Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)ccc1Br
Reaction time: 23 h

Procedure:
To a mixture of 4-bromo-3-chlorophenol (2.5 g), potassium carbonate (2.165 g) and N,N-dimethylformamide (26 mL), benzyl chloride (1.8 mL) was added under cooling with ice. Raising the temperature to the ambient level, the system was stirred for 23 hours. The reaction mixture was poured in saturated saline solution and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, and dried over anhydrous magnesium sulfate. Distilling the solvent off, the remaining crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=10:1) to provide 4-benzyloxy-1-bromo-2-chlorobenzene (3.029 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[O:24][C:23]([C:25]([NH2:32])([CH3:31])[CH2:26][CH:27]2[CH2:30][O:29][CH2:28]2)=[N:22][N:21]=1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:32][C:25]([C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)([CH3:31])[CH2:26][CH:27]3[CH2:30][O:29][CH2:28]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: Cc1nnc(C(C)(N)CC2COC2)o1
Product: Cc1nnc(C(C)(CC2COC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(oxetan-3-yl)propan-2-amine (example 190c) as starting materials and isolated (35 mg, 21%); MS (ESI, m/z): 441.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)[C:13]#[N:14]>C1COCC1>[C:13]([C:12]([NH:11][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:28])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)#[N:14]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(Cl)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-chlorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=441, RT=0.74 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.C(#N)C.Cl[C:18]1[N:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:18]2[N:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c2c1OCC21CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CC#N
Product: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC21CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 13, 176 mg, 1 mmol) in dry Acetonitrile (4 ml) potassium carbonate (207 mg, 1.5 mmol) and then 2-chloro-5-nitropyrimidine (159 mg, 1 mmol) were added and the reaction mixture was stirred for 24 hours at 80° C. After cooling the reaction mixture was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated affording the title compound (258 mg) as an orange solid that was used in the next step as crude material without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH:10]([CH3:12])[C:9]([CH3:14])([CH3:13])[C:8]2[CH2:7][C:6]([CH3:16])(O)[CH:5](O)[CH2:4][C:3]1=2.CS(Cl)(=O)=O>N1C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:18])[CH2:11][CH:10]([CH3:12])[C:9]([CH3:14])([CH3:13])[C:8]2[CH2:7][CH:6]([CH3:16])[CH2:5][CH2:4][C:3]1=2
Reactant: CC1CC(C)(C)C2=C(CC(C)(O)C(O)C2)C1(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1CCC2=C(C1)C(C)(C)C(C)CC2(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
85 g (0.337 mol) of the 2,2,4,5,5,8-hexamethyl-bicyclo[4.4.0]dec-1(6)-ene-8,9-diol are dissolved at room temperature in 218 ml of pyridine. The solution is now cooled to 0° C. and 30.2 ml of methanesulphonyl chloride are slowly added dropwise during 20 minutes. The mixture is stirred at room temperature for a further 24 hours. The mixture is thereupon diluted with ether and washed with 1.480 l of 2N hydrochloric acid and 400 ml of saturated sodium chloride solution. The aqueous phase is extracted with ether and the combined organic phases are washed neutral with dilute sodium bicarbonate solution, dried over sodium sulphate and evaporated.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 100 °C
Yield: 80.7 %

Procedure:
A mixture of 2.00 g (10.5 mmol) of 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared as described in Example 13, 1.60 g (11.6 mmol) of anhydrous K2CO3 and 2.30 g (11.8 mmol) of ethyl 4-bromobutyrate in 40 ml of DMF is heated at 100° C. for 2 hrs under N2. The DMF is removed under vacuum and the residue taken up in 150 ml of EtOAc and 75 ml of water. The organic phase is washed with 5% aqueous NaOH, then with saturated NaCl, dried (MgSO4), and the solvent removed to leave 2.58 g of 6-[4-[3-carboethoxy-propyloxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 81%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][S:18]([CH3:21])(=[O:20])=[O:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[C:31]2[C:30]([N:32]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH3:38])[CH2:33]3)=[N:29][CH:28]=[N:27][C:26]=2[NH:25][CH:24]=1.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[C:31]4[C:23]([CH3:22])=[CH:24][NH:25][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:33][C@@H:34]2[CH3:38])=[N:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: CS(=O)(=O)N=C(Nc1cccc(Br)c1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NS(C)(=O)=O)Nc4cccc(Br)c4)[C@@H](C)C3)c12

