Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10](Br)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:15]=[N:14][C:5]3[NH:6][C:7]4[CH:12]=[N:11][C:10]([C:20]5[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=5)=[CH:9][C:8]=4[C:4]=3[CH:3]=2)[CH:19]=[N:18]1
Reactant: Brc1cnc2[nH]c3cnc(Br)cc3c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)cn1
Temperature: 25 °C

Procedure:
A suspension of 3,6-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (9.3 mg, 28 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17.8 mg, 85.3 μmol) and bis(triphenylphosphine)palladium(II) dichloride (1.0 mg, 14 mop in acetonitrile (0.18 mL) and 2N aqueous sodium carbonate solution was heated under microwave irradiation at 140° C. for 20 minutes. The reaction mixture was allowed to cool to ambient temperature and the resultant precipitate collected by filtration, and the solid washed sequentially with water, DCM, and 20% MeOH in DCM. The filtrate was combined, the layers separated, and the aqueous phase extracted into 20% MeOH in DCM. The combined organic phase was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 0-20% MeOH in DCM) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.01 (s, 1H), 8.83 (m, 2H), 8.78 (m, 1H), 8.39 (s, 1H), 8.21 (d, J=9.4 Hz, 2H), 7.97 (d, J=7.0 Hz, 2H), 3.98-3.91 (s, 6H). LCMS (Method D): RT=7.53 min, M+H+=330.
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[CH2:14]([NH2:16])[CH3:15].[H-].[Na+]>CS(C)=O>[CH2:14]([NH:16][C:3](=[O:13])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH3:15]
Reactant: CCN
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCNC(=O)Cc1ccc(OC)cc1

Procedure:
Using the procedure for Example 22, (4-methoxy-phenyl)-acetic acid methyl ester Compound 22a was reacted with ethylamine and sodium hydride in DMSO at room temperature to provide N-ethyl-2-(4-methoxy-phenyl)-acetamide Compound 24a. Compound 24a was reacted with borotribromide in dichloromethane to yield N-ethyl-2-(4-hydroxy-phenyl)-acetamide Compound 24b.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br>>[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: Fc1c(Cl)cccc1CBr
Product: Oc1cc(O)nc(SCc2cccc(Cl)c2F)n1

Procedure:
The subtitle compound was prepared by the method of Example 19 step i) using 2-mercaptopyrimidine-4,6-diol (20.0 g) and 3-chloro-2-fluorobenzyl bromide to afford the subtitle compound as a white solid. Yield: 36.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 0 °C
Yield: 80.9 %

Procedure:
A solution of 2-amino-5-iodobenzoic acid (14.2 g, 50 mmol) and formamidine acetate (6.75 g, 65 mmol) in ethanol (200 mL) was refluxed for 20 hours. After cooling to 0° C. the solid product was collected by filtration. Further drying in a vacuum provided 6-Iodo-4-quinazolinone (11 g, 81%) as a gray solid.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:22][CH2:21][C:17]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]([NH2:20])=[O:19])[CH2:16][CH2:15]1.[BH4-].[Na+]>CO.O>[OH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:15][CH2:16][C:17]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]([NH2:20])=[O:19])[CH2:21][CH2:22]1
Reactant: NC(=O)C1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Finely-ground 1-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)-methyl]-4-anilino isonipecotamide, hydrochloride (1:1) (5.0 g) is slurried in methanol (100 ml) and cooled in ice. To this mixture is added an aqueous solution of sodium borohydride (3.0 g) in water (25 ml). The resulting mixture is stirred for 15 hours at room temperature under nitrogen. Dilution of the reaction mixture with water (200 ml), extraction with methylene chloride, and concentration of the dried organic solution give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[Br:17][C:18]1[S:22][C:21]([C:23]2[O:24][CH:25]=[C:26]([CH2:28]Cl)[N:27]=2)=[CH:20][C:19]=1[CH3:30]>>[Br:17][C:18]1[S:22][C:21]([C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)=[CH:4][CH:3]=3)[N:27]=2)=[CH:20][C:19]=1[CH3:30]
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: Cc1cc(-c2nc(CCl)co2)sc1Br
Product: Cc1cc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)sc1Br
Yield: 93 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole to give 2-(5-bromo-4-methyl-2-thienyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 93%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 85-86° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[O:23]CC2C=CC(OC)=CC=2)[CH:12]=[CH:11][C:10]=1[N:33]1[S:37](=[O:39])(=[O:38])[N:36]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:35](=[O:46])[CH2:34]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[OH:23])[CH:12]=[CH:11][C:10]=1[N:33]1[S:37](=[O:39])(=[O:38])[N:36]([CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:35](=[O:46])[CH2:34]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COc2ccc(C)cc2Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(O)c(Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)c1

