Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(CCO)[CH2:27][CH2:26]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH2:20][CH:25]3[CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 14.5 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 0.17 g (0.72 mmol) of tetraethyl orthotitanate and 7.5 g of 2-cyclopropyl-ethanol is stirred at 130° for 14.5 hours, about 2 ml of solvent being distilled off after 0.5 hour. The mixture is subsequently evaporated to dryness in vacuo, the residue is taken up in chloroform and chromatographed on silica gel while eluting with ethyl acetate. After crystallization of the resulting oil from ethyl acetate/n-hexane, there is obtained 2-cyclopropylethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 163°-164°.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[S:3]([O:6][C:7]1[C:15]2[N:11]([CH:12]=[CH:13][CH:14]=2)[C:10]([C:16](OCC)=[O:17])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[BH4-].[Na+].O>CO>[F:22][C:2]([F:1])([F:21])[S:3]([O:6][C:7]1[C:15]2[N:11]([CH:12]=[CH:13][CH:14]=2)[C:10]([CH2:16][OH:17])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c2cccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)(Oc1ccc(CO)n2cccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 190.3 %

Procedure:
To a solution of ethyl 8-(((trifluoromethyl)sulfonyl)oxy)indolizine-5-carboxylate (30 g, 89 mmol) in MeOH (300 mL) was added NaBH4 (13.5 g, 0.356 mol) at 0° C. under N2. The reaction mixture was stirred at rt overnight. After the completion, to the reaction was added water, extracted with EtOAc, washed with brine, dried and concentrated to give the desired product 5-(hydroxymethyl)indolizin-8-yl trifluoromethanesulfonate (50 g, crude).
Reaction SMILES: [C@H:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[NH:18][N:19]=[C:20]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[N:25]=[CH:24]4)[C:14]=2[CH2:13]1)=[O:11].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(N(C(C)C)CC)(C)C>ClCCl>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH:2]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]3[NH:18][N:19]=[C:20]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH3:30])[N:25]=[CH:24]5)[C:14]=3[CH2:13]1)=[O:11])[CH2:3][CH2:4]2
Reactant: Fc1ccccc1CBr
Reactant: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CC[C@H]5CC[C@@H]3N5)CC4)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CCC5CCC3N5Cc3ccccc3F)CC4)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dichloromethane (1.78 mL) was added to N-((1S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-3-(1-methyl-1H-indazol-5-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (72.3 mg, 0.178 mmol) in a flask. 2-Fluorobenzylbromide (0.0214 mL, 0.178 mmol) was added to the reaction. At room temperature, diisopropylethylamine (0.0920 mL, 0.534 mmol) was added dropwise to the reaction. The reaction was allowed to stir at room temperature for 1 hr. The reaction was quenched using water, was extracted three times using dichloromethane. The dichloromethane extractions were combined, dried over sodium sulfate, filtered, and concentrated. The crude was further purified using HPLC. The endo and exo products were separated. LC-MS: 514.3 [M+H]. LC/MS RT=2.17 and 2.238 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][N:16]1[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17]1.[H-].[Na+]>O1CCCC1.CO.CCOC(C)=O>[CH3:15][N:16]1[CH2:20][CH2:19][C@@H:18]([O:21][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(F)c1
Reactant: CN1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CC[C@@H](Oc2cc([N+](=O)[O-])ccc2C(F)(F)F)C1
Reaction time: 48 h
Yield: 45.6 %

