Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCNC4)n3)ccc21
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCN(CCCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from 3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide and 5-chloropentyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[CH2:13]([O:17][CH2:18][CH2:19]O)[CH2:14][CH2:15][CH3:16].[OH-].[K+]>>[CH2:13]([O:17][CH2:18][CH2:19][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[C:1]([OH:12])=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: CCCCOCCO
Agent: [K+]
Agent: [OH-]
Product: CCCCOCCc1cccc(C(=O)O)c1C(=O)O
Temperature: 90 °C

Procedure:
148.1 of anhydrous phthalic acid and the molar equivalent 118.2 n of 2-butoxyethanol were added to a 500 ml glass round-bottomed flask equipped with stirring blades, thermometer and Dimroth condenser, heated while slowly stirring, and after the generated heat at about 90° C. wore off, raised to a temperature of 130° C., which was maintained for 1 hour. The mixture was subsequently cooled to 60° C. The acid value (number of mg of KOH necessary to neutralize 1 g of a sample) of the reaction solution was 226.0. Since the acid value for the case where the reaction is 100% complete is 210.7, the reaction rate was computed to be 93%.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH-](O[C:37]([CH3:39])=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:2][N:1]1[C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]=[C:37]1[CH2:39][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 72 %

Procedure:
To a solution of 2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (0.2011 g, 0.58 mmol) in dichloromethane (5.8 mL) was added 1-Methyl-1H-benoimidazole-2-carbaldehyde (0.1844 g, 1.15 mmol) and NaBH(OAc)3 (0.2462 g, 1.16 mmol), and was stirred at room temperature for four days. The organic phase was washed with NaHCO3 (2×10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (47:2:1 CH2Cl2—MeOH—NH4OH) provided 103 mg (36%) of 2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione. 1H NMR (CDCl3) δ 1.30-1.44 (m, 2H), 1.48-1.63 (m, 3H), 1.84-1.96 (m, 2H), 2.03-2.07 (m, 1H), 2.54-2.81 (m, 4H), 3.51 (t, 2H, J=7.2 Hz), 3.95 (s, 3H), 3.99-4.06 (m, 2H), 4.19 (d, 1H, J=13.5Hz), 6.94-6.98 (m, 1H), 7.13-7.21 (m, 2H), 7.24-7.29 (m, 2H), 7.63-7.68 (m, 3H), 7.74-7.78 (m, 2H), 8.40 (d, 1H, J=3.6 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14]1>C(O)C.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:13][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:15]([OH:22])=[O:14]
Reactant: O=C1OC(c2c(O)c3ccccc3oc2=O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To a solution 4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one (60 mg) in ethanol was added 10% Pd/C (10 mg) then stirred under a hydrogen balloon for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid as white solid (50 mg). MS: 295[M−H].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][CH:24]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:26][CH2:25]1
Reactant: CC1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-methylpiperidine (1.2 equiv) to give 167 (15.8 mg, M+1 395.1)
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:22]3[CH2:26][CH2:27][CH2:28][C:21]=3[S:20][C:19]=2[N:18]=[C:17]1[CH3:29]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:24](=[O:25])[C:23]4[C:22]5[CH2:26][CH2:27][CH2:28][C:21]=5[S:20][C:19]=4[N:18]=[C:17]3[CH3:29])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1nc2sc3c(c2c(=O)n1N)CCC3
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1nc2sc3c(c2c(=O)n1NC(=O)CC12CC4CC(CC(C4)C1)C2)CCC3

Procedure:
1-Adamantaneacetyl chloride (BBB-SCI) and 5-amino-6-methyl-1,2,3,5-tetrahydro-8-thia-5,7-diaza-cyclopenta[a]inden-4-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.77 (m, 14 H) 1.88-2.01 (m, 3 H) 2.03-2.19 (m, 2 H) 2.36 (s, 3 H) 2.38-2.44 (m, 2 H) 2.82-3.00 (m, 4 H) 10.82 (s, 1 H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11].[CH2:12]([O:19][C:20](=[O:27])[C:21]#[C:22][C:23]([F:26])([F:25])[F:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:19][C:20](=[O:27])/[CH:21]=[C:22](/[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11])\[C:23]([F:26])([F:25])[F:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(CCO)cc1I
Reactant: O=C(C#CC(F)(F)F)OCc1ccccc1
Solvent: CO
Product: O=C(/C=C(/Nc1ccc(CCO)cc1I)C(F)(F)F)OCc1ccccc1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
2-(4-Amino-3-iodo-phenyl)-ethanol (6.0 g, 23 mmol, 1.0 eq) was added to the solution of the 4,4,4-trifluoro-but-2-ynoic acid benzyl ester (5.7 g, 25 mmol, 1.1 eq) obtained from previous step in methanol (20 mL) at room temperature. The reaction mixture was stirred for 1 hour. After the solvent was removed, the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 9.5 g of the desired enamine as pale yellow liquid (84.0% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[O:4][CH2:5][CH2:6][N:1]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:17][CH:18]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CNCCO1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCOC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 61.5 %

