Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[S:12][C:13]2[C:14](=[C:16]([C:20](Cl)=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:15]=1.[NH2:23][CH2:24][C@@H:25]1[CH2:30][C@H:29]2[C@H:27]([CH2:28]2)[N:26]1[C:31]([C:33]1[N:34]=[C:35]([CH3:45])[S:36][C:37]=1[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)=[O:32]>C(#N)C>[CH3:45][C:35]1[S:36][C:37]([C:38]2[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=2)=[C:33]([C:31]([N:26]2[C@H:25]([CH2:24][NH:23][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:13]4[S:12][C:11]([Cl:10])=[N:15][C:14]=34)=[O:21])[CH2:30][C@H:29]3[C@@H:27]2[CH2:28]3)=[O:32])[N:34]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c1
Reactant: O=C(Cl)c1cccc2sc(Cl)nc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4sc(Cl)nc34)C[C@@H]3C[C@@H]32)c1
Reaction time: 0.5 h

Procedure:
DIPEA (0.61 mmol) and 2-chloro-benzothiazole-4-carbonyl chloride (0.31 mmol) are added successively to a solution of ((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (0.31 mmol) in acetonitrile (1.0 mL). The mixture is stirred for 30 min and purified by prep. HPLC to give the desored product. LC-MS (acidic): tR=1.06 min; [M+H]+=523.0.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[C:9]([C:13]1[CH:50]=[CH:49][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH:29]3[C@H:33]4[O:34]C(C)(C)[O:36][C@H:32]4[C@H:31]([N:39]4[C:43]5[N:44]=[CH:45][N:46]=[C:47]([NH2:48])[C:42]=5[CH:41]=[CH:40]4)[CH2:30]3)[CH:25]([CH3:27])[CH3:26])=[N:19][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[NH2:48][C:47]1[C:42]2[CH:41]=[CH:40][N:39]([C@@H:31]3[CH2:30][CH:29]([CH2:28][N:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:18]4[NH:17][C:16]5[CH:49]=[CH:50][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][C:15]=5[N:19]=4)[CH:25]([CH3:27])[CH3:26])[C@@H:33]([OH:34])[C@H:32]3[OH:36])[C:43]=2[N:44]=[CH:45][N:46]=1
Reactant: CC(C)N(CCCCc1nc2cc(C(C)(C)C)ccc2[nH]1)CC1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCCCc1nc2cc(C(C)(C)C)ccc2[nH]1)CC1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
TFA (0.75 ml) followed by water (0.1 ml) was added to a solution of 7-[(3aS,4R,6aR)-6-({[4-(5-tert-butyl-1H-1,3-benzodiazol-2-yl)butyl](propan-2-yl)amino}methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in DCM (1.5 ml) and stirred at 50° C. for 2 hours. The reaction mixture was then evaporated in vacuo. MeOH (2 ml) was added to the residue and cooled to 0° C. This was basified with 7N ammonia in MeOH (3 ml) and then evaporated to dryness. The product was filtered though a short silica gel column, eluting with 7N ammonia in MeOH:DCM (5/95-1/9). This gave separation of two products plus a mixture of both. The mixed fractions were combined and purified on a prep. TLC plate, eluting twice with 7N ammonia in MeOH:DCM (1:9) to give a white solid (39 mg, 56%); MS (ESI+) for C30H43N7O2. m/z 534.48 [M+H]+; HPLC purity 98% (ret. time, 4.68 min); 1H NMR (250 MHz, MeOD) δ ppm 8.05 (1H, s), 7.48 (1H, s), 7.34-7.43 (1H, m), 7.22-7.31 (1H, m), 7.17 (1H, d, J=3.50 Hz), 6.59 (1H, d, J=3.50 Hz), 4.77-4.90 (1H, m), 4.29 (1H, dd, J=7.08, 5.86 Hz), 3.95 (1H, t, J=5.33 Hz), 3.09 (1H, s), 2.91 (2H, t, J=7.39 Hz), 2.64-2.78 (1H, m), 2.44-2.63 (3H, m), 2.14-2.41 (2H, m), 1.75-1.98 (2H, m), 1.48-1.68 (3H, m), 1.35 (9H, s), 1.04 (6H, dd, J=12.33, 6.55 Hz).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([NH2:20])=O)=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)Cl>CN(C=O)C>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]#[N:20])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C(N)=O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCn1c(C#N)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Yield: 109.7 %