Procedure:
The carbamimidate from step B (100 mg, 0.27 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from Example 1, step B (63 mg, 0.27 mmol), and triethylamine (77 μl, 0.27 mmol) were combined in MeCN (1.5 ml) and heated to reflux for 2 hours. The mixture was concentrated and purified by preparative HPLC to afford (S)—N-(3-bromophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N′-(methylsulfonyl)piperazine-1-carboximidamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[NH:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][C:6]=1[N+:22]([O-:24])=[O:23].I[CH3:27].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:25])[N:4]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=[CH:7][C:6]=1[N+:22]([O-:24])=[O:23])[CH3:27]
Reactant: COC(=O)Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-carbamic acid methyl ester (2.03 g, 5.86 mmol) in anhydrous dimethylformamide (20 ml) was added iodomethane (1.82 ml, 29.3 mmol), followed by portion wise addition of NaH (0.35 g, 60%, 8.79 mmol). The reaction was stirred under nitrogen for 2 h. The reaction was quenched with NH4Cl (sat) (10 ml) and brine (10 ml), and the aqueous layer was extracted with ether (3×30 ml). The combined organics were dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexanes, then 30% ethyl acetate/hexanes to give [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-methyl-carbamic acid methyl ester (0.93 g, 89%) as an oil. Analysis calculated for C18H20N2O6 : C, 59.99; H, 5.59; N, 7.77. Found: C, 59.30; H, 5.34; N, 7.62.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([C:14]([C:16]2[C:21]([N:22]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])COC)=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.O>OS(O)(=O)=O.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[C:13]([C:14]([C:16]2[C:21]([NH:22][S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of (3-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-carbamic acid tert-butyl ester (25 mg, 0.0394 mmol) in 5% H2SO4 in TFA (4 mL) and water (1 mL) was stirred at 50° C. for 6 h. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution until pH 7-8. The mixture was extracted with EtOAc (2×15 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified to afford N-[2-(2-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (9.3 mg) in 48% yield. ESMS m/z (relative intensity): 491 (M+H)+ (100).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl>ClC(Cl)C>[CH2:8]1[C:9]2([CH2:14][CH2:13][N:12]([C:1]([Cl:4])=[O:2])[CH2:11][CH2:10]2)[CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: C1CCC2(C1)CCNCC2
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CCC2(CCCC2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1.57 ml of phosgene (20% solution in toluene, 2.96 mmol) were initially charged in 5 ml of dichloroethane and cooled to −20° C., then a mixture of 8-azaspiro-[4,5]decane (750 mg, 2.96 mmol) and triethylamine (1.28 ml, 9.2 mmol, 3.1 eq.) was added slowly. After 30 min, the mixture was allowed to come to RT; after 1 h, according to LC-MS, a little starting material was still present but also three new peaks. Subsequently, the mixture was added to 2 N aqueous HCl, the aqueous phase was extracted with dichloromethane, and the organic phase was washed with saturated NaHCO3 solution and dried over sodium sulfate; subsequently, the mixture was concentrated by rotary evaporation under reduced pressure. Crude yield: 592 mg
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CS(O[CH2:13][CH2:14][CH:15]1[CH2:19][C:18]2[CH:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=[CH:23][C:17]=2[O:16]1)(=O)=O>>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][CH:15]1[CH2:19][C:18]2[CH:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=[CH:23][C:17]=2[O:16]1
Reactant: CS(=O)(=O)OCCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Reactant: C[C@H]1CCCN1
Agent: Br
Product: C[C@@H]1CCCN1CCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1