Procedure:
Using N-(morpholin-2-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (120 mg, 0.341 mmol) and 3-(methoxycarbonyl)phenylboric acid (123 mg, 0.682 mmol), the same procedure was followed as in Example 2 to give 102 mg (62%) of the desired compound as a colorless powder.
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:22][N:23]([CH3:28])[CH:24](C)[CH2:25]N.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CN(C=O)C>[CH3:22][N:23]([CH3:28])[CH:24]([CH3:25])[CH2:20][N:2]1[C:12]2[C:11](=[CH:16][C:15]([I:17])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1
Reactant: CC(CN)N(C)C
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(C)N(C)C)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
(Z)-Ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (0.500 g, 1.28 mmol, Intermediate 24), N2,N2-dimethylpropane-1,2-diamine hydrochloride (0.177 g, 1.28 mmol), and potassium carbonate (0.194 g, 1.41 mmol) were combined in THF (10.0 mL). The reaction was heated at 60° C. for 2 hrs. After 2 h, DMF (5.0 mL) was added followed by potassium carbonate (0.530 g, 3.83 mmol). The reaction was heated at 90° C. for 6 h. The reaction mixture was cooled to 0° C. and 1N HCl was slowly added until pH was around 4. The resulting precipitate was filtered, washed with water and dried overnight to yield a light yellow solid (0.428 g).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[S:13][C:6]=12.O=S(Cl)[Cl:31]>>[Cl:31][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CO)cc4)sc23)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Yield: 100 %

Procedure:
The alcohol 51 (880 mg, 2.22 mmol) was suspended in SOCl2 (10 ml) and the reaction mixture was refluxed for 1 hour, cooled and carefully poured onto ice/water. A precipitate was formed which was collected by filtration, washed with additional cold water and dried under vacuum to afford the title compound 52 (919 mg, 100% yield), which was used without additional purification. MS (m/z): 415.1(100%) (M+H), 417.1 (36%) (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl.[Cl:10][C:11]1[CH:36]=[CH:35][C:14]2[O:15][C:16]3[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=3[C@@H:18]3[C@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1>CC(C)=O.C(OCC)(=O)C>[Br:1][C:36]1[C:11]([Cl:10])=[CH:12][C:13]2[N:19]3[CH2:20][CH2:21][CH2:22][C@@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C@H:18]3[C:17]3[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=3[O:15][C:14]=2[CH:35]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(Br)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 130.3 %