Procedure:
A solution of 2-fluoro-4-nitrobenzotrifluoride (12.4 g, 59.3 mmol, 1.0 eq) and (R)-1-methyl-pyrrolidin-3-ol (6.0 g, 59.3 mmol, 1.0 eq) in anhydrous tetrahydrofuran (150 ml) was cooled to 0° C. then slowly treated with portions of 60% sodium hydride (4.7 g, 0.12 mol, 2 eq) over 5 min. Without removing the ice bath, the reaction was allowed to come to room temperature and stir for 48 hrs. Quenched with water (50 ml) and brine (100 ml) then extracted into diethyl ether (5×100 ml). Extracts dried over anhydrous magnesium sulfate and decolorizing charcoal for 1 hr. Filtered through Celite. The filtrate was treated with silica (35 g) then evaporated to give the crude product suspended on silica. Column chromatography on silica (1% MeOH/EtOAc→5% MeOH/EtOAc) gave the product (Rf≡0.3 in 1% MeOH/EtOAc) as an orange oil (7.85 g, 46%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:12])[CH:5]=1.[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[CH2:24].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:6]2[N:7]=[C:8]([CH3:10])[N:9]=[C:4]([C:3]3[CH2:24][CH:23]([CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]4)[O:1][N:2]=3)[CH:5]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: COc1ccc(CNC(=O)c2cc(C=NO)nc(C)n2)cc1
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COc1ccc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)OC(C)(C)C)CC4)C3)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a cold solution of (6-((hydroxyimino)methyl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.2 g, 0.66 mmol, Preparation #B.1.1) and tert-butyl 4-vinylpiperidine-1-carboxylate (0.168 g, 0.799 mmol, Preparation #E.1.2) in chloroform (20 mL) was added iodobenzene diacetate (0.343 g, 1.06 mmol) in one portion. The mixture was allowed to warm to RT and stirred for about another 1 h. The reaction mixture was quenched with water (20 mL) and the product was extracted with chloroform (2×20 mL). The organic layer was washed with water (2×15 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by column chromatography using silica gel (60-120 mesh) eluting with 50% n-hexane and EtOAc. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford tert-butyl 4-(3-(6-(4-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate 0.1 g (29%). MS m/z: 510 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:34])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH3:35].CO>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:34])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: CO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 45 °C

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.381 mmol) and ammonia in MeOH 7M (6 ml, 42.0 mmol) and heating to 45° C. overnight, the title compound was obtained as a light yellow solid (128 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.34-7.43 (m, 1H), 7.30 (t, J=6.3 Hz, 1H), 7.13-7.27 (m, 3H), 6.71 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 3.17-3.27 (m, 1H), 1.30 (d, J=6.9 Hz, 6H). MS (ESI): 506.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:26][CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:10][CH2:9]1
Reactant: OCCCCl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCCO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
A mixture of (S)-N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.200 g, 0.595 mmol), 3-chloro-1-propanol (299 μL, 3.57 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 mL) was heated to reflux for 7 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was dissolved in 10% methanol/chloroform and absorbed onto silica gel (2 g). Chromatography of this material over silica gel (10 g), eluting with 1%, 3%, and then 6% methanol/chloroform, afforded, after concentration of appropriate fractions, 0.096 g (41%) of the title compound as a white solid with mp 154°-155.5° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17](O)=[O:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C(CN1CCC(c2noc3cc(F)ccc23)CC1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCC(CN1CCC(c2noc3cc(F)ccc23)CC1)c1ccccc1
Yield: 90.3 %

Procedure:
To 3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino)-2-phenylpropanoic acid (1.8 g, 5 mmol) in 25 ml dry toluene, stirred at 0° C., a solution of LiAlH4 in THF (5 ml, 1M, 5 mmol) was added dropwise. 20 min. after addition was completed the mixture was allowed to warm to room temperature for 15 min. whereupon H2O was added dropwise to precipitate aluminum hydroxide. To the organic phase was added 50 ml ether, and the mixture was washed with water and concentrated in vacuo to get 1.6 g of 3-(4-(6-fluoro -1,2-benzisoxazol-3-yl)piperidino)-2-phenylpropanol as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[N+:8]([O-:10])=[O:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[K].CC(C)([O-])C>C(O)C>[CH3:1][N:2]1[C:6]([CH:7]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=[C:3]1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cnc([N+](=O)[O-])n1C
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCO
Product: Cn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]
Yield: 16 %