Procedure:
A solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxamide (300 mg) in anhydrous DMF (7 ml) at 0° C. was treated dropwise with POCl3 (237 uL). The ice-bath was removed and after 2 hours the mixture was partitioned between water and Et2O. The aqueous layer was re-extracted with Et2O and the combined extracts separated, washed with water (×2), brine, then dried (MgSO4) and concentrated, giving a yellow oil (312 mg). The oil was taken up in cyclohexane and purified by SPE (Si, 10 g) eluting with EtOAc/cyclohexane mixtures. Concentration of the product fractions gave the title compound as a colourless oil (150 mg, 53%); m/z. 330.3[MH+].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]#[N:23])[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCc1cccc(OCc2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
LAH (0.615 g, 0.0162 mol, 3.0 eq) was dissolved in THF (20 ml), and to this solution was added dropwise a THF solution (20 ml) of (3-benzyloxyphenyl)-acetonitrile (1.2 g, 0.0054 mol, 1.0 eq) under ice-cooling. After the completion of the dropwise addition, the mixture was refluxed under heating for 3 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium sulfate solution (about 3040 ml) was added under ice-cooling. After filtration through Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform/methanol=10/1) to give 2-(3-benzyloxyphenyl)ethylamine (0.434 g, 35.3%) as a pale-yellow amorphous.
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[NH2:8][C:9]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)OCc2ccccc2)CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(CC(=O)O)CCCC1
Reaction time: 1 h

Procedure:
A mixture of benzyl 2-(1-(tert-butoxycarbonylamino)cyclopentyl)acetate (82 mg, 0.246 mmol) and HCl in 1,4-dioxane (1230 μl, 4.92 mmol) was allowed to stir for 1 hour. The reaction mixture was concentrated to give 2-(1-aminocyclopentyl)acetate hydrochloride (66 mg); 1H NMR (400 MHz, CDCl3) δ ppm 1.65-1.68 (m, 4H) 1.98-2.08 (m, 2H) 2.19-2.26 (m, 2H) 2.94 (s, 2H) 5.17 (s, 2H) 7.31-7.39 (m, 5H) 8.65 (br s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:15]
Reactant: Nc1ncc(Cl)cn1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ncc(Cl)cn1

Procedure:
The method described in Referential Example 242 was performed by use of 2-amino-5-chloropyrimidine and methyl chlorooxoacetate, whereby the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:10]1C=N[N:12]=[N:11]1>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:7]2[N:10]=[N:11][NH:12][N:8]=2)[CH:9]=1
Reactant: c1nnn[nH]1
Reactant: N#Cc1cncc(Br)c1
Product: Brc1cncc(-c2nn[nH]n2)c1

Procedure:
5-Bromo-nicotinonitrile (10.0 g, 55 mmol) was converted to the corresponding tetrazole (10.8 g, 75%) using the reaction conditions previously described in Step (a) of Example 1. 1H NMR (DMSO-d6) δ 9.17 (s, 1H), 8.89 (2, 1H), 8.59 (s, 1H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([O:35]CC4C=CC=CC=4)=[O:34])[CH:27]=[CH:26]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Pd].O1CCOCC1.C(O)(=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=[CH:26]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: [H][H]
Reactant: COC(=O)COc1ccc(-c2ccc3cc(C(=O)OCc4ccccc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 82.4 %

