9.29 g of succinic anhydride, and the mixture was stirred temperature for 2 hours. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The resulting crude crystal was recrystallized from ethyl acetate-hexane to obtain 16.11 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylpropionyl)benzene.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][OH:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-(-)-4-(4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 5, 970 mg) and triethylamine (0.50 mL) in dry methylene chloride (9.5 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (0.20 mL) dropwise. The resulting mixture is stirred at 0° C. for one hour, diluted with methylene chloride (40 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 163-165° C.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C1(C)C=CC=CC=1>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.C(O)C>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=[C:26]([C:21]3[CH:22]=[C:23]([C:12]4[C:11]5[C:6]([C:5]6[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=6[CH:13]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:24]=[C:19]([Br:18])[CH:20]=3)[N:27]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc(-c2cc3ccccc3c3ccccc23)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
In a stream of argon, 0.71 g (3.21 mmol) of 9-phenanthreneboronic acid, 1.50 g (3.21 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 37.0 mg (0.0321 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 120 mL of toluene and 15 mL of ethanol, and the resultant suspension was heated to 60° C. and maintained at that temperature for 12 hours while being stirred. The obtained reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (2:1) mixed solvent as an eluent to give 0.54 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-3-bromophenyl]-1,3,5-triazine as a white solid (yield: 30%).
Reaction SMILES: [C:1]1([CH2:6]Br)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.Cl>O1CCCC1.[Zn]>[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:19])[CH:16]([CH:2]2[CH2:3][CH2:4][CH2:5][C:1]2=[CH2:6])[OH:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Reactant: BrCC1=CCCC1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CCCC1C(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 53 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of (cyclopent-1-enyl)methylbromide (3.8 g) in tetrahydrofuran was added to a stirred mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (3.5 g) and zinc powder(1.6 g) in tetrahydrofuran at 20° C. under an inert atmosphere. The temperature increased to 53° C. slowly and after 2 hours, ethyl acetate and hydrochloric acid (1N) were added and the organic phase washed with brine, dried (magnesium sulphate), evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (2:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-ol (3.66 g), NMR: 1.46(s,3H), 1.61(s,3H), 1.88(s,3H), 1.5-1.9(4H), 2.24(2H), 2.50(1H), 3.24(d,1H), 3.80(s,1H), 4.93(s,1H), 5.06(s,1H), 5.19(d,1H), 5.26(d,1H), 7.22-7.38(5H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]C#N)[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([SH:9])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S)cc1Cl
Temperature: 50 °C

Procedure:
A solution of 2-chloro-4-thiocyanoaniline (36.9 g., 0.20 mole) in ethanol (100-200 ml.) is added to a stirred solution of sodium sulfide nonahydrate (48.04 g., 0.20 mole) in water (100 ml.) and the mixture warmed (50° C.) for 90 minutes. The cool reaction mixture is poured into water (1 liter) and dilute hydrochloric acid added to bring the pH up to 6.0-6.5. The product is extracted with ether, the ether washed with water and then dried. Removal of the drying agent and ether leaves 2-chloro-4-mercaptoaniline as a yellow oil.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:10][CH2:9][C@@H:8]2[N:4]1[C:5](=[O:19])[C@H:6]([NH:11]C(=O)OC(C)(C)C)[CH2:7]2)#[N:2].C1(SC)C=CC=CC=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:11][C@@H:6]1[CH2:7][C@H:8]2[N:4]([C@H:3]([C:1]#[N:2])[CH2:10][CH2:9]2)[C:5]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2CC[C@@H](C#N)N2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N#C[C@@H]1CC[C@H]2C[C@@H](N)C(=O)N21

Procedure:
80 mg of tert-butyl ((2R,5S,7aS)-5-cyano-3-oxohexahydropyrrolizin-2-yl)carbamate were C reacted with 10% thioanisole in 1 ml of trifluoroacetic acid for 30 min. The solvents were then removed in vacuo, and the residue was stirred with diusopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[SH:10])=[O:4].C(N(CC)CC)C.Br[CH2:19][CH2:20][C:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([F:23])[F:22]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[S:10][CH2:19][CH2:20][C:21]([F:23])([F:22])[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4]
Reactant: COC(=O)c1scnc1S
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
4-Mercapto-thiazole-5-carboxylic acid methyl ester (0.41 g, 2.16 mmol) is dissolved in DMF (6 ml) and triethylamine (0.45 ml, 3.24 mmol) and 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (synthesized according to the methods described in sections a) to e) of example 1) (0.55 g, 2.16 mmol) are added successively. The resulting mixture is stirred at RT for 16 h. After completion of the reaction, the mixture is poured onto water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layers are washed with brine (20 ml), dried over sodium sulfate and concentrated to dryness. The crude is purified by column chromatography (silica gel, 20% EtOAc/hexane) yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid methyl ester (0.42 g, 1.2 mmol, 56%).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6](N(CC)CC)C.[C:13](Cl)(=[O:15])[CH3:14].C(OCC)(=O)C>ClCCl>[C:13]([NH:5][C:1](=[O:4])[C:2]([CH3:6])=[CH2:3])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: C=CC(N)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NC(C)=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 4 %

Procedure:
23.7 g of acrylamide and 60 ml of triethylamine were dissolved in 100 ml of dichloromethane in a flask. To the solution was then added dropwise 27.6 g of acetyl chloride at a temperature of −30° C. After the termination of the dropwise addition, the mixture was then stirred at a temperature of 0° C. for 10 hours. Triethylamine hydrochloride thus precipitated was then filtered off. The filtrate was then subjected to distillation under reduced pressure to remove the solvent therefrom. The residue thus obtained was then subjected to column chromatography with ethyl acetate as a developing solvent and silica gel as a filler to obtain 1.5 g of the desired compound (yield: 4%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17](Cl)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>ClCCl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:17]([CH:12]1[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:20][CH3:21])[N:4]([CH2:3][CH2:2][F:1])[C:16]=2[CH2:15][CH2:14][CH2:13]1)=[O:18])[CH3:23]
Reactant: CCNCC
Reactant: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
9-(2-fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (18) (371 mg, 1.2 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. diethylamine (177 mg, 2.4 mmol, 250 μL) was then added and the reaction was stirred overnight at RT. The reaction was quenched with 10% aqueous potassium carbonate (2 mL). The dichloromethane layer was collected through a phase separator then concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A): ethyl acetate (B) (50-100% (B), 50 g, 35.2 CV, 40 mL/min) to afford a pale yellow solid. The solid was next triturated with a minimum amount of diethyl ether to afford 240 mg (58%) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethyl amide (non-radioactive imaging agent 5). The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 13.0, 14.6, 19.9, 21.9, 28.0, 36.3, 40.5, 41.9, 43.1 (d, JCF=23 Hz), 54.7, 82.0 (d, JCF=173 Hz), 99.7, 102.1, 108.3, 117.0, 121.5, 135.3, 137.4, 153.3, and 174.8.