Procedure:
A mixture of 7.2 g. of 1,5-dimethyl-2-nitroimidazole, 41.2 ml. of benzaldehyde and 7.9 g. of potassium dazole, tert-butoxide in 300 ml. of ethanol is refluxed for 35 minutes under nitrogen. The residue, which is obtained by evaporation of the reaction mixture under vacuum, is extracted with ethyl ether and filtered. The ethyl ether solution after concentration yields an oily residue which is chromatographed through 300 g. of silica gel by eluting with chloroform. After evaporation of the solvent under vacuum at 40° C., an oily residue is obtained which crystallizes on standing. After washing with a small amount of methyl ethyl ketone, 1.9 g. (16%) of a product which melts at 170°-180° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:25]([NH:27][C:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26 in 5 ml tetrahydrofuran was added 0.015 ml of ethyl isocyanate, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, to the reaction mixture was added with 1 ml of 5 N hydrochloric acid and the mixture was stirred for further 1 hour. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was sequentially washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. To the residue was added diisopropyl ether, and the mixture was filtered, to give 28 mg of the title compound as a colorless powder.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.Cl.[O:15]1C[CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].C(OC(=O)CC)(=O)CC>O>[OH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[NH:10][CH:9]=[C:8]2[CH2:11][CH2:12][NH:13][C:16](=[O:15])[CH2:17][CH3:18]
Reactant: C1CCOC1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: CCC(=O)OC(=O)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CCC(=O)NCCc1c[nH]c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of serotonin hydrochloride (10 g, 47.5 mmol.) in water (50 mL) were added, under argon atmosphere, tetrahydrofuran (20 mL) and a solution of sodium carbonate (5.3 g) in water (20 mL). The mixture was cooled to 0° C., to which was added propionic anhydride (6.2 g, 49.9 mmol.). The mixture was stirred for 2 hours at room temperature. The reaction mixture was subjected to extraction with ethyl acetate. The extract solution was washed with 1N HCl, a saturated aqueous solution of sodium hydrogencarbonate and water, which was dried and then concentrated to afford the title compound (yield 10.0 g, 98.0%) as an oily product. This compound was used, without refining further, for the subsequent reaction.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH2:11][CH:12]([CH2:17][C:18](OC)=[O:19])[C:13](OC)=[O:14])[CH:6]=[N:7]2)=[N:3][CH:2]=1.C(O)(C)(C)C.[BH4-].[Li+]>O>[OH:19][CH2:18][CH2:17][CH:12]([CH2:13][OH:14])[CH2:11][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: COC(=O)CC(Cn1cnc2c(N)ncnc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1ncnc2c1ncn2CC(CO)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl 2-(adenine-9-ylmethyl)succinate (2.93 g, 0.010 mol) was dissolved by warming with tert. butanol (120 ml), lithium borohydride (1.10 g, 0.05 mol) was added in portions and the mixture was stirred at ambient temperature for 3 h, water (10 ml) was added and stirring was continued over night. Inorganic material was filtered off and washed with tert. butanol and the filtrate evaporated to small volume. Chromatography on silica (ethyl acetate+methanol+water 7+2+1) afforded pure 9-(4-hydroxy-2-hydroxymethylbutyl) adenine.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])(=O)=O>ClCCl>[Cl:16][CH:10]1[S:9][CH2:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:12]
Reactant: O=C1CSCN1c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C1C(Cl)SCN1c1ccccc1

Procedure:
This compound was prepared by a procedure similar to that described in Preparative Example 2, Step 2 above, but using 3-phenyl-4-thiazolidinone (prepared as in Step 1 above) (0.38 g), sulphuryl chloride (0.29 g), and dichloromethane (5 ml). This product was used directly in Step 3.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:10][C:11]([O:13]CC(C1C=CC(Br)=CC=1)=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH2:1]([O:8][C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:10][C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCCCCCCCC[C@H](CC(=O)OCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Zinc dust (<10 micron, 382 mg, 5.87 mmol) was added portionwise to a solution of 117 (320 mg, 0.587 mmol) in acetic acid (15 mL). The reaction mixture was stirred at 60° C. for 2 h and then diluted with DCM (20 mL). The solids were filtered off through a pad of Celite and the residue was washed with DCM (3×5 mL). The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: DCM/methanol, 100/1, v/v) to afford 107 as an amorphous solid (198 mg, 97%). Rf=0.40 (toluene/ethyl acetate, 3/1, v/v); [α]25D=−2.3° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.35-7.25 (m, 5H, aromatic), 4.55 (s, 2H, CH2Ph), 3.86 (m, 1H, H-3), 2.62 (dd, 1H, J2a,2b=15.6 Hz, J2a,3=6.9 Hz, H-2a), 2.53 (dd, 1H, J2a,2b=15.6 Hz, J2b,3=5.1 Hz, H-2b), 1.66-1.45 (m, 3H, H-4, H-13), 1.38-1.10 [m, 16H, H-(5-12)], 0.85 (d, 6H, J15,16=6.9 Hz, H-14); 13C NMR (75 MHz, CDCl3): δ 176.76 (C═O), 138.04-127.73 (aromatic), 75.70 (C-3), 71.53 (CH2Ph), 39.42 (C-2), 39.03 (C-12), 34.09 (C-4), 22.66 (C-14); HR MS (m/z) calculated for C22H36O3 [M+Na]+, 371.2557. found, 371.1906.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:24])[C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nccc(-c3cccnc3)n2)cc1
Reaction time: 0.75 h