Procedure:
4.24 g (7.58 mmol) of the diester obtained in Example 4 in solution in the dioxane/acetic acid mixture (99/1) are treated with 800 mg of Pd-C (10%) at a pressure of 7 bar of hydrogen at 40° C. for 6 h. The reaction medium is then filtered on celite, evaporated, washed with water and recrystallized from the acetate/tetrahydrofuran mixture. 2.94 g (82%) of a solid are isolated, which solid melts at 283°-285° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(N(CC)CC)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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:12]#[C:11][CH2:10][CH2:9][OH:13])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,4-Dicloropyrimidine (4.47 g, 0.03M) was dissolved in triethylamine (250 ml) under argon. (Ph3P)2PdCl2 (420 mg, 0.006M, CuI (28 mg, 0.00015M) and 3-butyn-1-ol (2.36 ml, 0.03M) were added and the mixture was stirred at ambient temperature for 18 hrs. After evaporation to dryness, water (250 ml), was added and extracted with dichloromethane. The combined organic phases were dried and evaporated to dryness. The residual oil was chromatographed, eluting with iso-hexane/ethyl acetate 1:1 to yield 4-(2 chloro-4-pyrimidyl)-3-butyn-1-ol as an oil (3.3 g) NMR (CDCl3) d, 8.5, (d, 1H); 7.3, (d, 1H); 3.9, (t, 2H); 2.8, (m, 2H); 1.6, (s, 1H). Mass Spec found MH+ 183. This material was hydrogenated as described above, but in the presence of 1 equivalent of triethylamine, to give the required saturated alcohol which was oxidised using the previously described Swem oxidation to give the required 4-(4-pyrimidyl)-butan-1-al. NMR CDCl3 d, 9.8, (s, 1H); 9.1; (s, 1H); 8.5, (d, 1H); 7.1, (d, 1H); 2.8, (t, 2H); 2.5, (t, 2H); 2.1, (m, 2H). Mass spec found MH− 149. 3-(5-fluoropyrimidin-2-yl)propanal. To a stirred solution of (E)-1-ethoxy-3-(5-fluoropyrimidin-2-yl)prop-2-enyl ethyl ether and (Z)-1-ethoxy-3-(5-fluoropyrimidin-2-yl)prop-2-enyl ethyl ether (9.7 g, 43 mmol) in dry ethanol (100 ml) at room temperature under an atmosphere of argon, was added 10% palladium on activated charcoal (1.0 g). The reaction flask was then evacuated and filled with hydrogen gas. The mixture was then stirred for 18 hours at room temperature. The reaction was then filtered through a pad of celite and evaporated under reduced pressure to give a yellow oil (8.7 g, 89%). To a solution of this oil (15 g, 66 mmol) in THF (200 ml) at room temperature was added an aqueous solution of hydrochloric acid (36 ml of a 2M solution, 72 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was then diluted with ethyl acetate (100 ml) and the pH of the mixture brought to pH=9 by the addition of aqueous sodium hydrogen carbonate solution (saturated, 100 ml). The layers were then separated and the aqueous phase extracted with ethyl acetate (3×100 ml). The combined organic extracts were then dried (Na2SO4), filtered and evaporated under reduced pressure to give 3-(5-fluoropyrimidin-2-yl)propanal (16 g) which was used without further purification. 1H NMR (CDCl3): 9.90 (s, 1 H), 8.50 (s, 2 H), 3.33 (dd, 2 H, J=6.9, 6.9 Hz), 3.00 (dd, 2 H, J=6.9, 6.9 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[OH-].[Na+].[CH2:23]([OH:26])[CH2:24][CH3:25]>>[CH2:23]([O:26][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[CH2:24][CH3:25]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCO
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
2-Chloro-adenosine (3.5 g) was added to a hot solution of NaOH (3.2 g) in n-propanol (80 ml), the mixture was heated under reflux for 3 hours. The volatiles were removed in vacuo, the residue taken into water (40 ml), cooled and acidified with 1M hydrochloric acid to pH 7. After 15 min the suspension was filtered and the filtrate evaporated. The residue was taken up in ethanol, and adsorbed onto silica which was placed on a chromatography column. Elution with 9:1, and then 4:1 CHCl3 afforded the sub-title compound (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](S)=[N:7][C:6]=2[CH:11]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: Clc1ccc2scnc2c1

