Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH2:25](I)[CH3:26]>C1COCC1>[CH2:25]([C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1)[CH3:26]
Reactant: CCI
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Solvent: C1CCOC1
Product: CCc1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butylithium at −78° C. After stirring at −78° C. for 10 min, ethyl iodide was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.89(s, 2H), 6.07(s, 1H), 3.72(d, 1H), 3.34(m, 1H), 2.58(q, 2H), 2.16(s, 3H), 2.12(s, 3H), 2.09(s, 6H), 1.4-1.7(m, 4H), 1.25(t, 3H), 0.96(t, 6H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.CI.[C:28](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C(=O)/C=C/c2cn(C)c3ccccc23)cc(OC)c1OC
Yield: 81.6 %

Procedure:
Compound 1 (1.0 g) obtained in Example 1 was dissolved in acetone (50 ml), and methyl iodide (1.42 g) and potassium carbonate (1.0 g) were added thereto, followed by heating under reflux for 72 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate (20 ml) in a condition of heating under reflux, and insoluble matters were filtered off. Hexane (25 ml) was added to the filtrate, and the precipitated crystals were collected by filtration to give Compound 2 (0.85 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1.CO.[ClH:41]>>[ClH:41].[ClH:41].[ClH:41].[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Agent: Cl
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Yield: 92 %

Procedure:
tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate (45 mg, 0.087 mmol) was stirred in 4 N HCl in dioxanes (3 mL) and methanol (2 mL) for 30 min, at which time the solvent was evaporated to give the title compound (45 mg, 92%). LCMS calc. for C27H32N7O3 (M+H)+: m/z=417.2. found: 417.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:19][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: OCCc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OCCc2ccccn2)ccc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.1 %

Procedure:
To a stirring ice-cooled mixture of 5.0 g of 4-hydroxy-2-methoxybenzaldehyde, 4.5 g of 2-(2-pyridyl)ethanol and 10.3 g of triphenylphosphine was added dropwise 15.8 g of a 40% solution of diethyl azodicarboxylate in toluene. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, purified by silica gel column chromatography (hexane/acetone system) and further purified by silica gel column chromatography (hexane/AcOEt system) to give 5.84 g of the title compound (69% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH:11]1([C:15]2[N:23]3[C:18](C(=O)NC=N3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[CH:11]1([C:15]2[N:23]3[C:18]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncnn2c(C3CCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrous pyridine (10 mL) was added phosphorus oxychloride (POCl3) (0.578 mL, 6.20 mmol) and stirred at rt for 15 min. This mixture was dropwise charged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3H imidazo[5,1-f][1,2,4]triazin-4-one (0.653 mg 2.07 mmol) in anhydrous pyridine (14 ml) and stirred for 1.5 h. The reaction mixture was cooled to 0° C. quenched with 2M NH3 in isopropanol (IPA) until basic then allowed to reach rt and stirred for an additional 2 h. The reaction mixture was filtered through a fritted Buchner funnel and washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography on silica gel [eluting with 30% EtOAc in DCM] resulting in the title compound as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H), 2.49-2.62 (m, 2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08 (100) [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1C=CC=CC=1>CCO>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1O
Yield: 89.6 %

Procedure:
A solution of ketone 12 (200 mg, 1.20 mmol) in EtOH (2.0 mL) was treated with compound 19 (0.27 g, 1.32 mmol) and pyridine (0.5 mL) and the resulting mixture heated at reflux for 3 h then cooled and the solvent evaporated under reduced pressure. The ensuing residue was partitioned between CH2Cl2 (10 mL) and H2O (10 mL). The separated aqueous fraction was extracted with CH2Cl2 (1×5.0 ml) and the combined organic fractions were dried (MgSO4) then filtered and concentrated under reduced pressure to give a light-yellow solid. Recrystallisation (isopropanol) of this material afforded the title compound CP30218 (340 mg, 89%) as pale-yellow crystals, m.p. 105.0-105.7° C.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:5]12[N:8]([C:16]([Cl:15])=[O:18])[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: C1CC2CCC(C1)N2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1C2CCCC1CC2
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a cooled (10° C.) solution 8-aza-bicyclo[3.2.1]octane (295 mg, 2.00 mmol) and pyridine (486 μL, 6.02 mmol) in DCM (10 mL) was added triphosgene (595 mg, 2.00 mmol) portionwise. The reaction was allowed to reach room temperature and stirred overnight. The mixture was quenched with HCl (1M aqueous, 10 mL) and stirred for 30 min. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with HCl (1M aqueous), brine, dried (MgSO4) and concentrated in vacuo, to give the title compound (244 mg, 70%). 1H NMR (400 MHz, CDCl3): 1.46-1.70 (4H, m), 1.72-1.92 (5H, m), 2.04-2.11 (2H, m), 4.39-4.44 (2H, m).
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](OC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([NH:54][C:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@H:23]3[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]3)=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:18]=2)=[O:20])[CH2:50][CH2:49]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NC4CCN(Cc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C
Yield: 77.5 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (1.0 g, 1.83 mmol) and 1-benzyl-4-piperidinylamine (2.4 ml, 11 mmol) was heated at 105 ° C. for 4 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2, by volume) changing to dichloromethane:methanol (95:5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (1.0 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](=[O:13])[CH2:11][OH:12])=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CO.[BH4-].[Na+].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:35][C:34]1[CH:36]=[CH:37][C:31]([S:28]([O:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:14]#[N:15])[CH:4]=[C:3]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[C:2]=2[Cl:1])(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CCC(=O)CO)c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC(O)CCc2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.9 %

Procedure:
To a round bottom flask was added tert-butyl (2-chloro-5-cyano-3-(4-hydroxy-3-oxobutyl)phenyl)carbamate (500 mg, 1.476 mmol) and MeOH (1 mL). The solution was then cooled to 0° C. before NaBH4 (100 mg) was added. The reaction was then stirred at 0° C. for 30 min and then slowly warmed to room temperature, and stirred for additional 1 h. The reaction was then quenched with aq. NaHCO3, extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was then dissolved in DCM (10 mL). Pyridine (1 mL) was added. After the reaction was cooled to 0° C. Ts-Cl (310 mg, 1.623 mmol) was added, and the reaction was then allowed to warm to room temperature and stirred for 5 h. The reaction was then taken up with DCM, washed with brine, and concentrated in vacuo to give 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxybutyl 4-methylbenzenesulfonate (810 mg) as a yellow solid.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([Mg]Br)[CH3:12]>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]([OH:10])[CH2:11][CH3:12]
Reactant: CC[Mg]Br
Reactant: COc1ccccc1C=O
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a time-dried flask containing a solution of o-anisaldehyde (2.00 g) in dry tetrahydrofuran (9.8 mL) at 0° C. under nitrogen is added a solution of ethylmagnesium bromide (3M in diethyl ether, 5.4 mL) in dry tetrahydrofuran (5.4 mL) over 25 min. The resulting mixture is stirred at 0° C. for 1 hr, quenched with saturated aqueous ammonium chloride (15 mL), and the layers are separated. The aqueous phase is extracted with diethyl ether (2×30 mL) and the combined organic phase is washed with saline (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil which is then chromatographed on silica gel (230-400 mesh, 250 g), eluting with a gradient of ethyl acetate/hexane (5/95-10/90). Pooling of fractions having an Rf =0.44 by TLC (ethyl acetate/hexane, 25/75) and removal of solvent gives the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:19]2)=[O:17])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH:15]([C:11]2([OH:14])[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCC(O)(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
1.04 g of 1-t-Butoxycarbonyl-4-{1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-4-hydroxypiperidine was dissolved in 10 ml of methanol, and 20 ml of 4M hydrogen chloride/1,4-dioxane solution was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 1M aqueous sodium hydroxide solution and a saturated aqueous sodium solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 9 ml of acetonitrile, and 640 μl of 37% formalin, 190 μl of acetic acid and 160 mg of sodium cyanoborohydride were added, followed by stirring at room temperature for an hour. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1) to give 0.44 g of 4-{1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-1-methylpiperidin-4-ol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
A mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.060 g, 0.15 mmol, Example #E.1), methanol (5 mL), THF (5 mL) and 2 M aqueous NaOH (3 mL) was stirred at rt for about 18 h. Subsequently, 1 M aqueous HCl (7 mL) was added and the volatiles were removed in vacuo. The residue was treated with water (20 mL) and then extracted with ethyl acetate (2×70 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method a) to give 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoic acid (0.016 g, 0.04 mmol, 27%) as an off white solid: LC-MS (Table 1, Method a) Rt=3.0 min; m/z 401 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.58-2.75 (2H, m) 3.06 (1H, t, J=11.8 Hz) 3.68-3.76 (1H, m) 3.77 (3H, s) 5.82 (1H, d) 7.03 (1H, s) 7.14-7.18 (1H, m) 7.42 (1H, d, J=8.0 Hz) 7.66-7.72 (2H, m) 7.79 (1H, d, J=8.0 Hz) 7.89 (1H, d, J=1.7 Hz) 8.43-8.48 (1H, m).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:21][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccccc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2ccccc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a mixture of cyclohexyl(3-methyl-1-benzofuran-2-yl)methanol (843 mg) synthesized above and toluene (20 mL) was added thionyl chloride (256 μL), and the mixture was stirred at room temperature for 2.5 hr and at 50° C. for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (862 mg, 95%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([C:24](OC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:9][CH2:8][C@@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:25])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN1CCO[C@@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
(R)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 11; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 300 mg, 0.92 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM). The solvents were removed in vacuo to give [(2R)-4-methylmorpholin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (175 mg, 72%) as a light yellow gum
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C:20]=3[F:34])[CH2:15][CH2:14]2)=[CH:9][N:8]=1)(=O)=O.C1COCC1.[CH3:42][O:43][CH2:44][CH2:45][NH2:46].O>CCOC(C)=O>[F:34][C:20]1[C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:9]=[N:8][C:7]([NH:46][CH2:45][CH2:44][O:43][CH3:42])=[N:12][CH:11]=3)[CH2:14][CH2:15]2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:25][OH:26]
Reactant: COCCN
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCN(c3cnc(OS(=O)(=O)C(F)(F)F)nc3)CC2)c1F
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCNc1ncc(N2CCN(c3cccc(CO)c3F)CC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5-{4-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin-2-yl trifluoromethanesulfonate (200 mg) was mixed with THF (4 ml), and 2-methoxyethanamine (864 mg) was added thereto, followed by stirring at 60° C. overnight. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (5 ml), and a 1 M TBAF/THF solution (1.6 ml) was added thereto, followed by stirring at room temperature overnight. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain [2-fluoro-3-(4-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}piperazin-1-yl)phenyl]methanol (105 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH:15][C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCn1cnc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cnc(-c2ccccc2)c1)c1ccco1

Procedure:
A mixture of 2.0 g. of 4-phenyl-1H-imidazole-1-propanamine, 50 ml. of methylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.0 ml. of 2-furoyl chloride was added. The mixture was stirred for eighteen hours, methylene chloride was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was washed onto a filter with diethyl ether, giving the desired product, m.p. 120°-122° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH:4]2[C:3](=[O:2])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)=[CH:27][CH:28]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(c3ccccc3)C2=O)cc1
Temperature: 80 °C

Procedure:
To the solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (227.3 mg, 0.5 mmol) (from Example 1e supra) in glacial acetic acid (15 mL) was added concentrated sulfuric acid (0.2 mL) in one portion. The reaction mixture was heated at 80° C. overnight. The reaction mixture was then diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude products which was crystallized from ethyl acetate-hexanes to give 6-(4-methoxy-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as brown crystalline solid. (Yield 174.2 mg, 82.4%).