Procedure:
N-bromosuccinimide (9.2 mg, 0.05 mmol) and 0.5 μL of 1N HCl were added to trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (20 mg, 0.05 mmol) in 512 μL of acetone. The resulting mixture was stirred at room temperature for 30 min. The mixture was diluted with ethyl acetate, washed with saturated aq. sodium bicarbonate and water, dried (Na2SO4) and evaporated to give trans-N-(8-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide as a white solid (31 mg, 100%). Data: 1H-NMR (400 MHz, CDCl3) 1.85 (m, 4H), 2.27 (m, 2H), 3.20 (m, 1H), 3.64 (m, 1H), 4.44 (d, J=8.0, 1H), 4.65 (m, 1H), 6.26 (b, 1H), 7.02 (s, 1H), 7.10 (dt, J=8.0, 2.0, 1H), 7.16 (m, 2H), 7.30 (dt, J=8.0, 3.0, 1H), 7.35 (s, 1H). (m/z)=477 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:20][CH2:19]1)=[CH:3][C:2]([C:37]1[CH:36]=[C:35]([O:48][CH3:49])[C:34]([OH:50])=[C:33]([Cl:32])[CH:38]=1)=[CH:11][CH:10]=2)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl (trans-4-((6-bromo-3-butyrylquinolin-4-yl)amino)cyclohexyl)carbamate (49 mg, 0.10 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) to afford the desired product (36 mg, 63%) as a yellow solid. ESI MS m/z 568 [C31H38ClN3O5+H]+
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19](/[C:23](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]\S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>O1CCCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(Br)cc1Cl
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1Cl
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
To tetrahydrofuran (20 mL) at −100° C. was added tert-butyllithium (1.7M in pentane, 4.30 mL, 7.31 mmol) dropwise over 5 min. 4-Bromo-2-chloro-1-methoxybenzene (0.81 g, 3.66 mmol) dissolved in tetrahydrofuran (5 mL) was added over 10 min. The mixture was stirred for 5 min then was (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.241 g, 3.05 mmol) in tetrahydrofuran (10 mL) added over 10 min. The reaction mixture was held at −100° C. for 20 min and then slowly allowed to reach r.t. over night. Hydrogen chloride-methanol solution (14.63 mL, 18.29 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to give the title compound (570 mg, 42%). MS (ES+) m/z 445, 447 [M+1]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18]([NH2:25])[N:17]=1>CN(C=O)C.O>[CH2:7]([N:22]1[CH:21]=[N:20][C:19]2[C:23]1=[N:24][C:16]([CH3:15])=[N:17][C:18]=2[NH2:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
K2CO3 (0.26 g, 1.88 mmol) and benzyl bromide (0.5 ml, ca. 2 mmol) were added to a solution of 70 mg (0.47 mmol) of 2-methyladenine in a mixture of DMF (15 ml) and water (5 ml), and stirred at room temperature for 16 h. The solvent was evaporated under vacuum, and the residue was extracted by chloroform. The resulting organic layer was dried over MgSO4, and evaporated under vacuum. 9-Benzyl-2-methyladenine was obtained by the purification of the residue using column chromatography (CH2Cl2 :MeOH=50:1-30:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([C:18](=[CH:21]NC1C=CC=CC=1)[C:19]#[N:20])=[O:17])([O-:12])=[O:11]>C(O)C>[NH2:20][C:19]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:21][C:18]=1[C:16](=[O:17])[C:15]1[CH:29]=[CH:30][CH:31]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: Nc1c(C(=O)c2cccc([N+](=O)[O-])c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 4-fluorophenylhydrazine (2.24 g, 15.57 mmol) and 2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (4.15 g, 14.16 mmol) in ethanol (50 ml) was heated at reflux under nitrogen atmosphere. After 1 h, the reaction mixture was cooled to room temperature and stirred for an additional 3 h. The solid was filtered and dried to give 5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.5 g) as a solid.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)C=CC=CC=1.N[CH2:29]CCNC1C(C)=CC=CN=1>>[NH2:17][CH2:16][CH2:15][CH2:14][N:7]([C:8]1[CH:13]=[C:12]([CH3:29])[CH:11]=[CH:10][N:9]=1)[CH3:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Reactant: Cc1cccnc1NCCCN
Product: Cc1ccnc(N(C)CCCN)c1

Procedure:
Substituting 2-bromo-4-methylpyridine (25.8 g) for 2-bromo-3-methylpyridine and using the corresponding molar proportions of the other reagents in the method of Example 36(i) gave 2-(3-aminopropylamino)-4-methylpyridine (16.1 g), bp 120°-24° C.; 0.01-0.02 mm Hg. (ii) Substituting 2-(3-aminopropylamino)-4-methylpyridine (7.5 g) for 2-(3-aminopropylamino)-3-methylpyridine and using corresponding molar proportions of the other reagents in the method of Example 36(ii) gave 2-[N-(3-aminopropyl)-N-methylamino]-4-methylpyridine (3.53 g) as an oil. (iii) Substituting 2-[N-(3-aminopropyl)-N-methylamino]-4-methylpyridine (1.0 g) for 2-[N-(3-aminopropyl)-N-methyl amino]-3-methylpyridine and using corresponding molar proportions of the other reagents in method of Example 36(iii) gave 2-[3-[N-methyl-N-(4-methylpyrid-2-yl)amino] propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 1H2O, 0.56 g (26%) mp indeterminate (from ethanol/water).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[OH-].[Na+].[CH:24](O)=[O:25]>C(OC(=O)C)(=O)C>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:25]
Reactant: O=CO
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=CNCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88 %

