Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([OH:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.F[P-](F)(F)(F)(F)F.[N:26]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:26]1([O:14][C:13]2[C:12]3[N:11]=[CH:10][N:9]([C:18]=3[N:17]=[CH:16][N:15]=2)[C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 26 h
Yield: 57 %

Procedure:
In a 50 mL round-bottomed flask equipped with a stirring bar were placed 2′-deoxyinosine 24 (0.504 g, 2.00 mmol) and BOP (1.770 g, 4.00 mmol). DMF (20 mL) and DIPEA (0.70 mL, 4.00 mmol) were added and the mixture was allowed to stir at room temperature for 26 h. The reaction mixture was evaporated with toluene several times. The crude product was dissolved in EtOAc and washed with water. The organic layer was separated, dried over Na2SO4 and concentrated. Chromatographic purification (SiO2, elution with 10% MeOH in CH2Cl2) afforded 0.421 g (57% yield) of compound 28 as a pale brownish-white foam. Rf (10% MeOH in CH2Cl2)=0.38. 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H, Ar—H), 8.24 (s, 1H, Ar—H), 8.16-8.14 (m, 1H, Ar—H), 7.57-7.54 (m, 1H, Ar—H), 7.49-7.46 (m, 1H, Ar—H), 6.46 (dd, 1H, H-1′, J=9.2, 5.5), 5.10 (dd, 1H, OH, J=11.3, 2.3, CD3OD exchangeable), 4.83 (br m, 1H, H-3′), 4.25 (br s, 1H, H-4′), 3.97 (dt, 1H, H-5′, J=12.8, 2.0), 3.82 (app td, 1H, H-5′, Japp˜11.9, 1.8), 3.07 (ddd, 1H, H-2′, J=13.4, 9.5, 4.9), 2.42 (dd, 1H, H-2′, J=13.6, 5.7), 2.05 (d, 1H, OH, CD3OD exchangeable). 13C NMR (126 MHz, DMSO-d6): δ 159.1, 153.1, 151.1, 144.8, 143.2, 129.1, 128.8, 125.2, 120.5, 120.3, 108.7, 88.9, 86.9, 72.2, 62.7, 40.9. FAB HRMS calcd for C16H16N7O4 (M++H) 370.1264. found 370.1258.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.C([O-])=O.[NH4+].CCCCCC>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: COCCOCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCO
Product: COCCOCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 1-[(2-methoxyethoxy) methoxy]-4-nitrobenzene (21), 100 mg of 10% Pd/C and 550 mg (8.7 mmol) of ammonium formate in 10 mL of absolute ethanol was stirred at room temperature for 18 hours. The reaction mixture was diluted with 100 mL of absolute ethanol and passed through a small pad of celite. The filtrate was concentrated and purified by silica gel column chromatography using 8:2 ethyl acetate:hexane as the eluent to yield 130 mg (0.65 mmol, 75%) of 4-[(2-methoxyethoxy)methoxy]benzenamine (22). NMR, IR and MS data confirmed compound identity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](F)(F)F)[CH:5]=[CH:6][C:7]=1[Cl:8].[Al+3].[Cl-:14].[Cl-:15].[Cl-:16]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:16])=[C:2]([Cl:1])[CH:7]=2)([Cl:15])[Cl:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: Clc1ccc(C(Cl)(Cl)c2ccc(Cl)c(Cl)c2)cc1Cl

Procedure:
reacting 3,4-dichlorobenzotrifluoride with 1,2-dichlorobenzene and AlCl3 to form bis(3,4-dichlorophenyl) dichloromethane;
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O>[CH2:12]([NH:19][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cc(Br)c2nonc2c1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: Brc1cc(NCc2ccccc2)c2nonc2c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 42.7 %

Procedure:
4,6-dibromobenzo[c][1,2,5]oxadiazole 4 (0.9678 g, 3.48 mmol) and benzylamine (1.9 mL, 17.4 mmol) were dissolved in DMSO (10.5 mL) under argon and stirred in a sealed tube for 3 days, after which time, the tube was heated to 60° C. for 12 hours. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl (aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The dark solid was recrystallized from EtOH and the dark crystals were collected by filtration and dried to afford 0.4516 g (43% yield) of N-benzyl-6-bromobenzo[c][1,2,5]oxadiazol-4-amine. This material (0.1980 g, 0.651 mmol), benzoylpiperazine hydrochloride (0.1771 g, 0.781 mmol) and Cs2CO3 (0.6353 g, 1.95 mmol) were added to a tube. The tube was evacuated and purged with argon (3×). Toluene (2 mL) and NMP (1.2 mL) were then added to the tube and its contents were degassed for 15 minutes, at which point Pd2(dba)3 (0.0119 g, 0.0130 mmol) and BINAP (0.0162 g, 0.026 mmol) were quickly added, the tube was sealed and heated at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl(aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The crude material was purified via chromatography (40% EtOAc/Hexanes) to give 0.188 g (70% yield) of TRV-1256. 1H NMR (500 MHz, CDCl3) δ=7.46-7.43 (m, 5H), 7.39-7.36 (m, 4H), 7.34-7.31 (m, 1H), 6.13 (d, J=1.0 Hz, 1H), 5.88 (s, 1H), 5.32 (t, J=5.5 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H), 3.90 (br s, 2H), 3.58 (br s, 2H), 3.29 (br s, 2H), 3.15 (br s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH:3]=[N:2]1.[F:20][C:21]([F:36])([F:35])[C:22]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:16]([C:17]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:22]([OH:27])([C:21]([F:20])([F:35])[F:36])[C:23]([F:24])([F:25])[F:26])=[CH:33][CH:32]=4)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cccnc1Nc1ccc2cn[nH]c2c1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1Nc1ccc2cn[nH]c2c1

