Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@H:18]([OH:20])[CH3:19])[C:15]([OH:17])=O)=[CH:5][CH:4]=1)#[N:2].[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][NH:30][C:15](=[O:17])[C@H:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C@H:18]([OH:20])[CH3:19])=[O:28])=[CH:31][CH:32]=1)#[N:22]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoic acid (1.50 g, 5.55 mmol) and 4-cyanobenzohydrazide (894 mg, 5.55 mmol) in anhydrous THF (80 mL) was added 1-Hydroxybenzotriazole monohydrate (850 mg, 5.55 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (2.13 g, 11.1 mmol) at −45° C. followed by triethylamine (1.55 mL, 11.1 mmol). The reaction mixture warmed to room temperature and stirred for 24 h, then quenched with 5% aq. citric acid (300 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×150 mL), sat. aq. NaHCO3 (3×150 mL), H2O (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a light brown solid (2.12 g, 92%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.84 (s, 1H), 10.44 (s, 1H), 8.48 (d, J=8.8 Hz, 2H), 8.04-7.93 (m, 4H), 7.91 (d, J=8.2 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 5.25 (d, J=4.5 Hz, 1H), 4.32-3.97 (m, 3H), 1.32 (d, J=6.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[NH:46]1[CH2:50][CH2:49][C@@:48]2([C:58]3[CH:57]=[CH:56][N:55]=[CH:54][C:53]=3[C:52](=[O:59])[O:51]2)[CH2:47]1.C(N(CC)C(C)C)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:46]3[CH2:50][CH2:49][C:48]4([C:58]5[CH:57]=[CH:56][N:55]=[CH:54][C:53]=5[C:52](=[O:59])[O:51]4)[CH2:47]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C1O[C@]2(CCNC2)c2ccncc21
Reactant: O=C(O)C1(c2ccc(O)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 193.7 %

Procedure:
A solution of 1-(4-hydroxyphenyl)cyclopropanecarboxylic acid (0.250 g, 0.00140 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.652 g, 0.00147 mol) in N,N-dimethylformamide (2.0 mL, 0.026 mol) was stirred at rt for 10 minutes. The solution then was cooled to 0° C. and (1R)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (0.53 g, 0.0014 mol) was added to the solution followed by N,N-diisopropylethylamine (610 μL, 0.0035 mol). The resulting mixture was stirred at room temperature overnight. After work-up, 0.95 g of the crude product was obtained, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](N)([NH:11][CH3:12])[CH:6]([CH:10]=1)[C:7]([O-:9])=[O:8].C(NC1C=CC(C(O)=O)=C(N[CH2:28][C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)C=1)(=O)C.CC1OC(C=O)=CC=1>ClCCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][C:31]2[O:30][C:29]([CH3:28])=[CH:33][CH:32]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CNC1(N)C=CC(Cl)=CC1C(=O)[O-]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(NCc2ccco2)c1
Agent: Cc1ccc(C=O)o1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc(Cl)cc2C(=O)O)o1

Procedure:
Reductive amination of 5-chloro-2-amino-methylanthranilate carried out as described for compound 1 using 5-methyl furaldehyde in DCE for 4 hrs. After workup, the product was isolated by FC using 10-30% acetone/hexanes to afford a light yellow solid. The ester was subsequently taken up in THF and saponified using 1N at 60° C. for 12 hrs. The solution was cooled, acidified and the product collected as an off-white solid.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([NH2:8])[C:4]=1[CH3:9].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)(=O)C>[Cl-:1].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:2][N+:3]2[CH:7]=[CH:6][N:5]([N:8]=[CH:16][C:15]3[CH:18]=[CH:19][C:12]([N:11]([CH3:20])[CH3:10])=[CH:13][CH:14]=3)[C:4]=2[CH3:9])=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 2 h

Procedure:
0.22 g of 1,3-diamino-2-methylimidazolium chloride is dissolved in 5 ml of glacial acetic acid, whereupon the solution is treated with a solution of 0.45 g of 4-dimethylaminobenzaldehyde in 5 ml of glacial acetic acid. After stirring for 2 hours, the yellow precipitate is removed by filtration. After drying, there is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride of decomposition point 264°-266°. The mother liquor is treated with ether, to yield a second portion of the desired product. The material obtained is recrystallized from hot water. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride of decomposition point 270°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:22][O:23]C2CCCCO2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[Cl:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(Cl)cc(C)c32)cc1

Procedure:
A solution of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (4.1 g, 9.5 mmol) and TsOH.H2O (359 mg, 1.9 mmol) in EtOH (50 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated. The mixture was diluted with CH2Cl2. The organic phase was successively washed with 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, without need of further purification. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.84 (d, J=3.79 Hz, 1H), 7.59 (d, J=8.34 Hz, 2H), 7.33 (d, J=8.34 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J=3.79 Hz, 1H), 4.84 (d, J=5.81 Hz, 2H), 3.14 (t, J=5.81 Hz, 1H), 2.52 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Cl.Cl[CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:26][C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[CH:8]=1)=[O:6]
Reactant: ClCc1cscn1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cscn3)c3ccccc3c2=O)cc1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Compound 4j was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 50 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one 3a, 19 mg (0.47 mmol) of 60% sodium hydride and 40 mg (0.25 mmol) of 4-chloromethyl thiazole hydrochloride were combined in 1 mL N,N-dimethylformamide and stirred at 70° C. for 2 h. The crude product was purified by flash chromatography using 20-100% ethyl acetate in hexane yielded 54 mg of the product as white solid: LC-MSD, m/z for C22H18N2O2S [M+H]+=375.5; HPLC retention time: 2.1 min; 1H NMR (400 MHz, CDCl3): δ 2.3 (s, 3H), 2.35 (s, 3H), 5.6 (s, 2H), 7.1-7.2 (m, 2H), 7.4-7.5 (m, 1H), 7.5-7.6 (m, 2H), 7.6-7.7 (m, 2H), 8.3 (s, 1H), 8.45-8.5 (m, 1H), 8.8-8.85 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: BrCCCCBr
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1cc(Br)ccc1N1CCCC1
Yield: 17.3 %

Procedure:
In a manner similar to that of Example 18a, by reacting 40 g of 4-bromo-2-trifluoromethylphenylamine (0.167 mol) with 16.6 g of sodium hydride (0.42 mol) and 49.7 mL of 1,4-dibromobutane (0.42 mol), 8.5 g of 1-(4-bromo-2-trifluoromethylphenyl)pyrrolidine (yield=17%) are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])O[C:14](=[O:22])[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:3]1.C[N:25](C=O)C.N>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])[NH:25][C:14](=[O:22])[C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:3]1
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3ccncc3)C(=O)OC2=O)c2ccccc21
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3ccncc3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
200 mg of 3-(1-methyl-3-indolyl)-4-(4-pyridyl)furan-2,5-dione were treated with 5 ml of DMF and 5 ml of 33% aqueous ammonia. The resulting solution was heated at 140° C. for 17 hours. After cooling, the suspension was diluted with water. The product was filtered off, washed with water and dried to give 144 mg of 3-(1-methyl-3-indolyl)-4-(4-pyridyl)-1H-pyrrole-2,5-dione, m.p. 332°-334° C.
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[C:20]1[N:26]([CH3:39])[C:27](=[O:38])[C:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[CH:29][C:19]2=1)=O)=[O:11])C1C=CC=CC=1.O.CCOC(C)=O>OS(O)(=O)=O>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[C:28]1[C:27](=[O:38])[N:26]([CH3:39])[C:20]2[N:21]([CH3:25])[C:22]3[C:18]([C:19]=2[CH:29]=1)=[CH:17][C:16]([C:14]1[O:11][C:10]([CH2:9][OH:8])=[N:12][CH:13]=1)=[CH:24][CH:23]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CNC(=O)COCc4ccccc4)ccc3n(C)c21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cnc(CO)o4)ccc3n(C)c21

Procedure:
A solution of compound A 2-benzyloxy-N-{2-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2-oxoethyl}acetamide (454 mg, 0.81 mmol) in 2 ml of H2SO4 is stirred at ambient temperature for 20 h. A mixture of H2O and EtOAc is added, the green solid obtained is filtered off, the filtrate is taken up and extracted with EtOAc, and these combined organic phases are concentrated with the precipitate without drying. The product is adsorbed onto silica with a minimum amount of pyridine and purification is carried out by chromatography on a silica column, elution being carried out with EtOAc and then EtOAc/5% MeOH. The residue is taken up in MeOH and the product is filtered and washed with a minimum amount of MeOH and then of Et2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([O:28]C)[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[O:33])[C:12]=2[CH:11]=1.OC1C=CC2N(CCCN3C=CN=C3)C3C=C(C4C=CC=CC=4)C4C(=O)NC(=O)C=4C=3C=2C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[O:33])[C:12]=2[CH:11]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4OC)cc1n2CCC(=O)NCCN(C)C)C(=O)NC3=O
Agent: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCn1ccnc1
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCC(=O)NCCN(C)C
Reaction time: 2 h
Yield: 83 %

Procedure:
Reaction of methyl ether (252) prepared as described in example 212 (80 mg, 0.15 mmol) according to The procedure described in example 80, except that the reaction was performed at 0° C. for 2 hours and chromatography was performed eluting with ethyl acetate/methanol/triethylamine (1:0:0 to 3:1:trace), gave amide (260) (65 mg, 83%) as a yellow/orange powder, mp 200–205° C. 1H NMR δ [(CD3)2SO] 11.00 (br s, 1H), 9.34 (s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.87 (br s, 1H), 7.66 (s, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.44 (t, J=8.2 Hz, 1H), 7.18 (dd, J=8.2, 0.7 Hz, 1H), 7.12 (m, 2H), 4.64 (t, J=6.6 Hz, 2H), 3.68 (s, 3H), 3.05 (m, 2H), 2.56 (t, J=6.6 Hz, 2H), 2.23 (v br s, 2H), 2.15 (br s, 6H). Found: C, 58.98; H, 5.12; N, 9.59. C28H27ClN4O5.2H2O requires: C, 58.90; H, 5.47; N, 9.81.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>O1CCCC1.C(OCC)C.[Cl-].[Al+3].[Cl-].[Cl-]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([Br:16])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(=O)C(Br)C1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A solution of (4-Oxo-cyclohexyl)-carbamic acid tert-butyl ester (10 grams, 46 mmol) and aluminum chloride (0.25 grams, 2 mmol) in tetrahydrofuran (30 mL) and diethyl ether (30 mL) was cooled to 0° C., then treated with bromine (2.4 mL, 46 mmol) over a period of 30 minutes. The reaction mass was stirred for 24 hours at 0-5° C. After completion of reaction, the obtained solids were filtered and lower filtrate was concentrated under vacuum. The obtained crude was triturated with diethyl ether and the resulted solids were filtered and dried under vacuum to obtain the title compound (9.0 grams).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.Cl.[NH2:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:15]([C@H:16]1[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][CH2:17]1)[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Product: O=C1c2ccc(Br)cc2CN1[C@H]1CC[C@@H](O)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 15, Step 1 starting from methyl 4-bromo-2-(bromomethyl)benzoate and cis-4-aminocyclohexanol hydrochloride. LCMS (M+H)+=310.0/312.0.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[O:27][CH3:28])(=[O:3])[CH3:2].[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][N:38]=2)[CH2:33][CH2:32]1)[CH3:30]>C1(C)C(C)=CC=CC=1>[CH2:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[C:39]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:9]([O:27][CH3:28])[CH:10]=3)[N:38]=2)[CH2:35][CH2:36]1)[CH3:30]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CCCOC(C)=O)c(OC)c1
Reactant: CCN1CCN(c2nccc3ccccc23)CC1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(CCCOC(C)=O)c(OC)c3)cc3ccccc23)CC1
Yield: 40.8 %

Procedure:
2-(3-Acetoxypropyl)-5-tributylstannylanisole (0.92 g) and 3-bromo-1-((4-ethylpiperazin-1-yl)isoquinoline (0.37 g) were reacted in the presence of tetrakistriphenylphosphine (0.3 g) in xylene in nitrogen atmosphere for 4 hr. After cooling, the reaction solution was filtered and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.28 g of the title compound.
Reaction SMILES: C([NH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][C:22]1([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]4[O:40][C:41]5[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=5[N:43]=4)=[CH:35][CH:34]=1)[CH2:23]3)[CH2:27]2)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:48]>>[ClH:48].[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[C:36]1[CH:35]=[CH:34][C:33]([CH2:32][O:31][C:22]23[CH2:30][CH:26]4[CH2:25][CH:24]([CH2:29][CH:28]([CH2:27]4)[CH:21]2[NH2:20])[CH2:23]3)=[CH:38][CH:37]=1
Reactant: c1ccc(C(NC2C3CC4CC(C3)CC2(OCc2ccc(-c3nc5ccccc5o3)cc2)C4)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: NC1C2CC3CC(C2)CC1(OCc1ccc(-c2nc4ccccc4o2)cc1)C3
Reaction time: 2 h

Procedure:
N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]-decan-2-amine (0.88 g; 0.0014 mole) is combined with ethanolic HCl (20 ml). After 2 hours, TLC indicates the reaction is complete. The reaction mixture is evaporated to dryness and purified on a flash column, using 10% MeOH/CH2Cl2 to obtain 1-[4-(benzoxazol-2-yl)benzyloxy]-tricyclo[3.3.1.13,7 ]-decan-2-amine hydrochloride (m.p. 291°-293° C.).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[Si:33]([O:32][CH2:31][CH2:30][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CCO[Si](C)(C)C(C)(C)C)c2ncnn12
Temperature: 50 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.7 mL), potassium carbonate (0.6 g), sodium iodide (0.033 g) and N,N-dimethylformamide (15 mL) was stirred at 50° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 71%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH:3]1[C:18](=O)[CH2:19][NH:20][C:21]1[N:22]=[C:23]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:24]2=[N:25][CH:26]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH:3]1[C:18]1[N:22]2[C:23]3[CH:29]=[CH:28][N:27]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:32])=[O:31])[C:24]=3[N:25]=[CH:26][C:21]2=[N:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CN(C(=O)OCc5ccccc5)CCC4C)cnc32)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CN(C(=O)OCc5ccccc5)CCC4C)n23)cc1
Temperature: 60 °C
Yield: 77.8 %

Procedure:
To the solution of benzyl 4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)piperidine-1-carboxylate (1.2 g, 2.2 mmol) in 1,4-dioxane (15 mL) was added Lawesson's reagent (0.44 g, 1.1 mmol) and the mixture was heated at about 60° C. for about 90 min. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0-1.5% MeOH/DCM to yield benzyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate (0.93 g, 78%) as a yellow amorphous solid: LC/MS (Table 2, Method a) Rt=2.49 min; MS m/z: 544 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.C(N(CC)CC)C.Cl[C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH2:20][CH:21]=2)[N:15]=1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Reactant: Clc1nccs1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1ncc(C2=CCN(c3nccs3)CC2)nc1-c1nc2ccccc2[nH]1
Temperature: 160 °C
Yield: 28.5 %

Procedure:
A solution of 3-(1H-benzo[d]imidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (100 mg, 0.1922 mmol) in DMSO (2.000 mL) was treated with triethylamine (58.35 mg, 80.37 μL, 0.5766 mmol) and 2-chlorothiazole (27.57 mg, 0.2306 mmol) and heated in the microwave for 40 minutes at 160° C. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound (20.6 mg, 15% Yield). 1H NMR (400.0 MHz, DMSO) d 2.89 (s, 2H), 3.80 (t, J=5.7 Hz, 2H), 4.21 (d, J=2.5 Hz, 2H), 6.86 (s, 1H), 6.94-6.96 (m, 1H), 7.28-7.31 (m, 3H), 7.69 (s, 2H) and 8.41 (s, 1H) ppm; MS (ES+) 376.0
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:38])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:37])[C:19](=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:12][CH2:11]1.[CH3:45][N:46]([CH2:54][CH2:55][CH:56]=O)[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>>[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:38])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([C:19](=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH2:32][N:31]([CH2:56][CH2:55][CH2:54][N:46]([C:47]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:53])[CH3:45])[CH2:30][CH2:29]3)[CH3:37])[CH2:14][CH2:15]1
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc2c(c1)CCNC2
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc2c(c1)CCN(CCCN(C)C(=O)OC(C)(C)C)C2
Yield: 79.4 %

Procedure:
The compound (47 mg, 78.6 μmol) obtained in Example 63b and tert-butyl methyl(3-oxopropyl)carbamate (Bioorg. Med. Chem., 12, 19, 2004, 5147-5160) (18 mg, 94.3 μmol) were used to give the title compound (48 mg; yield, 79%) as a colorless oily substance according to the method described in Example 41a.