Procedure:
Step 1): To a cooled solution (0°-5° C.) of 4-aminometyl-1-diphenylmethylpiperidine (3.0 g, 0.01 mol) in formic acid (7.5 ml), acetic anhydride (6 ml) was added and the reaction mixture was stirred at room temperature for 17 hours. An aqueous NaOH solution was added to adjust the mixture to pH 12 and the mixture was extracted with ether. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was recrystallized (diisopropyl ether) to give 4-(N-formylamino)methyl-1-diphenylmethylpiperidine (2.9 g, 88%); mp 125° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([CH3:19])=[CH2:18])=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1>CCOC(C)=O.C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 3 h
Yield: 89.7 %

Procedure:
2-(4-Hydroxyphenyl)-7-isopropenyl-1,3-benzoxazol-5-ol (64 mg, 0.24 mmol) was dissolved in a mixture of EtOAc (5 mL) and absolute ethanol (5 mL) and placed under an inert atmosphere with argon. To this mixture was added 10% Pd—C (25 mg). The solution was hydrogenated on a Parr apparatus at 25 psi for 3 h. The solution was filtered through celite and rinsed with ethanol. The filtrate was concentrated and the residue purified by flash chromatography (50% EtOAc/petroleum ether) to give (58 mg, 90% yield) of the product as a tan solid, m.p. 200° C.; MS m/e 270 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>OS(O)(=O)=O.O.CC(C)=O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NC1CCCCC1O)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
A mixture of CrO3 (0.70 g) in concentrated H2SO4 (0.61 mL) was diluted with H2O to the volume of 6 mL. To a solution of benzyl 2-hydroxycyclohexylcarbamate (1.60 g, 6.43 mmol) in acetone (5.4 mL) at 0° C. was added Jones Reagent (5.51 mL, 1.17 M, 6.43 mmol) dropwise over 5 min. The reaction mixture was stirred at room temperature for 1.5 h, quenched with 20% aq. K2CO3 to pH=8. The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over Na2SO4, filtered and concentrated. The resulted crude yellow oil was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-30% over 8 min, 30-45% over 10 min) to give benzyl 2-oxocyclohexylcarbamate as a colorless oil at a retention time of 8.5-11 min (1.26 g, 79% yield). HPLC: RT=2.69 min, Purity 99% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 5H, m; 5.76 ppm, 1H, s; 5.11 ppm, 2H, m; 4.27 ppm, 1H, m; 2.65 ppm, 1H, dd, J=6.60, 2.75 Hz; 2.52 ppm, 1H, m; 2.38 ppm, 1H, m; 2.13 ppm, 1H, m; 1.89 ppm, 1H, m; 1.77 ppm, 1H, m; 1.64 ppm, 1H, m; 1.42 ppm, 1H, m.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>C(O)C>[CH2:1]([O:8][CH2:9][C:10](=[N:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)[CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(COCc1ccccc1)C1CCOC1=O
Solvent: CCO
Product: O=C1OCCC1C(COCc1ccccc1)=Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 65.5 %

Procedure:
In 2.0 ml of ethanol were dissolved 1.83 g of 2-benzyloxyacetyl-γ-butyrolactone and 0.50 g of 3-aminopyrazole. To the solution, were added 60 μl of a boron trifluoride methanol complex, and the mixture was stirred for 16.5 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (elution solvent: hexane:ethyl acetate=1:1→1:2) to obtain 1.18 g (yield: 65.5%) of the intended product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C(O[CH:12]=[C:13]([CH3:16])[CH:14]=O)C>>[CH3:16][C:13]1[CH:12]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]#[N:8])[CH:14]=1
Reactant: N#Cc1cn[nH]c1N
Reactant: CCOC=C(C)C=O
Product: Cc1cnc2c(C#N)cnn2c1

Procedure:
By the procedure described in Example 2, 5.40 g of 5-amino-4-pyrazolecarbonitrile is reacted with 5.70 g of 3-ethoxy-2-methylacrolein in 25 ml of glacial acid to give the desired product as colorless prisms, mp 193°-194° C.