Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[Cl:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1cccc(Cl)c1Cl
Yield: 73.1 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2,3-dichlorophenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.5 g, 73%). EI-MS m/z 342(M+H)+.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]3/[C:13](=[CH:22]/[C:23]#[N:24])/[C:14]4[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=4[CH2:16][CH2:17][C:11]=3[CH:10]=2)[CH:2]=1.Cl[C:34](=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:8][C:9]2[CH:26]=[CH:25][C:12]3/[C:13](=[CH:22]/[C:23]#[N:24])/[C:14]4[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=4[CH2:16][CH2:17][C:11]=3[CH:10]=2)[C:34](=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:2]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CNc3cccc(-c4ccccc4)c3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)N(Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N)c1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
[step 1] Compound 43 (200 mg, 0.49 mmol) obtained in Example 43 was dissolved in DMF (1 mL), and the mixture was cooled to 0° C. Methyl 3-chloro-3-oxopropanoate (99 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 7 hr. To this mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the precipitate was collected by filtration to give (E)-[2-(N-(biphenyl-3-yl)-3-methoxy-3-oxopropanamido)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile quantitatively.
Reaction SMILES: BrC1C=CC=CC=1.[Li].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[CH2:18]([N:20]([CH2:23][CH3:24])[C:21]#[N:22])[CH3:19]>O.C(OCC)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=[C:21]([N:20]([CH2:23][CH3:24])[CH2:18][CH3:19])[N:22]=1
Reactant: CCN(C#N)CC
Reactant: N#Cc1ccccc1N
Agent: [Li]
Solvent: CCOCC
Solvent: Brc1ccccc1
Solvent: O
Product: CCN(CC)c1nc(N)c2ccccc2n1
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere 4.7 g. (0.03 mol) of bromobenzene dissolved in 35 ml. of anhydrous diethyl ether, are added to 0.42 g. (0.06 mol) of lithium. To the solution obtained, a solution of 0.03 mol o-aminobenzonitrile in 15 ml. of anhydrous diethyl ether is added dropwise at room temperature. After about 10 minutes, a solution of 0.03 mol diethylcyanamide in 10 ml. of anhydrous diethyl ether is added dropwise. The reaction mixture is then refluxed under the nitrogen atmosphere for 4 hours. The next day the mixture is decomposed by addition of water. The ethereal layer is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation of solvent. Some petroleum ether (boiling range 28°-40°C.) is added to the residue, the solid is filtered off and crystallized from a mixture of methanol and water. 4-Amino-2-diethylaminoquinazoline, m.p. 125°-128°C., is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22](OCC(Cl)(Cl)Cl)=[O:23])([CH3:12])[CH3:11]>C1COCC1>[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22]([O:9][C@@H:6]1[CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]1)=[O:23])([CH3:12])[CH3:11]
Reactant: CN1CC[C@@H](O)C1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)O[C@@H]1CCN(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2.8 %