Procedure:
2-(1H-Indazol-6-ylamino)pyridine-3-carboxylic acid (500 mg, Step A) was reacted with 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenylamine (340 mg) and EDC (500 mg) and HOBt (270 mg) in DMF at RT overnight. The reaction was diluted with CH2Cl2 and washed with H2O followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography to give the title compound. MS (ES+): 496(M+H)+; (ES−): 394(M−H). Calc'd. for C22H15F6N5O2−495.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[OH-].[Na+]>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:6]([CH3:7])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1Br
Yield: 69 %

Procedure:
To 2.51 g (~0.017 mole) of freshly distilled 4-chloro-N-methylaniline (b.p. 102-103° C.) is added 4.26 g (~0.017 mole) of 2-bromo-benzenesulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is added dropwise with stirring until the solution is slightly alkaline. The 2-bromo-4'-chloro-N-methylbenzene-sulfonanilide is formed as viscous liquid. It is washed with water several times until the wash water is neutral. The compound is dried overnight at room temperature. The yield is 4.2 g (69% yield). 1H NMR (deuterioacetone): δ6.8-7.9 (m, 8 ArH), 3.2 (s, 3H, N--CH3).
Reaction SMILES: CCOP(OCC)([CH:6]1[NH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])=O.C(N(CC)CC)C.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=[C:6]2[NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a stirred solution of diethyl 5-hydantoylphosphonate (10 g, 42.3 mmol) and triethylamine (5.70 g, 56 mmol), in dry acetonitrile (100 ml) at room temperature was added a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (8 g, 36.3 mmol) in dry acetonitrile (75 ml), dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight, after which volatiles were removed in vacuo. The residue was diluted with 0.05N HCl (120 ml) and the precipitate collected by filtration. Recrystallization of this material with methylene chloride/methanol/diethyl ether afforded the title compound as a pale yellow solid (8.54 g). m.p. 220-222° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:67][CH:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:26])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: NC1CCCCC1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)O)OC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)OC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinecarboxylic acid (302 mg, 0.81 mmol), HATU (343 mg, 0.90 mmol), and Hünig's base (0.21 mL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes. Cyclohexylamine (0.105 mL, 0.92 mmol) was then added and stirring continued at room temperature for 17 hours. LC-MS indicated abot 50% conversion so another portion each of Hünig's base (0.21 mL, 1.20 mmol) and HATU (343 mg, 0.90 mmol) were added. After about 10 minutes more cyclohexylamine (0.105 mL, 0.92 mmol) was added, and the mixture was stirred for an additional 1.5 hours, then diluted with EtOAc (25 mL) and washed successively with water, saturated aqueous NaHCO3, and brine (25 mL each). The organic phase was then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, 10-40% EtOAc in hexanes gradient) to give the title compound (328 mg) as a yellow oil. LC-MS (ES) m/z=453 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:34])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]=[C:18]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22](=[O:29])[NH:21][C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]3=4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:37]([N:21]1[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18](=[CH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)([OH:34])[CH2:10][CH2:11]2)[C:19]2[CH:33]=[CH:32][CH:31]=[CH:30][C:20]1=2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1Nc2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol hydrochloride (Example 39)(300 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 200 mg), benzyl bromide (0.15 ml) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the titled compound (180 mg).
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([CH:21]=[CH2:22])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(Br)cc2)C[C@@H]2CC[C@H]1N2C
Product: C=Cc1ccc([C@H]2C[C@@H]3CC[C@H]([C@H]2C(=O)OC)N3C)cc1

Procedure:
Scheme 5 provides exemplary synthetic route for 2β-carbomethoxy-3β-4′-(Z-2-iodoethenyl)phenyl)tropane (ZIET) and [123I] ZIET. The preparation of ZIET involved a five-step sequence of reactions. In this synthetic approach 2β-carbomethoxy-3β-(4′-bromophenyl)tropane was treated with vinyltributyltin to yield 2β-carbomethoxy -3β-(4′-ethenylphenyl)tropane. The vinyltropane derivative was converted to 2β-carbomethoxy-3β-(4′-formylphenyl)tropane followed by reaction with triphenyl-phosphoniumiodomethyne yllide to give ZIET.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:30]([Cl:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1N=C2C=CC=CC2=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:21][C:22]1[C:30]([Cl:31])=[CH:29][C:25]([C:26]([NH:20][CH2:19][CH:16]2[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:15]2)=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN(CCCCN1CCC(CN)C1)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN(C)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.8 %