Procedure:
Following the same procedure as in step 2 of Example 337 using 5-chloro-1,3-benzothiazole-2-thiol (1.0 g, 4.96 mmol, 1.00 equiv) and iron powder (2.8 g, 10.00 equiv) in acetic acid (15.0 mL). The crude product was purified through a silica gel column with ethyl acetate/petroleum ether (1:50-1:10) to afford the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]3)[NH:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([C@H:24]3[CH2:25][CH2:26][C@H:27]([CH2:30][NH:31][S:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)(=[O:9])=[O:8])[CH2:28][CH2:29]3)[NH:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine-3-sulfonyl chloride (0.34 mmol) was added to a solution of C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexyl}-methylamine (0.31 mmol) and triethylamine (0.62 mmol) in CH2Cl2 (5 mL). The mixture was stirred overnight at room temperature, diluted with CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (90:10 CH2Cl2/MeOH) to give Pyridine-3-sulfonic acid trans-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-amide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])([CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(c2ccccc2Cl)CCN(Cc2ccccc2)CC1
Reaction time: 3 h
Yield: 10 %

Procedure:
A solution of 1-Benzyl-4-methyl-piperidin-4-ol (4.5 g, 22 mmol) in chlorobenzene (60 mL) was treated with anhydrous AlCl3 (15 g, 110 mmol). This mixture was stirred for 3 hr at reflux, then quenched into ice (250 g), basified with sodium hydroxide, and extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2→490:10 CH2Cl2/methanol) to yield 0.59 g (10%) of the title compound, ESI-MS m/z: 300 [M+1].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:22]=4)[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:42]>>[ClH:42].[ClH:42].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:22]=[N:21][NH:20][CH:19]=4)[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cc23)CC1
Agent: Cl
Product: CN1CCN(c2ccnc3ccc(-c4cn[nH]c4)cc23)CC1

Procedure:
186 mg 4-(4-methylpiperazin-1-yl)-6-(1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 169 and 2.6 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 127 mg of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: N#CCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 434 %

Procedure:
A solution of 2-(4-fluorophenyl)acetonitrile (2 g, 14.8 mmol) in DME (50 mL) was degassed. KOtBu (6.63 g, 59.2 mmol) was added in portions. After addition was completed, the mixture was stirred for 5 min at room temperature and a brown suspension was formed. Then 5-bromo-2-(trifluoromethyl)pyridine (6.69 g, 29.6 mmol) was added followed by Pf(dppf)Cl2 (1.35 g, 1.48 mmol). The resulting mixture was heated to 60° C. for 4 h. The reaction mixture was cooled to room temperature and quenched by aq. NH4Cl to pH=5˜6. The mixture was extracted with EtOAc (50 mLx3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash combi (Petroleum ether/EtOAc=15:1) to give 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (18 g, ˜70% purity +350 mg, pure, yield: 51.8%). 1H NMR (CDCl3 400 MHz) c58.98 (s, 1H), 7.89 (dd, J=8.4, 2.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.40-7.30 (m, 2H), 7.20-7.10 (m, 2H), 5.26 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl.Cl[C:9]([N:11]1[C:17]2[S:18][C:19]([CH2:21][CH3:22])=[CH:20][C:16]=2[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[N:14][CH2:13][CH2:12]1)=[O:10]>O1CCCC1>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:15]1[C:16]2[CH:20]=[C:19]([CH2:21][CH3:22])[S:18][C:17]=2[N:11]([C:9](=[O:10])[NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH2:12][CH2:13][N:14]=1
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1Cl
Reactant: CN(C)CCN
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N(C(=O)NCCN(C)C)CCN=C2c1ccccc1Cl
Temperature: 0 °C