Procedure:
NaH (0.19 g, 5.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL) at 0° C. and (R)-1-methylpyrrolidin-3-ol (0.47 mL, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and added to a solution of Intermediate 2 (1.33 g, 4.00 mmol) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (R)-1-methylpyrrolidin-3-ol in THF were added after 18 and 26 h, respectively. After 44 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4%, 5%, 10% and 20% MeOH in DCM (200 mL)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 30% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid]). The residue was de-salted using K2CO3 in DCM to give (3R)-1-methylpyrrolidin-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo-[4,5-c]pyridine-5-carboxylate (32.3 mg, 2.7%) as a colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[CH:12]=[CH:11][N:10]=1.[N:25]([CH2:28][CH3:29])=[C:26]=[O:27]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:26]([NH:25][CH2:28][CH3:29])=[O:27])[C:17]=23)[CH:12]=[CH:11][N:10]=1
Reactant: Fc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)ccn2)c1
Reactant: CCN=C=O
Solvent: CC#N
Product: CCNC(=O)n1ncc2nccc(Nc3ccnc(-c4cc(F)ccc4F)c3)c21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-(2-(2,5-Difluorophenyl)pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (50.7 mg, 0.157 mmol) was suspended in acetonitrile (16 mL), isocyanatoethane (12.32 μl, 0.157 mmol) was added and the reaction was stirred at 70° C. for 2 hours, cooled to give a solid. The solid was collected by filtration, rinsed with acetonitrile (3×15 mL) and ether (3×5 mL) and dried under high vacuum to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (3H, t, J=7.20 Hz) 3.36-3.46 (2H, m) 7.31-7.47 (3H, m) 7.52 (1H, d, J=5.31 Hz) 7.67 (1H, s) 7.77 (1H, ddd, J=9.47, 6.06, 3.16 Hz) 8.45 (1H, d, J=5.31 Hz) 8.58-8.63 (2H, m) 9.10 (1H, s) 11.43 (1H, s). MS [M+H] found 395.4.
Reaction SMILES: [Cl:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[ClH:1].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([Cl:1])=[CH:3][C:4]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: CN1CCC(O)c2cc(Cl)sc2C1
Product: CN1CCC(Oc2ccc(C(N)=O)cc2Cl)c2cc(Cl)sc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-chloro-7-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 24) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: OC([C:5]1[CH:6]=[C:7]2[C:30](=[CH:31][CH:32]=1)[C:11]1=[N:12][O:13][C:14]([C:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:17][N:16]=3)=[C:10]1[CH2:9][CH2:8]2)C#N.[OH2:33].Cl.[O:35]1[CH2:40][CH2:39][O:38]CC1>>[OH:35][CH:40]([C:5]1[CH:6]=[C:7]2[C:30](=[CH:31][CH:32]=1)[C:11]1=[N:12][O:13][C:14]([C:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:17][N:16]=3)=[C:10]1[CH2:9][CH2:8]2)[C:39]([OH:38])=[O:33]
Reactant: C1COCCO1
Reactant: O
Reactant: N#CC(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: Cl
Product: O=C(O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 100 °C

Procedure:
To (±)-2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetonitrile (Preparation 131A, 1.1 g, 2.5 mmol) in dioxane (18.0 mL) was added water (12.0 mL) and hydrochloric acid, 37% (12 mL). The reaction mixture was heated at 100° C. for 3 h. After cooling, it was concentrated to provide the product as a racemic mixture. LC/MS M+1=458.0. The individual enantiomers were separated using a chiral preparative column under SFC conditions (Chiralcel OJ-H 5×25 cm, column temperature 20° C., isocratic elution with mobile phase 35% acetonitrile+0.1 TFA in CO2, 280 mL/min, 250 nM). Isomer 1 (500 mgs), retention time on chiral HPLC, 7.26 min; Isomer 2 (600 mgs), retention time on chiral HPLC, 9.88 min. The absolute stereochemistry at the carbon anchoring the secondary alcohol, of Isomer 1 and Isomer 2 was not determined.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:27]=[CH:26][C:20]2[CH:21]=[C:22]([CH:24]=O)[O:23][C:19]=2[CH:18]=1.[C:28]([CH2:30]P(=O)(OCC)OCC)#[N:29].Cl>CN(C)C=O>[C:28]([CH2:30][CH2:24][C:22]1[O:23][C:19]2[CH:18]=[C:17]([O:16][CH2:15][C:5]3[N:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:8][C:4]=3[CH3:3])[CH:27]=[CH:26][C:20]=2[CH:21]=1)#[N:29]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C=O)oc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCC#N)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Sodium hydride (60%, oily, 0.20 g) was gradually added to a solution of 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran-2-carbaldehyde (1.50 g) and diethyl cyanomethylphosphonate (0.88 g) in N,N-dimethylformamide (30 ml) at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured over ice water and neutralized with 2N hydrochloric acid, followed by extraction with ethyl acetate (200 ml). After the ethyl acetate layer was washed with water and dried (MgSO4), palladium-carbon (5%, 0.70 g) was added, followed by catalytic reduction at room temperature under an atmospheric pressure of 1 atm. After the catalyst was filtered off, the filtrate was concentrated; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform (2:98, v/v), crystals of 2-(2-cyanoethyl)-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (1.34 g, 83%) were obtained, which was then recrystallized from dichloromethane-hexane to yield colorless prisms having a melting point of 92° to 93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:13]=[C:12]([Br:11])[CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1cccc(Br)c1
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: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cccc(Br)c2)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 6.9 grams (0.044 mole) of 4-chlorophenylboronic acid (commercially available), 25.0 grams (0.100 mole) of 1,3-dibromobenzene, 0.2 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), 75 mL of aqueous 2M sodium carbonate, and 75 mL of toluene, yielding 3-(4-chlorophenyl)phenyl bromide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[C:16](F)[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3cccc(F)c3)cc2N1

Procedure:
Prepared from {3′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K66) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (69 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=1.[C-:27]#[N:28].[K+]>O.C(O)C.O1CCCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH2:9][C:7]3[N:8]=[C:3]([CH2:2][C:27]#[N:28])[CH:4]=[CH:5][CH:6]=3)=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:12]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(Cc3cccc(CBr)n3)c(-c3ccccc3)[nH]c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(CC#N)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 88.3 %

Procedure:
To a solution of 3-[6-(bromomethyl)pyridin-2-ylmethyl]-6-methoxy-2-phenyl-1H-indole (1.37 g) in water/ethanol/tetrahydrofuran (4 mL/16 mL/4 mL) was added potassium cyanide (263 mg), and the mixture was stirred at 80° C. for 13.5 hours. The reaction mixture was left to be cooled and concentrated under reduced pressure. To the residue was added water, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.05 g). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 3.95 (2H, s), 4.39 (2H, s), 6.76 (1H, dd, J=2.3, 8.5 Hz), 6.91 (1H, d, J=2.3 Hz), 7.04 (1H, d, J=7.8 Hz), 7.23 (1H, d, J=7.5 Hz), 7.30-7.39 (2H, m), 7.39-7.49 (2H, m), 7.50-7.61 (3H, m), 8.05 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:18]1([SH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1)=[O:4]
Reactant: SC1CCCCC1
Reactant: COC(=O)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(SC2CCCCC2)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
After 6-bromo-pyridine-2-carboxylic acid methyl ester (0.30 g, 1.39 mmol) was dissolved in DMF (4 mL), K2CO3(0.575 g, 4.16 mmol) and cyclohexanethiol (0.25 mL, 2.08 mmol) were added thereto in turn, and the mixture was stirred at 70° C. for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, extracted with EtOAc, and purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.162 g, 46%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[OH:30][C:24]([C:26]([F:29])([F:28])[F:27])=[O:25].[C:17]1([C@@H:8]([NH2:7])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC1CCOCC1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CNC1CCOCC1)c1ccccc1

Procedure:
A solution of the tert-butyl carbamate (333 mg, 1.04 mmol) and TFA (1.0 ml) in CH2Cl2 (6.0 ml) was stirred at room temperature for 50 minutes. The excess solvent was removed under reduced pressure, giving the crude (R)-1-phenyl-N2-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine TFA salt as a pale yellow oil (849 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccn1
Agent: Br
Product: COC(=O)c1ccc(OCc2ccccn2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E from methyl 4-hydroxybenzoate and 2-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=O)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:37])[CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[CH:29]=2)[CH2:24]1.COC1C(OC)=CC=C2C=1CCC(NC)C2>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:37])[CH:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[CH:29]=3)[CH2:24]2)=[O:14])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(N(C)CCCN)CC2
Reactant: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Agent: CNC1CCc2c(ccc(OC)c2OC)C1
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-])CC2