Procedure:
A solution of 5-{2-benzyloxy-4-[2-(4-methoxybenzyloxy)-5-methylbenzyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (50 mg) in 10% TFA/methylene chloride (1 mL) is stirred at RT for 2 h. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:33][C:30]([CH2:34][NH2:35])([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:35][CH2:34][C:30]23[CH2:33][N:26]([CH2:32][CH2:31]2)[CH2:27][CH2:28][CH2:29]3)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: NCC12CCCN(CC1)C2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CC1)C2
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A suspension of 4-amino-5-chloro-2-methoxybenzoic acid (1.72 g, 8.5 mmol) in anhydrous tetrahydrofuan (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.0 mmol), stirred for one hour, then degassed under a stream of nitrogen for 10 minutes. A solution of 1-azabicyclo[3.2.1]octane-5-methanamine (1.27 g, 9.0 mmol) in anhydrous tetrahydrofuran (8 mL) was added, and stirring was continued at room temperature for 18 hours and at 50° C. for one hour. The mixture was concentrated in vacuo and partitioned between toluene (100 mL) containing a little 2-propanol and saturated sodium carbonate (50 mL). The organic layer was separated and the organic solution was dried (Na2SO4), concentrated in vacuo, and triturated from cold ether. Recrystallization from acetonitrile (2 crops) afforded 1.92 g (70%) of colorless crystals; mp 185°-187° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:23])([F:24])[F:25])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and 3-fluoro-phenylhydrazine according to the method described for example 43. MS: M=431.1 (M+H)+
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([NH2:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:21]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[CH2:32][CH2:31]2)[CH2:20]1>CN(C)C=O>[NH:41]1[C:42]2[C:38](=[CH:37][C:36]([N:33]3[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C@H:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]([C:1](=[O:5])[C:2]([NH2:4])=[O:3])[CH2:20]4)[CH2:35][CH2:34]3)=[CH:44][CH:43]=2)[CH:39]=[CH:40]1
Reactant: c1ccc2c(c1)NC[C@H]2CCN1CCN(c2ccc3[nH]ccc3c2)CC1
Reactant: NC(=O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)C(=O)N1C[C@@H](CCN2CCN(c3ccc4[nH]ccc4c3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of oxalamic acid (2.35 g, 0.026 mol) and 1,1′-carbonyldiimidazole (4.66 g, 0.029 mol) in dry N,N-dimethyl formamide (50 mL) was slowly added a solution of 5-{4-[(S)-2-(2,3-dihydro-1H-indol-3-yl)-ethyl]-piperazin-1-yl}-1H-indole (8.3 g, 0.024 mol) in N,N-dimethyl formamide (75 mL). The resulting mixture was stirred at room temperature for 1 h, filtered and poured onto brine. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/heptane/triethylamine 70:25:5) to give the title compound as an oil (6.5 g). The oil was precipitated from ethyl acetate to give a powder (4.1 g). Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.[N:13]12[CH2:20][CH2:19][C:16]([C:21]([O:23]CC)=O)([CH2:17][CH2:18]1)[CH2:15][CH2:14]2>C1COCC1>[N:13]12[CH2:14][CH2:15][C:16]([C:21]([C:3]3[CH:2]=[CH:1][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[OH:23])([CH2:17][CH2:18]1)[CH2:19][CH2:20]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: Br[Mg]c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: OC(c1ccc2ccccc2c1)(c1ccc2ccccc2c1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A solution of (2-naphthalenyl)magnesiumbromide (0.5 M in THF, 6.5 mL, 3.25 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1597 g, 0.871 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.265 g, 77.3%). EI-MS m/z 394 (M+H+) Rt (1.90 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[CH:18]3)[CH:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(S)-1-(3-aminophenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (10.0 mg) in CH2Cl2 (2 mL) was added triethylamine (13 μL) and benzoyl chloride (3.5 μL). The resulting solution was stirred at room temperature for 30 min. then the volatiles removed in vacuo. The residue was purified on silica gel (2%(2M NH3 in MeOH)/CH2Cl2) then HPLC (Zorbax Rx-SIL, 70:30 hexanes:ethanol) to yield 1.8 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.41 (d, J=5.5 Hz, 1H); 7.87 (m, 2H); 7.82 (m, 2H); 7.76 (s, 1H); 7.58 (m, 2H); 7.51 (m, 2H); 7.41 (t, J=7.9 Hz, 1H); 6.80 (d, J=5.5 Hz, 1H); 1.67 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: COc1ccccc1CC(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: COc1ccccc1CC(=O)N1CC[C@@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-methoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]1(=[O:11])[CH2:10][CH2:9][CH:8]=[CH:7]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[N:1]1[N:2]([CH:8]2[CH2:9][CH2:10][C:6](=[O:11])[CH2:7]2)[N:3]=[CH:4][CH:5]=1
Reactant: c1c[nH]nn1
Reactant: O=C1C=CCC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CCC(n2nccn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2,3-triazole (3.5 g.), cyclopent-2-enone (5.0 g.), benzyltrimethylammonium hydroxide (40% w/v solution in MeOH; 2.0 ml.) and dioxan (20 ml.) was stirred at room temperature overnight. The mixture was evaporated, treated with EtOAc, washed twice with water and once with brine, dried (MgSO4), and evaporated to give unpurified 3-(1,2,3-triazol-2-yl)cyclopentanone as a pale yellow oil. The n.m.r. spectrum of the product exhibited the following resonances: 7.62 (s, 2H); 5.3 (br quintet, 1H); 3.1-1.8 (m, 6H). (solvent CDCl3)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:21]=[CH:20][N:19]=1
Reactant: OB(O)c1ccccc1F
Reactant: Clc1cc(Cl)ncn1
Solvent: COCCOC
Solvent: O
Product: Fc1ccccc1-c1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 9 h
Yield: 33.5 %