Procedure:
A suspension of N-benzyl-N-methyl-4-(3-aminomethylpyrrolidin-1-yl)-butylamine (1.06 g), 4-amino-5-chloro-2-methoxybenzoic acid (0.78 g), dicyclohexylcarbodiimide (0.79 g), 2-hydroxybenzotriazole (0.52 g) and triethylamine (1.1 ml) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 12 hr. The solvent was evaporated, and water was added to the residue, which was followed by extraction with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.19 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-(N-methyl-N-benzylamino)butyl)pyrrolidin-3-yl)methyl)-benzamide.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>O1CCOCC1.CCOCC>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)C(C)C)cnc12
Yield: 19.2 %

Procedure:
3-isobutyryl-4-chloro-8-methoxyquinoline (6.0 g, 0.022 mol) and o-toluidine (6 ml, 0.055 mol) were heated in 1,4-dioxan (100 ml) for 45 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and brine. The solution was dried and evaporated to an oil, which was chromatographed (silica gel, dichloromethane) to afford a yellow oil. Trituration in ether gave yellow crystals of 3-isobutyryl-4-(2-methylphenylamino)-8-methoxyquinoline (1.41 g, 18.3%), m.p. 116°-8°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:33]=[CH:32][CH:31]=[CH:30][C:8]=1[C:9]([NH:11][CH2:12][C@H:13]([CH:27]([CH3:29])[CH3:28])[CH2:14][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:16]1[CH2:18][O:17]1)=[O:10].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(O)(C)C>[OH:17][C@H:16]([C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][C@H:13]([CH2:12][NH:11][C:9](=[O:10])[C:8]1[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:27]([CH3:29])[CH3:28])[CH2:18][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1)C(C)C
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN1CCCCC1)C(C)C

Procedure:
A solution of 0.030 g of tert-butyl (3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methyl-1(S)—(R)-oxiranylpentyl)carbamate in 0.60 ml of isopropanol and 0.050 ml of piperidine is stirred at 70° C. over 1 hour. The reaction mixture is concentrated by evaporation, and the residue is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.34 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.08 (gradient I).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[S:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=2[N:26]=[N:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:31]3[CH:30]=[CH:29][C:28]4[S:24][N:25]=[N:26][C:27]=4[CH:32]=3)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc2snnc2c1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3ccc4snnc4c3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with benzo[1,2,3]thiadiazole-5-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=494.1.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=O)[C:2]1C=CC=CC=1.[NH2:12][C:13]1[C:14]([CH3:23])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[N:16]2.Cl.C(N)C[NH2:27]>CC(C)=O.C1(C)C=CC=CC=1>[NH2:27][CH2:2][CH2:1][NH:9][C:10](=[S:11])[NH:12][C:13]1[C:14]([CH3:23])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[N:16]2
Reactant: NCCN
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1c(N)ccc2nccnc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cc1c(NC(=S)NCCN)ccc2nccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a refluxing solution of benzoyl isothiocyanate (1.6 g) in dry acetone (20 mL) is added dropwise a solution of 6-amino-5-methylquinoxaline (1.2 g) in dry acetone (50 mL) over 30 minutes. The mixture is refluxed an additional two hours, cooled to room temperature, and rotary evaporated to a residue. This material is suspended in 10% NaOH solution (50 mL) forming a mixture which is heated at 90° C. for 30 minutes, then cooled to room temperature and adjusted to pH=8 by adding concentrated HCl. The mixture is then cooled in an ice bath and suction filtered. The collected solid thiourea intermediate is dried on a vacuum line (16 h, 0.5 torr), suspended in bromobenzene (50 mL) and heated at reflux for six hours to effect conversion to the isothiocyanate intermediate which is not isolated. The solution is cooled, then added dropwise to a solution of ethylene diamine (5.0 mL) in toluene (10 mL). The resulting mixture is stirred for 16 hours and filtered. The solids are washed with toluene (20 mL) and dried under vacuum to yield 6-(N'-aminoethylthioureido)-5-methylquinoxaline.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ccc2nc(S)oc2c1
Solvent: CN(C)C=O
Product: Oc1ccc2nc(Cl)oc2c1

Procedure:
2-Sulfanyl-1,3-benzoxazol-6-ol (2.08 g) [see Preparation 33] was added to thionyl chloride (12.3 ml), followed by dimethylformamide (0.93 ml). The reaction mixture was heated to reflux for 5 minutes, after which time the mixture was allowed to cool. The solvent was removed under reduced pressure, the residue azeotroped twice with xylene, and the residue then partitioned between diethyl ether and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 0:100, by volume, hexane:ethyl acetate in 50% increments to afford 2-chloro-1,3-benzoxazol-6-ol (1.715 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.BrC[C:21]1[CH:26]=[CH:25][CH:24]=C[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:24]=[CH:25][CH:26]=[CH:21][N:22]=2)[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(Br)cc1NCc1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 2-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 1 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give the title compound (336 mg, 68%) as a yellow solid: