Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][Se:15][C:11]=2[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22](OC)=[O:23])=[CH:18][CH:17]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1.C(N1C2C=C[Se]C=2C(C2OC(CO)=CC=2)=N1)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][Se:15][C:11]=2[C:10]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)cc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Agent: OCc1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Product: OCc1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)cc1

Procedure:
Compound 67 (0.792 g, 0.002 mole) was used to replace compound 55 in the preparation of compound 57 to afford compound 69. Yield: 0.564 g (76.8%); white needle crystals; mp 158-160° C.
Reaction SMILES: [C:1]([C:3]1[C:27](F)=[CH:26][CH:25]=[CH:24][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](F)[C:16]=2[C:22]#[N:23])[C:7]=1[C:8]#[N:9])#[N:2].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.[C:37](=[O:40])([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:17]2[C:16]([C:22]#[N:23])=[C:15]([CH:20]=[CH:19][CH:18]=2)[O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:6]([O:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:27]([O:40][C:37]4[CH:34]=[CH:35][C:30]([NH2:29])=[CH:31][CH:32]=4)[C:3]=3[C:1]#[N:2])[C:7]=2[C:8]#[N:9])=[CH:32][CH:31]=1
Reactant: N#Cc1c(F)cccc1Oc1cccc(Oc2cccc(F)c2C#N)c1C#N
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1c(Oc2ccc(N)cc2)cccc1Oc1cccc(Oc2cccc(Oc3ccc(N)cc3)c2C#N)c1C#N

Procedure:
2,6-bis[3-(4-aminophenoxy)-2-cyanophenoxy]benzonitrile (p,p-3CN; 6b in FIG. 1) was prepared from 2,6-bis(2-cyano-3-fluorophenoxy)benzonitrile (2.00 g, 5.4 mmol), 4-aminophenol (1.29 g, 11.8 mmol), potassium carbonate (1.78 g, 12.9 mmol), and NMP (32 mL) using the same procedure as Example 3 to obtain 1.52 g (51.5%) of beige solid, m.p. 242.6-243.8° C. (dec.). 1H-NMR (DMSO-d6): 5.18 (s, 4H, Ar—H), 6.57-6.65 (m, 6H, Ar—H), 6.88-6.92 (m, 2H, Ar—H), 7.58-7.61 (t, 2H, Ar—H), 7.77-7.80 (t, 1H, Ar—H). Elemental analysis: Calcd.: C, 71.86; H, 3.84; N, 12.70. Found: C, 71.40; H, 4.00; N, 12.33.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(O)(C(F)(F)F)=O>CCOC(C)=O>[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[Cl:20])[C:4]=1[F:21])=[O:29]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1Cl
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3Cl)c2F)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (60 mg, 0.174 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (27.9 mg, 0.174 mmol) and HOBT (26.6 mg, 0.174 mmol) was added EDC (33.3 mg, 0.174 mmol) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(2,5-dichloro-3-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (28 mg, 0.046 mmol, 27% yield) as the TFA salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.66 (d, 1H), 7.29-7.49 (m, 2H), 6.97 (s, 1H), 4.64 (s, 2H), 2.34 (s, 3H). LC-MS (ES+) m/z 486.93, [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1Cl.ClCCl.[Cu]>[Cl:17][C:15]1[CH:16]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:12]=[C:13]([Cl:18])[CH:14]=1
Reactant: Clc1cc(Cl)cc(Br)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: Clc1cc(Cl)cc(-n2ccc3ccccc32)c1
Reaction time: 24 h
Yield: 68.1 %

Procedure:
A mixture of 5 g (43.7 mmol) of indole, 19.2 g (85.3 mmol) of 1-bromo-3,5-dichlorobenzene, 11.7 g (84.8 mmol) of potassium carbonate and 3.28 g (1.22 mmol) of copper powder in 14 mL of 1,2-dichlorobenzene was warmed at reflux. After 24 h, the mixture was cooled and diluted with dichloromethane and filtered through diatomaceous earth. The filter cake was washed with a 1:9 mixture of methanol-dichloromethane. The filtrate was pre-adsorbed onto silica gel and chromatographed on silica gel eluting with hexane. The partially purified material was placed under high vacuum to remove excess 1,2-dichlorobenzene and sublime excess 1-bromo-3,5-dichlorobenzene. A second chromatography on silica gel eluting with hexanes afforded 7.8 g (70%) of 1-(3,5-Dichlorophenyl)-1H-indole.
Reaction SMILES: [Br-:1].C([N+:9]12[CH2:15][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)C1C=CC=CC=1>C(O)C.[Pd]>[BrH:1].[N:9]12[CH2:15][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:11][CH2:10]1)[CH2:13][CH2:14]2
Reactant: CCOC(=O)C12CC[N+](Cc3ccccc3)(CC1)C2
Reactant: [Br-]
Agent: [Pd]
Solvent: CCO
Product: Br
Product: CCOC(=O)C12CCN(CC1)C2