Procedure:
The title compound of this paragraph is prepared from 4,5-dimethoxy-2-nitrophenylacetic acid (5.25 g, 0.0217 mol) and of 1-amino-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (6.04 g, 0.0218 mol) analogously to Example R(c). Yield: 8.6 g. Rf value: 0.8 (alumina, eluant: 95 parts by volume of methylene chloride+5 parts by volume of ethanol).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9](=[O:27])[C:10](=[CH:23]OCC)[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1[F:22])=[O:12])[CH3:7]>C(O)C>[CH2:6]([O:8][C:9](=[O:27])[C:10](=[CH:23][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1[F:22])=[O:12])[CH3:7]
Reactant: CC(C)(C)N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)C(=CNC(C)(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
A solution of 1.77 g (24.2 mmoles) tert-butylamine in 2 mL ethanol was added to a mixture of 7.05 g (22 mmoles) of 3-(2,3,4,5-tetrafluorophenyl)-3-oxo-2-(ethoxymethylene)-propanoic acid ethyl ester and 9 mL ethanol cooled in a bath containing ice and salt. More ethanol (2.3 mL) was added and the mixture was stirred at room temperature for 2 hours. After cooling at 0° C., the resulting precipitate was filtered and washed with ethanol to give 3.72 g of titled compound. MP 112° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][C@@:9]([CH3:10])([C:11]([O:13][CH3:14])=[O:12])[N:8]=[C:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reactant: BrCc1cccc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@](C)(Cc1cccc(Br)c1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methyl N-(diphenylmethylene)alaninate (2.6 g, 9.7 mmol) in DMF (20 mL) cooled to 0° C. was added NaHMDS (12.2 mL, 12.2 mmol, 1M in THF) slowly via syringe and the reaction mixture was stirred at 0° C. for 15 min at which point 3-bromo-benzyl bromide (2.55 g, 10.2 mmol) in DMF (10 mL) was added slowly via syringe. The reaction mixture was allowed to warm to rt over 16 h, quenched with aq NH4Cl and water, extracted with EtOAc, washed with aq LiCl (×3), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (120 g silica, 0-15% EtOAc in hexanes) to provide methyl 3-bromo-N-(diphenylmethylene)-α-methylphenylalaninate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[N+:17]([C:3]1[CH:4]=[C:5]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:6]=[CH:7][C:2]=1[S:27][C:24]1[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=1)([O-:19])=[O:18]
Reactant: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 0 °C
Yield: 92.3 %

Procedure:
A solution of the compound from Example 216A (1.86 g, 6.95 mmol), 4-aminothiophenol (0.88 g, 7.00 mmol), cesium carbonate (2.3 g, 7.00 mmol) in dimethylformamide (10 ml) was heated at 40° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (2.35 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5]([S:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=1.[F:26][C:27]([F:34])([F:33])[S:28]([O:31]C)(=[O:30])=[O:29].[CH2:35](OCC)C>C(Cl)Cl>[F:26][C:27]([F:34])([F:33])[S:28]([O-:31])(=[O:30])=[O:29].[Cl:1][C:2]1[CH:3]=[C:4]([N+:23]([O-:25])=[O:24])[C:5]([S:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:6][C:7]=1[N+:8]([CH3:35])([CH3:10])[CH3:9]
Reactant: CN(C)C(=O)c1ccccc1Sc1cc(N(C)C)c(Cl)cc1[N+](=O)[O-]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOCC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccccc1Sc1cc([N+](C)(C)C)c(Cl)cc1[N+](=O)[O-]
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
2-(4-Chloro-5-dimethylamino-2-nitro-phenylsulfanyl)-N,N-dimethyl-benzamide (22) (0.5 g, 1.32 mmol) and methyl trifluoromethanesulfonate (0.3 g, 1.83 mmol) was heated to reflux in 5 mL of methylene chloride for 72 h. After cooled down, ethyl ether was added to the mixture. Precipitate was collected and recrystalized from CH2Cl2/ethylether repeatedly. Highly hygroscopic pale yellow powder was dried in vacuo and used directly for F-18 radiolabeling without further purifications (Yellow powder. 0.31 g, 40%): IR (cm−, neat) 3060, 1623, 1553, 1519, 1256, 1154, 1027, 784, 640; 1H NMR (200 MHz CDCl3) δ 8.53 (s, 1H), 7.74–7.90 (m, 4H), 7.69 (s, 1H), 3.69 (s, 9H), 3.40 (s, 3H), 3.06 (s, 3H); HRMS calcd for C18H2135ClN3O3S (M+) 394.0992, found 394.0999.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1>C(O)C>[C:11]([NH:12][CH:8]=[N:9][C:7]1[CH:2]=[CH:3][CH:4]=[C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH:6]=1)#[N:10]
Reactant: Nc1ccc(-c2nc[nH]n2)cc1
Solvent: CCO
Product: N#CNC=Nc1cccc(-c2nc[nH]n2)c1
Yield: 191.6 %

Procedure:
A solution of 3-(4-amino-phenyl)-1,2,4-triazole (9.85 g) and N-cyano ethyl formimidate (5.1 g) in ethanol (100 ml) was stirred overnight at room temperature. The solid which crystallized out was filtered off and dried to give 12.5 g of the title compound; M.p. 247°-250° C. (dec.).