Procedure:
A 2.78 g portion of N-(4-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine was dissolved in 30 ml of dimethylformamide. A 528 mg portion of sodium hydride (50% in oil) was added, the reaction sealed and stirred for 45 minutes. A solution of 1.70 g of methyl iodide in 2 ml of dimethylformamide was added, the sealed mixture was stirred overnight and the solvent removed. The residue was partitioned between water and chloroform. The organic phase was dried, filtered and evaporated. The residue was crystallized from ether-hexane giving 1.4 g of the desired product as yellow crystals, mp 88°-90° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Yield: 76.2 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 4-chloro-3-nitroquinoline (109.70 g, 525.87 mmol) and dichloromethane (500 mL). To the solution was added triethylamine (79.82 g, 788.81 mmol) and 4-amino-1-butanol (46.87 g, 525.87 mmol) to give a homogeneous, dark yellow solution. The reaction was judged to be complete after heating at reflux for 30 minutes. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with chloroform (1×). The organic layers were combined and then concentrated under reduced pressure to afford 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (104.67 g, 400.60 mmol) as a dark yellow solid. This material was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:13][C:14]1[C:15]([O:37][CH3:38])=[CH:16][C:17]([O:35][CH3:36])=[C:18]([CH2:20][CH2:21][C:22]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[CH2:23]2)[CH:19]=1>>[Cl:13][C:14]1[C:15]([O:37][CH3:38])=[CH:16][C:17]([O:35][CH3:36])=[C:18]([CH2:20][CH2:21][C:22]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[O:27][C:26](=[O:28])[C:25]([CH2:2][C:3]3[NH:4][C:5](=[O:12])[C:6]4[S:11][CH:10]=[CH:9][C:7]=4[N:8]=3)=[C:24]([OH:29])[CH2:23]2)[CH:19]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=c1[nH]c(CCl)nc2ccsc12
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccsc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 20 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)thieno[3,2-d]-pyrimidine-4(3H)-one (Example B(56), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 20%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O-:18])=O)[CH2:8][CH2:7]1.[Li+].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[N:49]=[C:50]([C:52]1[CH:57]=[N:56][CH:55]=[CH:54][N:53]=1)[NH2:51]>ClCCl.N1C=CC=CC=1.C(N(CC)CC)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]2[O:18][N:51]=[C:50]([C:52]3[CH:57]=[N:56][CH:55]=[CH:54][N:53]=3)[N:49]=2)[CH2:10][CH2:11]1
Reactant: O=C([O-])CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: NC(=NO)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1nc(-c2cnccn2)no1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Yield: 18.2 %

Procedure:
To lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-5-oxobutanoate (Example 351, step ii) (0.292 g) in dichloromethane (6 ml) was added N,N-dimethylformamide (1.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.183 g), 1-hydroxybenzotriazole hydrate (0.130 g), N′-hydroxy-2-pyrazinecarboximidamide (0.110 g) and triethylamine (0.161 g). The reaction mixture was left to stir for 24 hours before removal of dichloromethane under reduced pressure. Pyridine (5 ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was azeotroped twice with toluene and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the title compound (0.067 g).