Procedure:
A suspension of ethyl 1-benzyl-1-azoniabicyclo[2.2.1]hept-4-ylcarboxylate bromide (D16, 130 g, 0.38 mole) in ethanol (500 ml) was hydrogenated over 10% palladium on charcoal catalyst (8 g) at atmospheric temperature and pressure for 18 h. The catalyst was removed by filtering through celite, washing several times with hot ethanol, and the filtrate concentrated in vacuo to give the title compound (D17) as a crystalline white solid (80.1 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11](OC(Cl)(Cl)Cl)=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1F
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Cl)cc1F
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a stirred solution of 20.0 g (0.13 mole) of 4-chloro-2-fluoroaniline in 250 ml of toluene was added dropwise a solution of 17.2 ml (0.13 mole) of trichloromethyl chloroformate in 40 ml of toluene. Upon completion of addition the reaction mixture was heated to reflux where it stirred for 16 hours. The solvent was separated from the reaction mixture by distillation to yield 21.8 g of 4-chloro-2-fluorophenyl isocyanate as an oil. The reaction was repeated several times.
Reaction SMILES: [Br:1][C:2]1[C:7]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:6][C:5]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[C:4]([Cl:57])[C:3]=1[OH:58].Br[CH2:60][CH2:61][OH:62].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:7]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)=[CH:6][C:5]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[C:4]([Cl:57])[C:3]=1[O:58][CH2:60][CH2:61][OH:62]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(O)c2Cl)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCO)c2Cl)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
To a solution of crude compound 78 (2.67 g, 3.1 mmol) in acetone (30 mL) were added 2-bromoethanol (0.33 mL, 4.63 mmol) and K2CO3 (640 mg, 4.63 mmol) at 0° C. The mixture was stirred at 50° C. for 15 hours. The mixture was filtrated and concentrated in vacuo. The resultant was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 79 (2.68 g, 95%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13](O)=[O:14])[CH2:8][CH:7]=1.C(Cl)(=O)C([Cl:20])=O>>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([Cl:20])=[O:14])[CH2:8][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)=CCCC1=CCC(CC(=O)O)CC1
Product: CC(C)=CCCC1=CCC(CC(=O)Cl)CC1
Reaction time: 1 h

Procedure:
To a 100 mL flask containing a stirbar is added the acid 2B (R=4-Methyl-3-pentenyl) (10 g) and oxalyl chloride (8.3 mL). The reaction is stirred under a nitrogen atmosphere for one hour after gas evolution ceases. Residual oxalyl chloride is removed in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[NH:17][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[N:17]([CH3:22])[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(N2CCN(Cc3ccccc3)CC2)c2sccc21
Temperature: -30 °C

Procedure:
To a stirred solution of 3-(4-benzyl-piperazin-1-yl)-1H-thieno[3,2-c]pyrazole (318.0 g, 1.07 mol) in THF (2.5 L) was added a mixture of potassium t-butoxide (134.4 g, 1.2 mol) in THF (1.5 L) dropwise over a period of 1 hour while keeping the reaction temperature below 25° C. After complete addition, the mixture was cooled to −30° C. and MeI (65.4 mL, 1.05 mol) was added dropwise over a period of 30 minutes. The mixture is then slowly warmed to room temperature overnight. To the reaction mixture is slowly added saturated NaHCO3 (1 L). The solution is then evaporated to remove the THF and the resulting aqueous mixture is taken up in EtOAc and washed with water and brine. The EtOAc extract is dried (Na2SO4), filtered and evaporated. The viscous concentrate is filtered through a silica gel plug with 1:1 EtOAc/heptane and evaporated yielding a viscous oil that is then dried under vacuum where it solidifies and yields 326.03 g (98%) as a 12:1 ratio of regioisomers in favor of the desired product.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.C([O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:43](=[O:48])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:39][CH2:38]2)=[CH:33][C:32]=1[F:49])C1C=CC=CC=1>>[F:49][C:32]1[CH:33]=[C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:43](=[O:48])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:39][CH2:38]2)[CH:35]=[CH:36][C:31]=1[OH:30]
Reactant: CCCCC(=O)N1CCN(c2ccc(OCc3ccccc3)c(F)c2)CC1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: CCCCC(=O)N1CCN(c2ccc(O)c(F)c2)CC1
Yield: 22 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-(4-benzyloxy-3-fluorophenyl)-1-valerylpiperazine (367 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=12:1) to provide 4-(3-fluoro-4-hydroxyphenyl)-1-valerylpiperazine (61 mg).
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][Br:20])[CH3:16]>>[Br-:20].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][N+:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1)[CH3:16]
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: CCOC(CBr)OCC
Product: CCOC(C[n+]1ccc(C=Cc2ccccc2)cc1)OCC
Product: [Br-]

