Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[N+](=[CH2:21])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>CCOCC>[CH3:21][O:12][C:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:13])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[Cl:1]
Reactant: C=[N+]=[N-]
Reactant: O=C1CCCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Product: COC1=C(C(=O)c2ccc(Cl)cc2Cl)C(=O)CCC1
Yield: 35 %

Procedure:
2-(2,4-Dichlorobenzoyl)cyclohexane-1,3-dione (2.85 g, 0.01 mol) was stirred as a suspension in 25 ml anhydrous ether. Diazomethane, generated from Diazald® (50 ml, 0.02 mol) was added at 0° at a rate slow enough to control effervescence. The resulting solution was stirred for an hour and the solvent allowed to evaporated under a stream of nitrogen in a beaker. The resulting oil was dissolved in ether and washed twice with saturated aqueous K2CO3. Evaporation of the solvent under reduced pressure yielded a solid (1.0 g, 35%, m.p. 81°-86° C.), the nuclear magnetic, infrared and mass spectra of which were consistent with the structure.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH2:12][CH3:13])[C:4]=2[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl.CO>[CH2:12]([N:11]1[C:4]2[CH:3]=[C:2]([N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[F:14])[CH2:26][CH2:25]3)[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10]1)[CH3:13]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCn1ccc2c(=O)[nH]c(Cl)cc21
Solvent: ClCCl
Solvent: CO
Product: CCn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cc21
Temperature: 140 °C
Yield: 65.3 %

Procedure:
A mixture of 6-chloro-1-ethyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (16 mg, 0.081 mmol) and 1-(2-fluorophenyl)piperazine (160 mg, 0.888 mmol) was heated at 140° C. in a sealed tube for 5 h. Flash chromatography (20/1 methylene chloride/methanol) afforded 1-ethyl-6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.28 Hz, 3H) 3.1 (d, J=4.77 Hz, 4H) 3.2 (d, J=4.77 Hz, 4H) 4.0 (q, J=7.19 Hz, 2H) 5.8 (s, 1H) 6.3 (d, J=3.01 Hz, 1H) 6.9 (d, J=3.01 Hz, 1H) 7.1-7.2 (m, 3H) 10.6 (s, 1H). LC-MS calcd. for C19H22FN4O [(M+H)+] 341, obsd. 341.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:5]([NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=O.S(Cl)(Cl)=O>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[N:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(C(=O)NC(C)(C)CO)cc1Br
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C2=NC(C)(C)CO2)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
3-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-4-methylbenzamide (1.7 g, 6.04 mmol, 1.0 eq) was treated with thionyl chloride (0.9 mL, 12.08 mmol, 2.0 eq) and the neat reaction mixture was stirred at room temperature for 12 h. The mixture is diluted with diethyl ether (50 mL) and the precipitated solid was filtered and washed with diethyl ether (20 mL). The solid collected was dissolved in sodium hydroxide solution (1N, 15 mL) and extracted with diethyl ether (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford the 1.0 g of the desired title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.12 (d, J=1.0 Hz, 1H), 7.75 (dd, J=1.0, 8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.09 (s, 2H), 2.42 (s, 3H), 1.37 (s, 6H); ESI-MS (m/z) 268, 270 [(MH)+, Br79,81].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[S:8][C:5]2=[N:6][CH:7]=1.[Br:20]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CBr)cnc2s1
Temperature: 25 °C
Yield: 106.8 %

