Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])[CH3:3].[CH:16]1[N:24]2[C:19]([C:20]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[OH:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:31]2[CH2:30][CH2:29][C:20]3([O:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]4[CH:16]=[CH:17][CH:18]=[C:19]34)[CH2:33][CH2:32]2)=[O:11])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)O
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-benzoic acid (120 mg, 0.573 mmol), spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (167 mg, 0.573 mmol), triethylamine (320 μL, 2.29 mmol), and EDC (110 mg, 0.573 mmol) were combined in DCM (5.8 mL). The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to provide (4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 432.0, found 433.1 (M+1)+; Retention time: 1.61 minutes (3 min run).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)O1.I[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[N:27]([C@H:35]2[CH2:40][CH2:39][C@@H:38]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH2:37][CH2:36]2)[N:26]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)[N:26]=[C:25]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:14]=3)[C:33]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (3.71 g, 0.0116 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.46 g, 0.0101 mol), tetrakis-(triphenylphosphine)palladium (0.700 g, 0.00061 mol) and sodium carbonate monohydrate (3.13 g, 0.0253 mol) was heated in a mixture of ethylene glycol dimethyl ether (140 mL) and water (70 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (300 mL) and ethyl acetate (300 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (150 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (95:4:1) as a mobile phase to give cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate (4.1 g, 0.0081 mol) as a white solid.
Reaction SMILES: Cl[C:2]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][N:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.C1COCC1.[NH3:40].CC(O)C>O>[NH2:40][C:2]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][N:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1
Reactant: Cn1cnnc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: N
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cnnc1C(N)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 1 h
Yield: 57 %

Procedure:
6-[chloro(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (0.0045 mol) was added at 5° C. to THF (25 ml) under N2 flow. NH3/2-propanol saturated (25 ml) was added dropwise. The mixture was kept for 1 hour, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (2.6 g) was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH; 50/50/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (1.6 g, 73%) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried. The residue (1.3 g, 59%) was purified by column chromatography over kromasil 10 μm (eluent: CH3OH/H2O; 60/40). The pure fractions were collected and the solvent was evaporated. The residue (1.4 g, 63%) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 1.26 g (57%) of 6-[amino(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, mp. 210° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cccnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyridin-3-yl-benzylamino)-methyl]-phenoxy}acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.59 (d, 1H), 7.89 (m, 3H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 3H), 7.17 (d, 2H), 7.10 (t, 1H), 6.74 (m, 1H), 6.64 (d, 1H), 6.58 (d, 1H), 4.37 (s, 2H), 4.34 (s, 2H), 4.32 (s, 2H), 1.48 (s, 9H); MS 545 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]>>[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:4][CH2:3][CH2:2][OH:1])[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCO
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCO)n4)cc3)cc12

Procedure:
Using 2-hydroxy-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.98 (t, 2H, J=7 Hz); 3.44 (bs, 2H); 3.55 (m, 4H); 4.70 (t, 1H, J=6 Hz); 7.17 (m, 3H); 7.48 (m, 2H); 7.92 (d, 2H, J=9 Hz); 8.18 (m, 3H); 8.38 (d, 1H, J=5 Hz); 8.68 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 427 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].CN(CCN)C.[CH3:28][O:29]C1C=CC=CC=1N1CCNCC1>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:29][CH3:28])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C(=O)NCCN(C)C)CC1