Procedure:
A reaction vessel was charged with 0.258 g of tetrakistriphenylphosphine palladium, 1.143 g of 2-fluorophenylboronic acid, and 3.153 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.106 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 9 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.519 g of 4-chloro-6-(2-fluorophenyl)pyrimidine.
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:4]([N:17]=[C:18]=[S:19])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[CH:8]=1>>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[C:6]([O:15][CH3:16])=[CH:5][C:4]=1[NH:17][C:18]([NH2:1])=[S:19]
Reactant: COc1cc(N=C=S)c(F)cc1-n1cnc(C)n1
Reactant: N
Product: COc1cc(NC(N)=S)c(F)cc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
Step B (4): Methanolic ammonia (1.0 M, 25 mL, 25 mmol) was added to a flask charged with 1-(5-fluoro-4-isothiocyanato-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (870 mg, 3.29 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated in vacuo. The resulting solid was dried under high vacuum to afford 1-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (930 mg, 100% yield). LC-MS (M+H)+ 282.1. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H) 7.88 (d, J=6.41 Hz, 1 H) 7.57 (d, J=10.99 Hz, 1 H) 3.86 (s, 3 H) 2.36 (s, 3 H).
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:9][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:6]1=O)C.[O-]CC.[Na+].S(O)(O)(=O)=O.[CH3:39][S:40][C:41](=[NH:43])[NH2:42]>C(O)C>[CH3:39][S:40][C:41]1[N:42]=[CH:4][C:5]2[CH2:9][N:8]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][C:6]=2[N:43]=1
Reactant: CSC(=N)N
Reactant: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1ncc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.83 g (12.63 mmol) of 4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one in anhydrous ethanol (50 mL) was added sodium ethoxide (11.8 mL, 21% in ethanol). After stirring for 5 min, 3.51 g (25.25 mmol) of 2-methyl-2-thiopseudourea sulfate was aided and the reaction mixture heated at reflux temperature for 1 h. The mixture was cooled to ambient temperature and 3.51 g (25.25 mmol) of 2-methyl-2-thiopseudourea sulfate was added followed by 11.8 mL (21% in ethanol) of sodium ethoxide. The reaction mixture was refluxed for 1 h and cooled to ambient temperature. This process was repeated two additional times at which point the reaction mixture was evaporated in vacuo, diluted with 200 mL of a 1:1 mixture of ethyl acetate and saturated aqueous brine. The layers were separated and the aqueous phase extracted with three 100-mL portions of ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was chromatographed on a Biotage® system (silica gel, 0 to 25% ethyl acetate/hexanes gradient) to yield the title compound as a white solid. LC/MS=410.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])=[O:28]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3 from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione, product of example 1 step D), and 3,3-dimethyl-butyryl chloride. MS (ESI): 427.1 (MH+).
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11](C(O)=O)[CH2:12][CH2:13][CH3:14]>C(#N)C>[C:7]([C:3]1[NH:1][C:11]([CH2:12][CH2:13][CH3:14])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCCC(N)C(=O)O
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CCCc1nc(C)c(C(C)=O)[nH]1
Reaction time: 23.7 h
Yield: 32.3 %

Procedure:
An acetonitrile (250 ml) mixture of 3-oximino-2,4-pentanedione (40 g, 0.31 moles) and d,l-norvaline (43.55 g, 0.372 moles) was heated to reflux under nitrogen. After 23.7 h the reaction mixture was allowed to cool, then suction filtered. The residue was washed with acetonitrile and the combined filtrates concentrated in vacuo. After dissolving the resulting oil in ethyl acetate (100 ml), it was washed with three 40 ml portions of 5% aqueous sodium hydroxide solution. The combined organic extracts were dried over anhydrous potassium carbonate and then concentrated in vacuo to give 0.1 moles (43.5% yield based on recovered d,l-norvaline) of 5-acetyl-4-methyl-2-propylimidazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[CH2:24]>C(#N)C>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH:23]=[CH2:22]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Methyl 3-hydroxy-4-nitro-benzoate 1b (7 g, 35.50 mmol) was dissolved in 100 mL of anhydrous acetonitrile followed by the addition of potassium carbonate (14.70 g, 106.50 mmol) and 3-bromopropene (6.2 mL, 71 mmol) successively, the reaction mixture was heated to reflux for 3 hours with stirring. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was added with 150 mL of ethyl acetate, washed with water (100 mL×3) and saturated sodium chloride solution (100 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 3-allyloxy-4-nitro-benzoate 1c (7.45 g, yield: 89.0%) as a yellow solid.