Procedure:
To a solution of 7.1 g of 2-dimethylaminoethylamine in 40 ml of tetrahydrofuran is added 7.8 g of 1-chlorocarbonyl-5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring. After the mixture is reacted for one and half hours at room temperature, the reaction substance is poured into 200 ml of ice-cold water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-(2-dimethylaminoethylcarbamoyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloric monohydrate as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 160°-162° C with decomposition.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][CH:8]([CH3:27])[C:9]([O:11][C:12]1[C:13]([CH3:26])=[C:14]([CH3:25])[C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=O)[C:16]=2[C:23]=1[CH3:24])=[O:10].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:17]1[C:16]2[C:23]([CH3:24])=[C:12]([O:11][C:9](=[O:10])[CH:8]([CH3:27])[CH3:7])[C:13]([CH3:26])=[C:14]([CH3:25])[C:15]=2[O:19][C:18]1([CH3:20])[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)C(C)C)C(=O)C(C)(C)O2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1c2c(C)c(OC(=O)C(C)C)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Potassium tert-butoxide (1.53 g, 13.68 mmol) is added portionwise at 0° C. and under nitrogen to a suspension of methyltriphenylphosphonium bromide (4.9 g, 13.68 mmol) in dry tetrahydrofuran (57 mL) and the reaction mixture is stirred for 1 hr at room temperature. The 5-(2-methyl-propionoxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (3.31 g, 11.4 mmol) in dry tetrahydrofuran (20 mL) is dropwise added at 0° C. to the yellow suspension and the reaction is stirred overnight at room temperature. Water is added and most of tetrahydrofuran is evaporated under reduced pressure. The residue is taken up in ethyl acetate, washed with brine, dried (magnesium sulfate) and the solvent is evaporated to dryness. Purification by flash chromatography eluting with heptane/ethyl acetate 95:5 and then 90:10 gave 2.8 g (85%) of 3-methylene-5-(2-methylpropionoxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran as a yellow oil. Rf=0.79 (heptane/ethyl acetate 70:30)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][C:16]1[C:24]2[O:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:18]2[CH:17]=[C:16]([CH3:15])[C:24]3[O:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[O:9])[CH:3]=1
Reactant: Cc1cccc2c1OCC2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.396 g (2.24 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 0.328 g (2.46 mmol) aluminium trichloride in 10 mL DCM were stirred for 20 min at RT. Then 0.300 g (2.24 mmol) 7-methyl-2,3-dihydro-benzofuran in DCM were added dropwise to the reaction mixture and this was stirred for 1.5 h at RT. After the addition of water and DCM to the reaction mixture the phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution, dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NCC[C@@H:32](O)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]([O:18][CH:34]1[CH2:33][CH2:32][CH2:38][CH2:37][O:36]1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C[C@H](O)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C[C@H](O)CCNC(=O)OC(C)(C)C
Product: CCOC(=O)C[C@@H](CCNC(=O)OC(C)(C)C)OC1CCCCO1
Yield: 75 %

Procedure:
The intended compound (2-b) was prepared in a yield of 75% by a method similar to the process A in EXAMPLE 2, except that ethyl (3R)-5-tert-butoxycarbonylamino-3-hydroxypentanoate (2-a), obtained by the above process B, was used instead of ethyl (3R)-5-benzyloxycarbonylamino-3-hydroxypentanoate (2-a).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>CC(O)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCCC(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: CC(=O)O
Product: CCCC(=O)Nc1ccc(C2CCN(Cc3ccc4c(c3)c3ccccc3n4CC)CC2)cc1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-3-carbaldehyde and N-[4-(4-piperidinyl)phenyl]butanamide: ESMS m/e: 454.2 (M+H)+.