Procedure:
6-Methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (2.9 g, 10.7 mmol), N-bromosuccinimide (NBS, 1.91 g, 10.7 mmol), CCl4 (200 mL) and benzoyl peroxide (0.021 g) were added into a three-neck flask (500 mL) under argon. The resulting yellow mixture was refluxed for 2 h. Additional NBS (1.91 g) and benzoyl peroxide (0.021 g) were added. Two hours later, more NBS (0.95 g) and benzoyl peroxide (0.021 g) were added and the mixture was continually refluxed for 3 h. The mixture was then cooled to room temperature. The solution was transferred into another flask and concentrated in vacuo to afford crude 6-(bromomethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (4.0 g), which was directly used for next step.
Reaction SMILES: ClC(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Br-:11].[Na+].CO.O.[CH3:16][N:17]([CH3:20])[CH:18]=[O:19]>>[Br-:11].[C:5]1([C:18]([N:17]([CH3:20])[CH3:16])=[O:19])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Phenyl N,N-dimethylformamide bromide was prepared by dropwise addition of phenyl chloroformate (6.5 ml; 50 mmol) to a stirred solution of sodium bromide (5.14 g; 50 mmol) in dimethylformamide at 0°-5° C. Sodium chloride precipitated, and the resulting suspension was stirred at 0°-5° C. for 4 hours and then at room temperature overnight. The mixture was cooled to 0° C. and 16-deacetoxy-16β-(acetylthio)fusidic acid acetoxymethyl ester (6.07 g; 10 mmol) was added with stirring. After stirring at 0°-5° C. for 4 hours, the mixture was left at room temperature for a further 4 days. On dilution of the stirred reaction mixture with methanol-water 1:1 (75 ml) an oily product precipitated, which was washed repeatedly by decantation with methanol-water 1:1 and finally taken up in ether, dried, and evaporated in vacuo. The amorphous residue thus obtained was purified by dry column chromatography on silica gel (petroleum ether-ethyl acetate 85:15) to give the desired compound as a colourless foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH:21]=[CH2:22].[Cl-].[NH4+]>CCOCC.O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:17]([OH:18])[CH2:22][CH:21]=[CH2:20])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C=O)Cc1ccccc1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: C=CCC(O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
N-((1R)-1-Formyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (6.0 g, 20.0 mmol) was dissolved in ether (150 mL). The solution was cooled to -78° C. and allylmagnesium bromide (22 mL of a 1.0 M solution in ether, 22 mmol) was added dropwise. After addition, the solution was warmed to room temp. It was given onto 10% ammonium chloride solution in water (200 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed with satd. sodium hydrogencarbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (260 g) with ethyl acetate/heptane 1:1 to give 4.00 g of N-((1R)-1-benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12]C(=O)OC(C)(C)C)[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])[C:6]2[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:5]1=2)(=[O:3])[CH3:2].[ClH:40]>O1CCOCC1.CCOCC>[ClH:40].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH2:12])[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])[C:6]2[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Yield: 78 %

Procedure:
A rt solution of tert-butyl(3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (316 mg, 598 μmol) in 4 M HCl in dioxane (2.99 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-5-acetyl-3-amino-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (216 mg, 78%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([OH:24])=O)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC#N
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1CC1CCCC1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1CC1CCCC1

Procedure:
Following the procedure of Example 9, 2-[4-(3-cyclopentylmethyl-4-methoxyphenyl)piperidin-1-yl]-2-oxo-acetic acid (2.2 mmol, 0.750 g), oxalyl chloride (2.42 mmol, 1.21 mL; 2M solution in CH2Cl2), DMF (4 drops), and saturated NH3 /CH3CN (22 mL) in dry toluene (22 mL) afforded a solid which was purified by flash chromatography (SiO2 : 40% EtOAc/hexane) to give the title compound as a white solid, mp=117°-118° C. (1.1 mmol, 0.388 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:8]2[CH:17]=[CH:18][O:19][C:7]=2[CH:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C1C(=O)N([Br:50])C(=O)C1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C:8]2[CH:17]=[C:18]([Br:50])[O:19][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2occc2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc2oc(Br)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 4-tert-butoxycarbonyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester (100 mg, 0.38 mmol) in DCM (1 mL) was added a solution of TBAF in THF (1.0 M, 0.57 ml, 0.57 mmol) followed by the addition of NBS (87 mg, 0.49 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (10 mL), washed with 10 mL of water and then with 10 mL of brine and dried with Na2SO4. The solid was removed by filtration. The filtrate was concentrated by evaporation. The crude product was purified by chromatography (0-20% EtOAc in hexane) to give 85 mg of 4-tert-butoxycarbonyl-2-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester (85 mg, 65%). 1H NMR (400 MHz, CDCl3) δ (ppm) 6.81 (s, 1H), 6.61 (s, 1H), 3.83 (s, 3H), 1.59 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCN[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 80 °C
Yield: 63.6 %

