Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1
Reactant: COc1ccc(CCNc2cc(CO)nc(Cl)n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCNc2cc(CO)nc(OC)n2)cc1
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of {2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol (6.5 g mg, 22.1 mmol, Intermediate (57)] 25 wt % sodium methoxide in MeOH (15.2 mL, 66.3 mmol), in MeOH (20 mL) is heated to 90° C. and stirred for 3 hours and concentrated by rotary evaporator to remove the solvent. The solid is dissolved in water and the solution is acidified to pH 8 with the addition of saturated ammonium chloride solution. Extracted twice with 150 mL ethyl acetate, combined the extracts, Dried over magnesium sulfate, filtered and concentrated to afford {2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol [5.6 g, 88%, Intermediate (58)] as a solid. LCMS: RT=2.35 minutes, MS: 290 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30]>C1COCC1.CN(C=O)C>[OH:26][C@H:25]([CH2:27][N:29]([CH3:30])[CH3:28])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CNC
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), and dimethylamine (1.24 ml of a 2M solution in THF, 2.48 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by trituration with methanol to give (2R)-7-(2-hydroxy-3-dimethylaminopropoxy)4-(indol-5-yloxy)-6-methoxyquinazoline (265 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 35 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 35%): 1H NMR (400 MHz, CDCl3) δ 8.54 (m, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.10-8.04 (m, 2H), 7.82-7.80 (d, J=8.5 Hz, 2H), −7.62-7.58 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 3.82 (d, J=5.8 Hz, 2H), 1.58 (s, 6H). MS (ESI) m/z: Calculated for C23H18ClF3N4O2S: 506.08. found: 507.0 (M+H)+.
Reaction SMILES: O1CCCC1.BrCCBr.[Cl:10][C:11]([Cl:17])(Cl)[C:12]([O:14][CH3:15])=[O:13].Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CCCCCCC.[Zn]>[Cl:10][C:11]([Cl:17])=[C:12]([O:14][CH3:15])[O:13][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C(Cl)(Cl)Cl
Reactant: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: BrCCBr
Product: COC(O[Si](C)(C)C)=C(Cl)Cl
Temperature: -55 °C
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
A 2-liter three-necked flask equipped with a mechanical stirrer, thermometer, condenser, pressure equalizing addition funnel and an argon inlet was charged with zinc dust (78.0 g, 1.19 mol) followed by the addition of anhydrous tetrahydrofuran (400 ml). To this mixture was added 1,2-dibromoethane (2 ml) to activate the zinc. The resulting mixture was heated at a gentle reflux for 25 minutes. After cooling to −55° C., a solution of methyl trichloroacetate (100.3 g, 0.565 mol) and chlorotrimethylsilane (80 ml, 0.648 mol) was added at a rate to maintain the reaction temperature at −55 to −60° C. (1 hour required). After the addition was complete, the mixture was allowed to stir at room temperature for approximately 90 minutes. The resulting mixture was diluted with heptane (700 ml) and filtered under nitrogen through a Celite 545 pad. The filtercake was washed with additional heptane (1×300 ml, 3×200 ml). The filtrate was then concentrated at reduced pressure on a rotary evaporator (approximately 10-15 mm Hg with a 22-27° C. water bath) to give crude (2,2-dichloro-1-methoxy-vinyloxy)-trimethylsilane as a dense oil (129.2 g). Quantitative proton NMR indicates this crude material contains 0.389 mol (68.8%) of (2,2-dichloro-1-methoxy-vinyloxy)-trimethylsilane.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9].[CH:14]12[NH:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][N:16]([C:22]([O:24][CH2:25][CH:26]1[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:15]2>>[CH2:8]([S:10]([N:21]1[CH:18]2[CH2:19][CH2:20][CH:14]1[CH2:15][N:16]([C:22]([O:24][CH2:25][CH:26]1[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:17]2)(=[O:12])=[O:11])[CH3:9]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CC2CCC(C1)N2
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1C2CCC1CN(C(=O)OCC1c3ccccc3-c3ccccc31)C2
Reaction time: 16 h

Procedure:
To the solution of (9H-fluoren-9-yl)methyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in DCM (2 mL) from step 2 was added triethylamine (100 mg, 138 μL, 1.0 mmol) and ethanesulfonyl chloride (190 mg, 140 μL, 1.4 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was washed with 50% saturated bicarbonate solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain (9H-fluoren-9-yl)methyl 8-(ethylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, which was used directly for the next step. LC/MS m/z 427.5 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:4]1[CH:3]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cncnc2)CC1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
5-Bromo pyrimidine (1.0 g, 6.29 mmol) and 1-Boc-piperazine (1.17 g, 6.28 mmol) were dissolved in toluene (20 mL) and the solution was purged with argon for 10 min. Sodium tert-butoxide (816 mg, 8.49 mmol) and catalytic Pd(PtBu3)2 (320 mg, 0.63 mmol) were added and the reaction mixture was heated to 120° C. for 10 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 80% EtOAc in petroleum ether) to get tert-butyl 4-(pyrimidin-5-yl)piperazine-1-carboxylate (700 mg, yield 42%). 1H NMR (300 MHz, MeOD) δ 8.57 (s, 1H), 8.48 (m, 2H), 3.61-3.58 (m, 4H), 3.30-3.27 (m, 4H), 1.47 (s, 9H). MS (ESI) m/z: Calculated for C13H20N4O2: 264.16. found: 265.0 (M+H)+
Reaction SMILES: O=C(C)[CH2:3][CH2:4][S:5][Sn:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10].S1C=CC=C1CC(O)=O.[CH3:29][S:30](C=C)(=[O:32])=[O:31].[Sn]=O>>[CH3:29][S:30]([CH2:3][CH2:4][S:5][Sn:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:32])=[O:31]
Reactant: CCCC[Sn](CCCC)(CCCC)SCCC(C)=O
Reactant: C=CS(C)(=O)=O
Agent: O=C(O)Cc1cccs1
Agent: O=[Sn]
Product: CCCC[Sn](CCCC)(CCCC)SCCS(C)(=O)=O
Yield: 41 %

Procedure:
This compound was prepared analogously to (5), starting from thiolacetic acid and methylvinylsulphone, leading to the intermediate sulphone (47%), treating subsequently with the tin oxide to give the required product (6) (41%). All spectroscopic and analytical data were consistent with the proposed structures.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1.Cl>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OCC1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20 %

Procedure:
Piperidin-2-ylmethanol (1.1 eq) was dissolved in dichloromethane (4 ml/mmol), cooled, and triethylamine (2.5 eq) was added. A solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (1 eq) in dichloromethane (2 ml/mmol) was added dropwise at 0° C., then the mixture was stirred for 90 min at room temperature. Hydrogen chloride solution (eq, 0.5 mol/l, 2 ml/mmol) was added, the mixture stirred for 15 min and the phases separated. The organic phase was washed with water, dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was used in the next stage with no further purification. Yield: 20%
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1>[C].[Pd].C(O)C>[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:11])([CH3:12])[CH2:7][CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: CC1=CC(C)(C)c2ccc(O)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1CC(C)(C)c2ccc(O)cc2O1
Yield: 85.8 %

Procedure:
A 100 ml autoclave was charged with 6.0 g of 7-hydroxy-2,4,4-trimethyl-4H-1-benzopyran synthesized by the method of Japanese Laid-Open Patent Publication No. 5475/1981, 1.0 g of 5% palladium-carbon and 20 ml of ethanol, and hydrogenation was carried out at 85° C. The resulting product was recrystallized from n-hexanetoluene to give 5.2 g (86%) of the desired product as colorless crystals (melting point 97°-98° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:26])[NH:17][C@H:18]([C:20]2C=CC=CC=2)C)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@@H:14]([O:15][C:16](=[O:26])[NH:17][CH2:18][CH3:20])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@@H](C)c1ccccc1
Product: CCNC(=O)O[C@@H](c1ccccc1)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using ((S)-1-phenyl-ethyl)-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Clc1nc(Cl)c2[nH]c3cc(Br)ccc3c2n1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: Clc1nc(N2CCNCC2)c2[nH]c3cc(Br)ccc3c2n1
Yield: 86.5 %