Procedure:
By the procedure described in Ex. 8 4-styrylpyridine and 2,2-diethoxyethyl bromide were reacted to obtain N-(2,2-diethoxyethyl)-4-styrylpyridinium bromide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[C:8]2[CH:18]=[CH:17][S:16][C:9]=2[NH:10][C:11](=[O:15])[C:12]=1[C:13]#[N:14].[O:19]1C=CC=[C:20]1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:20]([N:24]1[CH2:29][CH2:28][N:27]([C:7]2[C:8]3[CH:18]=[CH:17][S:16][C:9]=3[NH:10][C:11](=[O:15])[C:12]=2[C:13]#[N:14])[CH2:26][CH2:25]1)=[O:19]
Reactant: N#Cc1c(Cl)c2ccsc2[nH]c1=O
Reactant: c1coc(N2CCNCC2)c1
Reactant: c1ccoc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2ccsc2[nH]c1=O

Procedure:
To yield compounds of structure (III) wherein R2 is carbonitrile, R3 is furan, and R1 is as defined above, intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (50), was reacted with 1-(2-furyl)-piperazine to yield 4-[4-(furan-2-carbonyl)-piperazin-1-yl]-6-oxo-6,7-dihydro-thieno[2,3-b]-pyridine-5-carbonitrile, depicted by formula (52). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield target compounds of structure (III) with R2 as carbonitrile, R3 as furan, and R1 as defined above, as shown in Scheme 27.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][CH:21]=1.[CH:28]([C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:32]=1[NH2:33])([CH3:30])[CH3:29]>C(O)C>[CH:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:31]([CH:28]([CH3:30])[CH3:29])[C:32]=1[N:33]=[CH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:25]=1)([CH3:40])[CH3:39]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Solvent: CCO
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=Nc2c(C(C)C)cccc2C(C)C)n1

Procedure:
A mixture of 1.50 g (4.26 mmol) of 6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl) pyridine-2-carbaldehyde and 0.75 g (4.26 mmol) of 2,6-diisopropylaniline in 15 ml of dry ethanol was refluxed for 3 h. Crystals precipitated from this mixture at 0° C. were collected, washed by 3×5 ml of cold ethanol, and dried in vacuum. Yield 1.92 g (88%) of yellowish crystalline solid. Anal. calc. for C36H37N3: C, 84.50; H, 7.29; N, 8.21. Found: C, 84.73; H, 7.41; N, 8.02. 1H NMR (CDCl3): 8.35 (m, 1H, 8-H in naphthyl), 8.33 (s, 1H, CH═N), 7.98 (m, 1H, 4-H in Py), 7.92 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.89 (m, 1H, 5-H in naphthyl), 7.68 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.57 (m, 1H, 3-H in Py), 7.40-7.50 (m, 3H, 5-H in Py and 6,7-H in naphthyl), 6.98-7.17 (m, 5H, 3,4,6-H in 2,6-disopropylphenyl and 3,5-H in ortho-tolyl), 6.61 (m, 1H, 4-H in ortho-tolyl), 6.53 (m, 1H, 6-H in ortho-tolyl), 4.29 (m, 2H, CH2N), 3.93 (br. s, 1H, NH), 2.96 (sept, J=6.8 Hz, 2H, CHMe2), 2.06 (s, 3H, Me in ortho-tolyl), 1.16 (d, J=6.8 Hz, 6H, CHMeMe′), 1.15 (d, J=6.8 Hz, 6H, CHMeMe').
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl.C(OCC)(=O)C>[Si:26]([O:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[CH:6][CH:7]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: OCc1ccc(-c2cccc(Br)c2)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cccc(Br)c2)s1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(hydroxymethyl)-5-(3'-bromophenyl)thiophene (1.08 G; 4 mM) and triethylamine (1.4 mL; 10 mM) in 20 ml of methylene chloride at R.T. was added t-butyldimethylchlorosilane (1.5 g; 10 mM). This mixture was stirred overnight, diluted with 30 ml of ethyl acetate, washed with 2×15 ml of sat'd. sodium chloride solution, and dried over anhyd. magnesium sulfate. Solvent was removed to give a residue, which was purified on silica gel with ether:petroleum ether (1:20) as solvent mixture. Eluate was distilled to give 0.99 g of 2-(t-butyldimethylsilyloxymethyl)-5-(3'bromophenyl)thiophene as colorless liquid boiling at 167°-170°/~0.2 mm.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][NH2:34].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCN
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 59.8 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and 1,3-diaminopropane (3.3 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(3-aminopropylamino)-cholestan-3β-ol as a white solid (6.3 g, 60%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 20% yield.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[C:18]([C:24]([OH:26])=[O:25])=[C:19](Cl)[C:20]([Cl:22])=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C([N+]([O-])=O)C(NCC2C=CC=CC=2Cl)=C(C=1)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[C:18]([C:24]([OH:26])=[O:25])=[CH:19][C:20]([Cl:22])=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(Cl)c(Cl)c(C(=O)O)c2n1Cc1ccccc1Cl
Agent: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1NCc1ccccc1Cl
Product: CCCCc1nc2cc(Cl)cc(C(=O)O)c2n1Cc1ccccc1Cl
Yield: 89.3 %

