Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.[Si:46](Cl)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 13.0 g (23.9 mmol) 5′-O-(4,4′-dimethoxytrityl)thymidine 16 in 50 ml DMF was added 3.0 g (44 mmol) imidazole and 3.6 g (23.9 mmol) tert-butyl-dimethylsilyl chloride. The solution was stirred at room temperature for 3 hours. DMF was then removed in vacuo and the residue was dissolved in 300 ml of ethyl acetate. The solution was washed with water and the organic layer was dried over MgSO4. After concentration of the solution and recrystallization from ethyl acetate/hexane, the solid product 5′-O-(4,4′-dimethoxy)-3′-(tert-butyldimethylsilyl)thymidine 17 was used directly for the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].O1CCCC1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl.O>[CH2:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCBr
Reactant: OCCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCOCCc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
17 g of 2-thiopheneethanol was cooled to 0° C., and to this, a suspension formed by adding 7.1 g of sodium hydride (60% in oil) to 110 ml of tetrahydrofuran was added dropwise. The solution was stirred at 0° C. for 20 minutes under a nitrogen atmosphere, and to this, 27 g of 1-bromononane was added dropwise. The resulting solution was heated to 90° C. and stirred for 8 hours. 100 ml of water and 100 ml of dichloromethane were added to the reaction solution to separate the organic layer. The organic layer was washed with 300 ml of saturated salt water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane/dichloromethane) to obtain 20 g of 2-(2-nonyloxyethyl)thiophene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[S:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][C@@H:35]([C:37]2[N:38]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]([F:59])([F:58])[F:57])=[CH:50][CH:49]=3)[C:39](=[O:47])[C:40]3[CH:46]=[CH:45][CH:44]=[N:43][C:41]=3[N:42]=2)[CH3:36])[CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:34]([C@@H:35]([C:37]2[N:38]([C:48]3[CH:49]=[CH:50][C:51]([O:54][CH2:55][C:56]([F:57])([F:59])[F:58])=[CH:52][CH:53]=3)[C:39](=[O:47])[C:40]3[CH:46]=[CH:45][CH:44]=[N:43][C:41]=3[N:42]=2)[CH3:36])[CH2:33][CH:30]2[CH2:31][CH2:32][S:27][CH2:28][CH2:29]2)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@H](NCC1CCSCC1)c1nc2ncccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](c1nc2ncccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1)N(CC1CCSCC1)C(=O)Cc1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
The compound 4-fluoro-3-trifluoromethylphenylacetic acid (164 mg, 0.74 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (64 μL, 0.74 mmol) was added, then after 5 min, N,N-dimethylformamide (5.7 μL, 0.07 mmol) was added. The reaction stirred at 0° C. for 30 min. and room temperature for 1 h. The solution was added slowly to a mixture of D1 (208 mg, 0.43 mmol) and triethylamine (182 μL, 1.30 mmol) in dichloromethane at −78° C. The mixture was stirred for 30 min., then washed with saturated aqueous sodium bicarbonate and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was purified by chromatography (2% methanol with 0.1% ammonium hydroxide in dichloromethane), yielding 265 mg of 4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16](Br)=[CH:15][C:14]=3[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16]([C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=2[Cl:30])=[CH:15][C:14]=3[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ba+2]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(Cl)cc2Cl)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Yield: 66.7 %

Procedure:
The title compound (85 mg, 0.20 mmol) was prepared by following the procedure of example 3 from cis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (107 mg, 0.30 mmol), 2,4-dichlorophenylboronic acid (69 mg, 0.36 mmol), barium hydroxide octahydrate (142 mg, 0.45 mmol) and triphenylphosphine (7.9 mg, 0.03 mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) in DMF (3.0 mL)/H2O (0.6 mL): MS (ES) 422.1 (M+H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][N:11]2CC=C)=[CH:6][CH:5]=1.Cl.C.[OH-].[Na+]>[Ru](Cl)(Cl)Cl.C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[NH:11][CH2:12][CH2:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:15]2)=[CH:8][CH:9]=1
Reactant: C=CCN1CCN(c2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc([C@@H]2CN(c3ccccc3)CCN2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
To (R)-2-(4-chlorophenyl)-4-phenyl-1-(2-propenyl)hexahydropyrazine dihydrochloride (285 mg, 0.87 mmol) produced in Example 21, distilled water (2 mL), conc. hydrochloric acid (181 mg, 2.0 equivalents), ruthenium chloride (9 mg, 0.04 equivalent) and activated charcoal (9 mg) were added. The mixture was stirred at 100° C. for 18 hours. Toluene (4 mL) and 30 wt % aqueous solution of sodium hydroxide (258 mg, 2.2 equivalents) were added thereto. The formed insolubles were removed by filtration, and washed with toluene (2 mL). After the organic layer and aqueous layer of the filtrate were separated, the organic layer was washed twice with distilled water (6 mL). The organic layer was concentrated and dried under vacuum, to obtain 89 mg of the title compound as brown oil (yield: 29%, chemical purity: 83.8 area %). The retention time in the chemical purity analysis method was 3.7 min.