Procedure:
1.3 g (4.10 mmol) 7-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole (Example 4) and 1.3 g (14.8 mmol) piperazine were heated in 50 ml toluene at 65° C. for 3 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 1.3 g (87%) 7-bromo-2-chloro-4-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 366, 368 [M+H]+
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]=[O:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.[CH3:44][O:45][CH2:46][CH2:47][NH2:48]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:31]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:32])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: COCCN
Product: COCCNC(=O)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N)n2)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 151 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinecarbaldehyde and 2-methoxyethylamine (Sigma-Aldrich, St. Louis, Mo.), and the desired product 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(2-methoxyethyl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinecarboxamide was isolated as a yellow solid (8% for two steps). 1H NMR (400 MHz, CDCl3) δ 12.08 (s, 1H); 9.19 (d, J=2.54 Hz, 1H); 8.78 (d, J=2.54 Hz, 1H); 8.35 (d, J=2.54 Hz, 1H); 8.12 (dd, J=8.80, 2.74 Hz, 1H); 6.79 (d, J=8.80 Hz, 1H); 6.72-6.76 (m, 1H); 3.95 (s, 3H); 3.66-3.72 (m, 2H); 3.63 (q, J=4.56 Hz, 2H); 3.38 (s, 3H); 2.55 (s, 3H). m/z (ESI, +ve ion) 411.0 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])([CH3:3])[CH3:2].[Cl:12][CH2:13][C:14](O)=O.N>Cl>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=[C:14]1[CH2:13][Cl:12])([CH3:3])[CH3:2]
Reactant: O=C(O)CCl
Reactant: CC(C)Nc1ccccc1N
Agent: Cl
Agent: N
Product: CC(C)n1c(CCl)nc2ccccc21
Yield: 64.5 %

Procedure:
N-isopropyl-o-phenylenediamine (2.8 g, 18.6 mmol), which is a known compound, was reacted with monochloroacetic acid (2.64 g, 28 mmol) in hydrochloric acid. The reaction mixture was made to weak by alkaline alkali with aqueous ammonia and the obtained oily material was refined in a usual manner to give the title intermediate (2.5 g, 12 mmol).
Reaction SMILES: CO[C:3](=O)[CH2:4][CH2:5][C@H:6]([NH2:37])[C:7](=[O:36])[NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:22]([Cl:35])[CH:21]=1.ClC1C=C(NC2C3C(=CC=C(N)C=3)N=CN=2)C=CC=1OCC1C=CC=C(F)C=1>>[Cl:35][C:22]1[CH:21]=[C:20]([NH:19][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([NH:8][C:7]([CH:6]4[CH2:5][CH2:4][CH2:3][NH:37]4)=[O:36])[CH:10]=3)[N:15]=[CH:14][N:13]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: COC(=O)CC[C@H](N)C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: O=C(Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1)C1CCCN1
Yield: 82 %