Yield: 49 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.9 g (0.03 mole) of 1,1'-carbonydiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine and 5.8 g (0.03 mole) of 1-(2-methoxyphenyl)piperazine in a total volume of 200 ml of tetrahydrofuran gave an oil which solidified. After trituration with petroleum ether (30°-60° C.), the collected solid was recrystallized from benzene-petroleum ether to yield 4.5 g (49%) of the title compound as an off-white solid, m.p. 98°-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][O:11][C:12]#[C:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:26])[C:22]([NH2:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[NH:25][C:15](=[O:17])[C@H:9]([CH2:10][O:11][C:12]#[C:13][CH3:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)C(C)(C)N
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-tert-butoxycarbonyl O-propynyl-L-serine 13 (6.26 g, 25.7 mmol) was dissolved in DMF (50 mL). Aminoisobutyric acid methyl ester hydrochloride 2 (3.95 g, 25.7 mmol) was dissolved in DMF (50 mL) and N,N-diisopropylethylamine (3.32 g, 25.7 mmol) added. The resulting solution was added to the solution of 13 in one portion and the mixture cooled to 0° C. (ice bath). HOBt hydrate (3.94 g, 25.7 mmol) and then EDC hydrochloride (5.43 g, 28.3 mmol) were added in portions together with additional DMF (50 mL). The reaction mixture was stirred for 1 h at 0° C., after which the ice bath was removed and stirring continued for 42 h at room temperature. The solvent was evaporated and the residue taken up in EtOAc (300 mL). The solution was washed with 2 M HCl (3×100 mL), 7.5% (w/w) K2CO3 solution (3×100 mL) and brine (100 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a yellow/orange, viscous oil which was deemed to be of satisfactory purity to be used in subsequent steps without further purification (7.94 g, 90%); 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H, NH(Aib)), 6.69 (d, J=8.5 Hz, 1H, NH(propSer), rotamer 1), 6.32 (d, 1H, NH(propSer), rotamer 2), 4.21-4.08 (m, 1H, CαH), 4.13 (d, J=2.1 Hz, 2H, CH2CCH), 3.57 (dd, J=9.9, 4.8 Hz, 1H, CHH), 3.54 (s, 3H, OCH3), 3.47 (dd, J=9.6, 7.4 Hz, 1H, CHH) 3.42 (t, J=2.3 Hz, 1H, CCH), 1.38 (s, 9H, (CH3)3), 1.35 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR (75 MHz, d6-DMSO) δ 174.0, 169.0, 154.9, 79.9, 78.1, 77.1, 69.3, 57.5, 54.9, 53.7, 51.7, 28.0, 24.6; HRMS (m/z): [M+Na]+ calcd. for C16H26N2O6Na, 365.1688. found, 365.1695; Anal. Calcd. for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.1; H, 7.7; N, 8.0.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])[CH:18]=2)=[CH:13][CH:12]=1.FC1C=CC(CC(C2C=CC=CC=2)=O)=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:66].Cl.Cl[C:69]1[CH:70]=[N:71][CH:72]=[C:73]([O:75][CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH:74]=1>CN(C=O)C.O>[Cl:66][C:72]1[C:73]([O:75][CH:76]2[CH2:81][CH2:80][N:79]([C:26](=[O:28])[CH2:25][NH:24][C:22]([C:19]3[CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)[NH:21][N:20]=3)=[O:23])[CH2:78][CH2:77]2)=[CH:74][CH:69]=[CH:70][N:71]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccc(F)cc2)[nH]n1
Reactant: Cl
Reactant: Clc1cncc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(Cc1ccc(F)cc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccnc2Cl)CC1)c1cc(-c2ccc(F)cc2)[nH]n1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
DIPEA (226 mg, 1.75 mmol) was added to a stirred solution of {[5-(4-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (130 mg, 0.5 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (4-fluorophenyl)acetophenone) in DMF (2 mL) followed by HOBt (71 mg, 0.52 mmol) and EDCI.HCl (100 mg, 0.52 mmol). After 2 minutes 3-chloro-5-(piperidin-4-yloxy)-pyridine hydrochloride (125 mg, 0.5 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 40% ethyl acetate in hexane as eluent) to afford 134 mg (58.5% Yield) of 5-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 458, 93.27%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.0 (m, 2H), 7.8 (m, 2H), 7.7 (d, 1H), 7.4 (m, 1H), 7.25 (m, 2H), 7.1 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([OH:6])C.[Br:7][C:8]([CH3:13])([CH3:12])[C:9](Br)=[O:10].[CH:14](Cl)(Cl)Cl>>[Br:7][C:8]([CH3:13])([CH3:12])[C:9]([O:6][CH2:4][CH2:3][CH2:2][CH:1]=[CH2:14])=[O:10]