Procedure:
Prepared using General Procedure 6. To the solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (90.0 mg, 0.25 mmol) and K2CO3 (103.5 mg, 0.75 mmol) was added methyl 3-bromopropanoate (41.8 mg, 0.25 mmol). The reaction was heated to 80° C. for 30 min and repeated four time at 80° C. for 30 min with additional methyl 3-bromopropanoate (41.8 mg, 0.25 mmol) added each time. The solvent was evaporated, and the residues partitioned between EA and water. The organic layer was collected, dried over MgSO4, and purified by chromatography (MeOH/DCM with 0.025% TEA) to give 71 mg (63%) of (R)-methyl 3-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)propanoate as a solid. LCMS-ESI (m/z) calculated for C25H26N4O4: 446.5. found 447.2 [M+H]+, tR=2.61 min. 1H NMR (400 MHz, CDCl3) □δ 8.40 (d, J=2.1, 1H), 8.31 (dd, J=8.9, 2.2, 1H), 8.04 (d, J=7.6, 1H), 7.49 (d, J=7.5, 1H), 7.35 (t, J=7.6, 1H), 7.09 (d, J=9.0, 1H), 4.77 (dt, J=12.2, 6.1, 1H), 4.31 (t, J=6.8, 1H), 3.73-3.58 (m, 3H), 3.43 (ddd, J=17.4, 8.7, 4.6, 1H), 3.24-3.08 (m, 1H), 3.04-2.85 (m, 2H), 2.56 (t, J=6.5, 2H), 2.47 (dtd, J=12.8, 8.4, 4.7, 1H), 1.99-1.82 (m, 1H), 1.54-1.32 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.C(N(CC)CC)C.Cl[C:31](=[O:42])[CH:32]([P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[F:33]>CN(C=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:31](=[O:42])[CH:32]([P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[F:33])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: CCOP(=O)(OCC)C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-amino-4-(3-chloro-4-fluorophenylamino)-7-methoxy-quinazoline (1.0 eq.) and triethylamine (1.5 eq.) were dissolved in DMF (10 ml), and the mixture was stirred at 0° C. for 30 min. A solution of diethyl (2-chloro-1-fluoro-2-oxoethyl)phosphonate (1.5 eq.) in DMF (5 ml) was added dropwise slowly into the mixture mentioned above, and stirred overnight at room temperature. After the reaction finished, the mixture was quenched with saturated NaHCO3, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, then the crude product was purified by column chromatography (mobile phase 40:1 DCM/MeOH) and a light yellow solid of diethyl (2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-quinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate was given. (50% yield).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5](=[O:19])[CH:4]=1)[NH2:2].[CH3:20][N:21]=[C:22]=S.CO>CN(C=O)C>[CH3:20][NH:21][C:22]1[C:4]2[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[C:7](=[O:15])[N:8]([CH2:9][C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2cccs2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccs2)c1=O
Reaction time: 12 h

Procedure:
A solution of 6-hydrazino-3-propyl-1-(2-thienylmethyl)uracil (1.8 g, 6.4 mM) and methyl isothiocyanate (1.36 ml, 20 mM) in DMF (30 ml) was stirred at 60° C. for 5 hours and then at 110° C. for 12 hours. To the solution was added methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless crystals (0.9 g, 44%), m.p. >300° C.
Reaction SMILES: C([N:3]=[C:4]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#N.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:20][C@H:7]1[C@H:6]([NH:5][C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[NH:3])[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]1([CH3:18])[CH3:19])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccccc2)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(=N)Nc2ccccc2)c2cc(C#N)ccc2OC1(C)C
Yield: 112.4 %