Procedure:
The procedure of (13-1) of Example 13 was repeated except for using 448 mg of the compound obtained in Example 15 instead of the compound obtained in Example 12 to obtain the title compound (297 mg, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[O:20]=[C:21]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:26]3[CH2:27][CH2:28][C:23]4([C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:21](=[O:20])[O:22]4)[CH2:24][CH2:25]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)cnc12
Yield: 89 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.436 g, 1.74 mmol) obtained in Example 19, step 2 and 3-oxo-3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (Journal of Organic Chemistry, 1976, vol. 15, item 2628, 0.500 g, 2.09 mmol), the title compound (0.680 g, 89%) was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.Cl.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:20]1([CH:26]2[CH2:27][CH2:28][N:29]([C:10]([CH:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[O:12])[CH2:30][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1Cc2ccccc2C1)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
750 mg (4.6 mmol) of 2,3-dihydro-1H-inden-2-carboxylic acid (prepared as described in Hacksell, J. Med. Chem., 24, 429, 1981) were dissolved in 15 mL of CH2Cl2 and 0.65 mL (7.4 mmol) of oxalyl chloride were added dropwise at 0° C. under a nitrogen atmosphere. The solution was allowed to warm to room temperature in 2 h, then the solvent was removed in vacuo. The resulting acyl chloride was dissolved in 10 mL of CH2Cl2 and added to a solution of 909 mg (4.6 mmol) of 4-phenylpiperidine hydrochloride and 1.9 mL (13.8 mmol) of triethylamine in 15 mL of CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then water was added and the organic phase was washed with 5% HCl and dried. The solvent was removed in vacuo and the resulting crude product was purified by flash chromatography, eluting with a mixture Et2O/Petroleum ether 7:3, yielding 630 mg of the title compound. IR (cm−1)=2944, 1636, 1494. NMR (300 MHz, CDCl3, δ ppm): 7.35 (m, 2H); 7.25-7.1 (m, 7H); 4.85 (m, 1H); 4.15 (m, 1H); 3.55 (m, 1H); 3.4-3.3 (m, 2H); 3.3-3.1 (m, 3H); 2.85-2.6 (m, 2H); 2.0-1.9 (m, 2H); 1.75.1.6 (m, 2H). MS (m/z): 306.0 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:26][N:15]1[CH2:16][CH2:17][N:18]2[C:19](=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]2)[C@@H:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=S1(=O)CCN2CCN[C@@H](c3ccc(Oc4ccccc4)cc3)C2=N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN2CCS(=O)(=O)N=C2[C@@H]1c1ccc(Oc2ccccc2)cc1
Reaction time: 20 h
Yield: 13.4 %

Procedure:
A mixture of (9S)-9-(4-phenoxyphenyl)-3,4,6,7,8,9-hexahydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (129 mg), potassium carbonate (100 mg) and iodomethane (0.022 mL) in DMF (4 mL) was stirred at 0° C. to room temperature for 20 hr. The reaction mixture was added with NH silica gel, evaporated, and purified by column chromatography (NH silica gel, eluted with EtOAc in hexane then 20% MeOH in EtOAc) then preparative HPLC (C18, MeCN in H2O with 0.1% TFA). The combined collected fractions were concentrated in vacuo. The resulting aqueous solution was added with NaHCO3 and NaCl, then extracted with EtOAc (2×100 mL). The organic layer was combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from EtOAc-IPE to give the title compound (18 mg) as a white solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:32])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1>CCOCC.[Cl-].[Zn+2].[Cl-]>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:32])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([F:30])([F:31])[C:26]([F:28])([F:29])[F:27])=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a suspension (30 ml) of zinc chloride (2.70 g, 19.84 mmol) in ether was added sodium borohydride (1.50 g, 39.68 mmol) at room temperature and the mixture was stirred as it was for 2 hrs. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(3-chlorophenyl)-3-oxo-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate (4.45 g, 9.92 mmol) in ether (20 ml), and the mixture was stirred at room temperature for 1 hr. The reaction was quenched with 1N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, 5:1) to give ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate (3.95 g, 89%) as a colorless transparent oil.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[CH:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:28]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:19][CH3:20])[C:4]([OH:3])=[O:21])=[CH:12][CH:11]=2)=[CH:33][CH:34]=1)[C:25]1[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(Cc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Step A (0.1 mmol, 1 eq) in 0.7 ml of DMF in a 16×100 mm tube treated with 4-hydroxydiphenylmethane (0.11 mmol, 1.1 eq) and Cesium Carbonate (0.3 mmol, 3 eq) and stirred at room temperature overnight. The reactants were filtered and washed with DMF several times. The solvent was evaporated under vacuo and the residue reconstituted in a mixture of Ethanol (2 ml) and NaOH (1M) (1 ml) and stirred at room temperature until reaction is completed by HPLC-MS. Then HCl (1M) was added (until pH=3) and the solvent were eliminated under vacuo. The residue was reconstituted in CH2Cl2/H2O and filtered through a hidrofobic syringer. The organic layer was separated, concentrated and purified by HPLC-MS to get the title compound. MS(ES) for C28H28O4[M+NH4]+: 446.2.