Reactant: ClC(Cl)Cl
Reactant: C=CCC(C)O
Reactant: CC(C)(Br)C(=O)Br
Product: C=CCCCOC(=O)C(C)(C)Br
Temperature: 0 °C
Reaction time: 4 h

Procedure:
160 mmol (13.9 g) penten-4-ol and 50 ml chloroform were introduced into a flask and cooled to 0° C. 160 mmol (36.8 g) bromoisobutyryl bromide in 20 ml chloroform were introduced slowly with cooling and the resulting solution was stirred for 4 h at room temperature. The reaction solution was washed three times with water, dried over MgSO4 and then concentrated by evaporation. The product was distilled in a high vacuum. Boiling point at 3.3×102 mbar: 50° C. Yield: 34.79 g (148 mmol; 92.5%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.C[NH:26][NH2:27]>C1COCC1>[NH:26]([C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1)[NH2:27]
Reactant: CNN
Reactant: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(Cl)n1
Solvent: C1CCOC1
Product: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(NN)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
To a solution of XXVIII (475 mg, 1.28 mmol) in dry THF (3 mL) was added methylhydrazine (273 μL, 5.13 mmol). The resulting solution was stirred at room temperature for 18 hrs, the solvent removed in vacuo and the residue taken up in CH2Cl2. The CH2Cl2 solution was washed with H2O, dried over MgSO4, filtered and CH2Cl2 evaporated in vacuo to afford XIX as a yellow oil (0.43 g, 88%): 1H NMR (DMSO-d6) δ 7.48 (app s, 2H), 7.47 (app s, 2H), 5.84 (s, 1H), 4.86 (bs, 2H), 3.42 (s, 3H), 3.19 (s, 3H); ESI/MS 381 (M+H), 366 (M−CH3).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:16]([CH3:28])=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:13][CH2:14][CH3:15])=[O:12]>>[C:11]([C:16]([CH3:28])=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:26])=[CH:20][CH:19]=1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: NCC(O)c1ccccc1
Reactant: CCOC(=O)C(C)=Cc1ccc(CC(C)=O)cc1
Product: CCOC(=O)C(C)=Cc1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-phenylethanamine (0.51 g) and 4-{2-carboethoxy-2-methylethenyl}phenylpropan-2-one (1.0 g). The title compound was isolated as an oil (1.4 g). The oil was dissolved in methanol and treated with fumaric acid (0.43 g) in methanol. Evaporation of the solvent gave an oil which was triturated with ethyl acetate and recrystallized from ethyl acetate to give the title compound hemifumarate (0.38 g) as a 50:50 mixture of diastereoisomers m.p. 135°-138° C. τ(CDCl3) 8.8 (3H, d, J=6 Hz), 8.7 (3H, t, J=7 Hz) 8.0 (3H, s), 6.35-7.5 (7H, m, 2H disappears with D2O), 5.8 (2H, q, J=7 Hz) 4.85 (1H, m), 3.15 (1H, s), 2.8 (9H, m), 2.47 (1H, s), 1.8 (2H, broad, disappears with D2O).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:17]([CH3:24])=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[N:14]=[CH:15][C:8]=12>>[Cl:3][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:17]([CH3:24])=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[N:14]=[CH:15][C:8]=12
Reactant: Cc1c(C#N)cccc1-n1ncc2c(O)ncnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(C#N)cccc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Phosphoryl trichloride (9.92 ml, 103.49 mmol) was added to 3-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT3) (1.3 g, 5.17 mmol). The resulting solution was stirred at 100° C. for 2 hours. The reaction mixture was evaporated (azeotroping with toluene ×3) giving a brown oil which was triturated with ice/water to give afford the product (1.200 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:30][CH2:31][CH3:32])[C:14]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)NCCC3)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCCc2c1c1cc(OC)ccc1n(Cc1ccc(OC)cc1)c2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
The compound of 9-methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (100 mg, 0.285 mmol) prepared in step 4 of Example 3 was dissolved in N,N-dimethylformamide (5 ml), added with sodium hydride (17 mg, 0.428 mmol) at 0° C. The reaction mixture was stirred for 1 hour at room temperature. After that, 1-bromopropane (0.039 ml, 0.428 mmol) was added and the mixture was stirred for one more hour at room temperature. The mixture was poured into water extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (56 mg, yield: 50%, yellow solid).