Procedure:
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 67D are processed as described in Example 1D to provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](S)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Sc1ncc(-c2ccc(Cl)cc2)o1
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccc(-c2cnc(Cl)o2)cc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g, 4.08 mmol) in water (4 mL) at ambient temperature. After heating to 80° C. ext. temp. for 18 h the cold mixture was filtered. The filtrate was diluted with acetic acid (40 mL) and stirred for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole-2-thiol which was of ca. 61% purity (HPLC-MS) and used as is in the next step. The crude oxazole-2-thiol compound (1.42 g, max. 3.88 mmol) was suspended in phosphorous oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext. temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with aq. sat. bicarbonate (100 mL) and water (50 mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO2, 5-40% ethyl acetate in heptanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 mg, 0.49 mmol, 13%, purity 96% HPLC-MS).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20]CC[C:17](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:27]1(C2CC(=O)C2)C=CC=CC=1>>[C:12]1([CH:15]2[CH2:16][C:17](=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]2)[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=C1CCCC(c2ccc(OCc3ccccc3)cc2)C1
Reactant: O=C1CC(c2ccccc2)C1
Product: CCOC(=O)C(C)=C1CC(c2ccccc2)C1

Procedure:
Following the general procedure described for ethyl {3-[4-(benzyloxy)phenyl]cyclohexylidene}acetate (Intermediate 891i), replacing 3-[4-(benzyloxy)phenyl]cyclohexanone with 3-phenylcyclobutanone (J. Org. Chem., 2005, 70(11), 4549-4552) and triethyl phosphonoacetate with triethyl phosphonopropionate the title compound was obtained; 1H NMR δ (CDCl3): 1.24-1.32 (3H, m), 1.75-1.76 (3H, m), 2.87-2.91 (1H, m), 3.19-3.23 (2H, m), 3.54-3.59 (2H, m), 4.09-4.21 (2H, m), 7.19-7.36 (5H, m); MS m/e MH+ 231.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:29])[C:7](=[O:28])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23](N)[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.N([O-])=[O:31].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:29])[C:7](=[O:28])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([OH:31])[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCc3ccnc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN1c2ncc(CCc3ccnc(O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 36.6 %

Procedure:
The product of Example 71 (14 mg, 0.03 mmol) was dissolved in conc. sulfuric acid (0.06 mL) and water (0.5 mL), and the resultant solution was cooled to 0° C. Sodium nitrite (2.9 mg, 0.04 mmol) was added, and the reaction mixture was warmed to room temperature. After 40 min, the product was extracted with ethyl acetate and recrystallized (ethyl acetate-hexanes) afforded the title compound (4.5 mg, 32%) as beige crystals, m.p. 243°-244° C.
Reaction SMILES: C[N:2](CC1C=CC=CC=1)[CH2:3][C:4]#C.O=[C:14]1O[C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17](O)=[C:15]1O>>[NH2:2][CH2:3][CH2:4][C:17]1[CH:15]=[CH:14][C:23]([OH:24])=[C:21]([OH:22])[CH:19]=1
Reactant: C#CCN(C)Cc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: NCCc1ccc(O)c(O)c1

Procedure:
Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μl volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H](C3C=CC=CC=3)C)[CH2:11][C@H:10]2[F:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:12]1[CH2:13][C@H:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]2)[C@H:10]([F:22])[CH2:11]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Solvent: ClCCl
Product: CCOC(=O)C1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Yield: 83.7 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-(1-(S)-phenylethyl]pyrrolidine (5.08 g, 16.63 mmol) was dissolved in dry dichloromethane (50 ml). Under ice cooling, benzyl chloroformate (3.56 ml, 25.0 mmol) was added dropwise into this solution. Then the liquid reaction mixture was heated under reflux for 1 hour and dichioromethane was evaporated under reduced pressure. The residue was subjected. to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1) to obtain 4.67 g (83.7%) of the title compound as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:11])=[N:8][CH:9]=1.Br[CH2:13][C:14]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].O>O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:14]([CH2:13][N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=2)[CH3:11])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CNc1ccc(Cl)cn1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1CN(C)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.1 mmol) in tetrahydrofuran (4 ml) was added 5-chloro-N-methylpyridin-2-amine (128 mg, 1.14 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred for 30 min. The mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred at 80° C. for 8 hr. After cooling to room temperature, the mixture was added water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 102 mg (33%) of the title compound:
Reaction SMILES: [OH-].[Li+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([O:26]C)=[O:25])([CH3:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C)(C(=O)OC)Cc1ccccc1-3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C)(C(=O)O)Cc1ccccc1-3
Temperature: 65 °C
Yield: 33.5 %