Procedure:
The solution of the title compound from Example 3 (2.52 g, 6.98 mmoles) and acetic anhydride (1.0 g, 9.8 mmoles) in pyridine (25 ml) was stirred for 60 hours at room temperature. The crude reaction mixture was partitioned between ethyl acetate and 5% aqueous hydrogen chloride. The organic layer was washed with distilled water, saturated sodium hydrogen carbonate solution, saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was recovered under vacuum to obtain 2.97 g of a white solid. The crude reaction product was recrystallized from ethanol in two crops to obtain 2.24 g of the title compound as a pure white solid, m.p. 239°-240° C. 1H NMR (DMSO-d6) δ 9.36 (s, 1H), 7.63 (m, 3H), 7.35 (m, 2H), 7.20 (m, 3H), 6.97 (d, J=8.80 Hz, 1H), 5.23 (m, 2H), 2.17 (s, 3H), 1.34 (s, 3H), 1.25 (s, 3H). 13C NMR (DMSO-d6) δ 169.69, 158.69, 155.75, 136.95, 132.94, 132.66, 129.03, 125.28, 124.25, 123.79, 118.86, 118.09, 116.62, 103.31, 78.43, 72.07, 49.49, 25.85, 20.67, 19.54.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:22])[F:23])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (70 mg, 0.44 mmol), 4-hydroxy-3-(trifluoromethyl)benzonitrile (91 mg, 0.49 mmol), K2 CO3 (92 mg, 0.66 mmol) in DMF (2 mL) was stirred at 50° C. overnight. Water (4 mL) was added and a precipitate was formed. The solid was filtered-off and it was triturated with MeOH to give the title compound (85 mg) as a brownish solid.
Reaction SMILES: C([O:3][C:4]([C@@:6]1([CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)=O)[CH2:7]1)=O)C.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[O:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15][C@@H:14]1[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@:6]([CH2:4][OH:3])([CH3:24])[CH2:7]1
Reactant: CCOC(=O)[C@@]1(C)CCCN(C(=O)[C@H]2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]1(CO)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of (S)-1-((R)-2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylic acid ethyl ester (27.7 g, 83.1 mmol) and THF (150 ml) was added to a cooled (0° C.) mixture of dry THF (150 ml) and LiAlH4 (10 g, 264 mmol). The reaction mixture was refluxed for 2 h, after which it was cooled to RT and water was added. The mixture was extracted twice with EtOAc and dried with Na2SO4. Solvent was evaporated to give 21.93 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[N:14][C:15]=2[NH:17][C@H:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=2)[CH2:19]O)[N:10]=[C:9]1[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=[O:36]>>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][N:14]3[C:13](=[O:36])[NH:12][C:11]=2[N:10]=[C:9]1[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](Cc1ccc(F)cc1)Nc1nc(Cl)nc2nc(C3CCCC3)n(Cc3ccccc3)c12
Reactant: O=S(Cl)Cl
Product: O=C1Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12

Procedure:
To Compound C3 obtained in Reference Example 38 was added thionyl chloride, and a cyclized compound was obtained in a manner similar to that in Example 66. From the resulting cyclized compound, a hydrolyzed compound was obtained in a manner similar to the method by which Compound 77a was obtained from the Compound 66 in Example 77. From the resulting hydrolyzed compound (590 mg, 1.33 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (400 μL, 2.65 mmol, 2.0 equivalents), an adduct (0.56 g, 74%) was obtained in a manner similar to that in Example 79, and the residue was dissolved in methanol (10 mL). To the mixture was added p-toluenesulfonic acid monohydrate and the mixture was stirred with heating at 60° C. for 2 hours. The reaction solution was concentrated and directly purified by silica gel column chromatography (chloroform:methanol=98:2 to 97:3). Then, the title compound in the free form was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. To the resulting free compound were added a 4 mol/L solution of hydrogen chloride in dioxane (2 mL) and methanol (2 mL), the mixture was concentrated, and the residue was crystallized from acetone and diethyl ether to obtain the title compound (210 mg, 49%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][C:27]=2[CH3:28])[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1ccsc1-c1nc(CCl)co1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Cc1ccsc1-c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3-methyl-2-thienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-methyl-2-thienyl)oxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 72-73° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[NH2:16])=[CH:9][CH:8]=1.[CH:20]1([CH2:26][CH:27]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[CH2:15][C@H:14]2[NH:16][CH2:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:11][CH:12]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2cccc(Br)c2)cc1
Reactant: O=CCC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1cccc(COc2ccc([C@@H]3C[C@H]3NCCC3CCCCC3)cc2)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 18.8 %

Procedure:
To a solution of (Trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropanamine (2 g, 6.2 mmol) and 2-cyclohexylacetaldehyde (790 mg, 6.2 mmol) in DCE (20 mL) sodium triacetoxy borohydrate (2.3 g, 2 equiv) was added slowly at 0° C. and stirred for 20 h. After completion, the reaction mixture was evaporated. The residue was dissolved in Methanol (15 mL) and NaBH4 (627 mg, 3 equiv) was added slowly at 0° C. to the reaction mixture and stirred for 3 h. After completion, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by flash column chromatography by using EtOAc: Pet ether to get (Trans)-2-(4-(3-bromobenzyloxy) phenyl)-N-(2-cyclohexylethyl)cyclopropane amine (500 mg, 21%) as a pale yellow liquid.