Reaction SMILES: [CH2:1](O)[C@@H:2]([OH:11])[C@H:3]1[O:8][C:6](=O)[C:5](O)=[C:4]1[OH:10].[NH3:13].[CH3:14]O>>[NH2:13][CH2:1][C@@H:2]([C@H:3]1[CH2:4][O:10][C:6]([CH3:5])([CH3:14])[O:8]1)[OH:11]
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Reactant: N
Reactant: CO
Product: CC1(C)OC[C@H]([C@@H](O)CN)O1
Reaction time: 24 h

Procedure:
Epoxide 22 was prepared (Y. L. Merrer et al., Tetrahed. Lett. 1988, 31, 1003; M. Pottie et al. 1991, 2, 329; A. H. Al-Hakim et al., Synthesis, 1985, 207) from inexpensive and enantiomerically pure D-isoascorbic acid. The epoxide was dissolved in a large excess of methanol and added to a large volume of a saturated solution of ammonia in methanol and allowed to stand for 24 hr. The solvent was evaporated to afford the aminoalcohol 23.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=[O:25])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]1([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccccc1)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccccc1)C1CCCNC1
Yield: 0.1 %

Procedure:
A solution of 3-(S)-Phenylcarbamoyl-piperidine-1-carboxylic acid benzyl ester (1.80 mol, 608 mg) and Pd—C 30% (100 mg) in CH3OH (10 mL) at 25° C. were added to a Paar hydrogenator low pressure reaction vessel. The mixture was reacted at 55 psi with vigorous shaking until hydrogen uptake subsided (2 h). The catalyst was filtered through a pad of celite. The filtrate was concentrated in vacuo which provided piperidine-3-carboxylic acid phenylamide (367 mg, 367 mg theoretical, 99%) as a white foam: LRMS m/z 205 (M++1, C12H16N2O requires 205).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.[H-].[Na+].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1>O>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([O:12][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=2)=[N:19][CH:20]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(COc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 4-fluorobenzyl alcohol (2.60 g, 20.6 mmol) was added sodium hydride (0.88 g, 22.2 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 10 minutes at room temperature. Next, 2,5-dibromopyridine (3.50 g, 14.8 mmol) was added at 0° C., and stirred for 19 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (3.75 g, 89.8%).
Reaction SMILES: [Br-].C([O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:18][N:17](CC2C=CC=CC=2)[C:16]2[C:15](=[O:26])[NH2+:14][C:13]([NH:27]C(=O)C)=[N:12][C:11]1=2)(=O)C>[Pd].CO>[OH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:26])[NH:14][C:13]([NH2:27])=[N:12][C:11]1=2
Reactant: CC(=O)NC1=NC2=C(C(=O)[NH2+]1)N(Cc1ccccc1)CN2CCCCOC(C)=O
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Product: Nc1nc2c(ncn2CCCCO)c(=O)[nH]1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
9-(4-Acetoxybutyl)-N2 -acetyl-7-benzylguaninium bromide (39.7 g; content 97.5%; 80.8 mmol) was added to a mixed solution of methanol (404 ml) and 7.48 g (1.62 mmol) of 5% Pd/C (water content 54%). The reaction was carried out at 50° C. for 4 h under hydrogen atmosphere (1 atm). After completion of the reaction (confirmed by HPLC), the reaction mixture was filtered through Celite, and the solvent was removed by distillation under reduced pressure. Then, water (130 ml) and 25% NaOH (45.2 g) were added to the residue and stirred overnight at 40° C. The mixture was neutralized by 2N HCl stirred at room temperature for 2 h. The precipitated crystals were filtered and dried at 50° C. under reduced pressure for a yield of 17.33 g of 9-hydroxybutylguanine (97.2% purity, 93.4% yield).