Procedure:
The procedure of Example 1(iii and iv) was followed using 5-chloro-2-[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid (1.50 g, 4.40 mmol) in place of 5-bromo-2-[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid to give 1.48 g (89.3%) of the title compound, which was recrystallized from methanol; mp 261°-262° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:6]2[O:5][CH:4]([CH2:3][N:2]([CH3:1])[C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC1Cc2cccc(-c3ccccc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1Cc2cccc(-c3ccccc3Cl)c2O1)C(=O)OCc1ccccc1
Yield: 90.1 %

Procedure:
Treatment of (±)-[(N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.932 g, 3.4 mmol) with diisopropylethylamine (0.66 g, 5.11 mmol) and benzyl chloroformate (0.778 g, 4.08 mmol) generally according to the procedure described for Intermediate 12 provided 1.25 g (86%) of (±)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:12][C@@H:13]1[N:14]([C:2]2[C:3]3[CH:10]([CH3:11])[S:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:18]1
Reactant: CC1SCc2ncnc(Cl)c21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 120 °C
Yield: 63.4 %

Procedure:
To a solution of 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (5 g, 27 mmol) and 2-(S)-methyl-4-Boc-piperazine (5.4 g, 27 mmol) in NMP (20 mL) was added DIEA (5 mL, 29 mmol). The mixture was heated to 120° C. for 24 hours. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (6×200 mL). The organic phase was dried and concentrated to afford (3S)-tert-butyl 3-methyl-4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (6 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 8.55 (s, 1H), 4.81 (m, 1H), 4.45 (m, 1H). 4.18 (m, 3H), 3.90 (m, 1H), 3.75 (m, 1H), 3.44-3.29 (m, 2H), 2.96 (m, 1H), 1.52 (m, 12H), 1.14 (d, J=6.4 Hz, 3H). MS (APCI+) [M+H]+ 351. The residue was purified by chiral HPLC separation (OD 250×20 mm; acetonitrile, 2 mL/min). The first peak (RT=3.93 min) was (S)-tert-butyl 3-methyl-4-((R)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate and the secondary (RT=4.26 min) was (S)-tert-butyl 3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=O)[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].S(Cl)(Cl)=O.C[N:26](C=O)C.N>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([NH2:26])=[O:20])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2c(cc(C(=O)O)n2CC(F)(F)F)c1Cl
Agent: N
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: N#Cc1ccc2c(cc(C(N)=O)n2CC(F)(F)F)c1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of 4-chloro-5-cyano-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid (0.026 g, 0.086 mmol) in toluene (3 mL) was added thionyl chloride (0.01 g, 0.09 mmol) and a catalytic amount of DMF. The mixture was heated at 60° C. The reaction was followed by TLC at 30 min intervals, and additional thionyl chloride was added accordingly (an additional 0.082 g, 0.68 mmol was added). Upon cooling, a solution of NH3 in MeOH (2M, 5 mL) was added and the mixture was stirred rapidly for 5 min. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (10-80% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-MeOH-hexanes to afford the title compound as a white solid (0.017 g, 65% yield): MS (ES) m/z 302 (M+1).