Procedure:
Lithium hydroxide (12 mg, 0.5 mmol) was added to a solution of methyl (±)-13-cyclohexyl-6,7-dihydro-6-carbomethoxy-6-methyl-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20.0 mg, 0.045 mmol) in methanol (1.0 mL) and tetrahydrofuran (1.0 mL) in a microwave vial. The vial was sealed and the contents heated at 65° C. for 50 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and was purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (6.5 mg, 34%). ESI-MS m/z 432 (MH+) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.18-1.51 (m, 6 H) 1.62-1.83 (m, 3 H) 1.89-2.14 (m, 4 H) 2.36 (d, J=13.73 Hz, 0.5 H) 2.72 (d, J=13.43 Hz, 0.5 H) 2.89-2.98 (m, 1 H) 3.01 (d, J=13.73 Hz, 0.5 H) 3.19 (d, J=14.04 Hz, 0.5 H) 3.32 (d, J=14.65 Hz, 0.5 H) 3.90 (d, J=14.60 Hz, 0.5 H) 3.94 (d, J=17.70 Hz, 3 H) 4.31 (d, J=14.65 Hz, 0.5 H) 4.89 (d, J=14.65 Hz, 0.5 H) 7.30-7.50 (m, 4 H) 7.75 (dd, J=23.04, 8.39 Hz, 1H) 7.86 (dd, J=24.87, 8.39 Hz, 1 H) 8.11 (s, 0.5 H) 8.28 (s, 0.5 H).
Reaction SMILES: CC[OH:3].[Br:4][C:5]1[CH:6]=[C:7]([N+:13]([O-])=O)[C:8]([C:11]#[N:12])=[N:9][CH:10]=1.C(OCC)(=O)C>[Ni].CCCCCC>[NH2:13][C:7]1[C:8]([C:11]([NH2:12])=[O:3])=[N:9][CH:10]=[C:5]([Br:4])[CH:6]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Ni]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 23 %

Procedure:
To a 100 mL round bottom flask, Raney Nickel (2.5 g) and EtOH (150 mL) were added. To the same flask was added 5-bromo-3-nitropyridine-2-carbonitrile (5 g, 0.0219 mol). The reaction mass was stirred under hydrogen for 14 h at ambient temperature. The catalyst was removed by filtration. The clear filtrate was evaporated to provide the crude product. The crude was subjected to column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to provide the title compound as a light yellow solid [1.1 g, 23%]. 1H NMR (300 MHz, DMSO-d6): δ 7.89 (brs, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.40 (brs, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.04 (brs, 2H): LC-MS (ESI): Calculated mass: 215.0; Observed mass: 216.8 [M+H]+ (RT: 0.38 min).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Cl[CH2:7][C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([F:23])[CH:12]=1)[CH3:10]>O>[F:23][C:13]1[CH:12]=[C:11]([CH:9]([C:8]2[N:5]=[C:3]([NH:2][CH3:1])[S:4][CH:7]=2)[CH3:10])[CH:16]=[CH:15][C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC(N)=S
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Solvent: O
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 70.6 %

Procedure:
To N-methylthiourea (5.55 g, 61.6 mmol) in water was heated with 1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (16.50 g, 59.6 mmol) at 90° C. for 3 hr. Treatment in same manner of Example 1 to give 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (13.15 g, 71% yield): mp 129°-129.5° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH3:24])=C(Cl)[N:16]=1>>[Cl:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH3:24])=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[N:16]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc(C(F)(F)F)cc1
Product: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-trifluoromethyl-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.