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C:11]([CH2:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][N:13]=[C:9]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2.[Br:29]N1C(=O)CCC1=O>C1COCC1>[Br:29][C:5]1[NH:4][C:3]2[C:2](=[O:1])[N:10]3[C:11]([CH2:14][NH:15][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:12][N:13]=[C:9]3[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To the solution of N-[(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]benzamide (0.11 g, 0.28 mmol) in THF (10 mL) was added N-Bromosuccinimide (0.076 g, 0.42 mmol). The mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated and purified by preparative LCMS. LCMS calculated for C19H21BrN7O2(M+H): 458.1; found: 458.0, 460.0.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH2:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[Br:27][C:28]1[CH:36]=[C:35]([F:37])[C:31]([C:32](O)=[O:33])=[C:30]([F:38])[CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH:25][C:32](=[O:33])[C:31]1[C:30]([F:38])=[CH:29][C:28]([Br:27])=[CH:36][C:35]=1[F:37])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: CCCOC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(Br)cc1F

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 8, starting from (S)-2-amino-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (4.67 g, 13 mmol) , 4-bromo-2,6-difluorobenzoic acid (3.12 g, 13.16 mmol), HBTU (4.99 g, 13.16 mmol), and DIPEA (6.8 mL, 39 mmol), and after ISCO column chromatography purification, resulted in an amorphous off-white solid (6.71 g, 89%). ES-HRMS m/e calcd for C26H26BrF2N3O5 (M+H)+ 578.1097, found 578.1096.
Reaction SMILES: CO.C([O:6][C@@H:7]([CH3:23])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])(=O)C.O.[OH-].[Li+].C(O)(=O)C>O>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[C@@H:7]([OH:6])[CH3:23])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](O)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Methanol (300 kg) was added to the residue from Example 7 containing (S)-1-(4-benzylpiperazin-1-yl)-1-oxopropan-2-yl acetate 4 and the mixture was cooled to 0-10° C. A solution of lithium hydroxide monohydrate (13.6 kg, 324 mol) in water (100 kg) was added at a rate to maintain the reaction temperature at 0-15° C. After aging for 2 h, the pH was adjusted to 7 at 5-15° C. with acetic acid (4.5 kg, 75 mol). The mixture was concentrated under reduced pressure. To the residue was added dichloromethane (150 kg) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×150 kg). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Ethyl acetate (31 kg) was added to the residue, followed by slow addition of cyclohexane (183 kg). The mixture was heated to 40-50° C. and stirred for 1 h. The mixture was cooled to 0-10° C. and aged for 8 h. The solid was collected by filtration, washed with cold cyclohexane and dried under reduced pressure at 50° C. for 12 h to afford (S)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one 5 (46 kg, 71% yield, 98% purity by HPLC). 1H NMR (300 MHz, CDCl3) δ 7.42-7.20 (m, 5H), 4.43 (q, J=6.4 Hz, 1H), 3.84 (broad s, 1H), 3.76-3.55 (m, 2H), 3.53 (s, 2H), 3.48-3.32 (m, 2H), 2.46 (s, 4H), 1.32 (dd, J=6.6, 3.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.CO>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[NH:3][CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CCC(C)NC1
Reaction time: 15 h

Procedure:
Methyl 6-methylnicotinate (4.9 g, 32.4 mmol) was combined with 10% Pd/C (wet, 2.5 g), methanol (40 mL) and acetic acid (50 mL) and hydrogenated at 40° C., (50 psi) for 15 hours. The mixture was filtered through a pad of Celite, washed with methanol, and concentrated under reduced pressure. The residue was co-evaporated with 80 mL of toluene and then with 50 mL of methanol. The residue was partitioned between 40 mL of dichloromethane and 20 mL of saturated K2CO3. The aqueous layer was extracted with dichloromethane and the combined organics dried with anhydrous K2CO3. The solution was concentrated and died under vacuum to 5.0 g of pale yellow oil. The cis/trans product mixture was not well separated by TLC (Rf=0.55 and 0.57, CH2Cl2:MeOH:NH4OH, 90:9:1). The crude product mixture was taken directly to the next step.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[Cl-].[CH3:39][O:40][NH3+:41].N1C=CC=CC=1.O>CN(C=O)C>[CH3:39][O:40][N:41]=[CH:35][C:27]1[NH:28][C:29](=[O:34])[C:30]2[C:25]([CH:26]=1)=[CH:24][C:23]1[CH2:22][CH2:21][C@@:18]3([C:17](=[O:37])[C:4]4=[C:5]([OH:16])[C:6]5[C:7](=[O:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10](=[O:12])[C:11]=5[C:2]([OH:1])=[C:3]4[C:19]3=[O:20])[C:32]=1[C:31]=2[OH:33]
Reactant: CO[NH3+]
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CON=Cc1cc2cc3c(c(O)c2c(=O)[nH]1)[C@@]1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(OC)=CC3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 3.4 mg (40.7 μmol) O-methylhydroxylammonium chloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h at room temperature. Then, it is added to 100 ml water, and the supernatant is sucked off from the red precipitate (HPLC clean).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:26][C:27]1[N:28]=[C:29]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:30]2[S:35][C:34](C=O)=[CH:33][C:31]=2[N:32]=1>>[CH2:19]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][C:34]2[S:35][C:30]3[C:29]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:28][C:27]([Cl:26])=[N:32][C:31]=3[CH:33]=2)[CH2:13][CH2:12]1)[CH2:15][CH2:16][O:17][CH3:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCCN(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COCCN(Cc1ccccc1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 69.5 %

Procedure:
The reaction mixture was cooled and diluted with dichloromethane (30 ml), washed with water, brine and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by silica flash chromatography to give 4-[benzyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (484 mg). 4-[Benzyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (442 mg), and 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (300 mg) were treated under standard reductive amination conditions to give benzyl-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-piperidin-4-yl]-(2-methoxy-ethyl)-amine (379 mg), as an oil which crystallized on standing.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH2:12]([O:11][CH:4]([O:3][CH2:1][C:2]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:13]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC(OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a 1000 mL round-bottomed flask was added ethyl 3,3-diethoxypropionate (20.0 g, 0.1051 mole), benzyl alcohol (22.7 g, 0.2102 mole), p-toluenesulfonic acid monohydrate (0.5 g, 0.0026 mole) and benzene (350 mL). Heating the mixture at 80° C., the solvent was distilled from the reaction mixture in 1.5 h period. The resulting residue was dissolved in ether (@ 300 mL) and washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to give ethyl 3,3-dibenzyloxypropionate (9) as a colorless oil (32.9 g, 99.5% yield): 1H NMR (CDCl3) d 1.22 (t, 3H, J=7.2 Hz), 2.79 (d, 2H, J=5.9 Hz), 4.12 (q, 2H, J=7.2 Hz), 4.60 (d, 2H, J=11.6 Hz), 4.70 (d, 2H, J=11.6 Hz), 5.22 (t, 1H, J=6 Hz), 7.27-7.36 (m, 10H); IR (Neat) 3100, 3080, 3040, 2990, 2940, 2920, 2885, 1740, 1630, 1458, 1375, 1315, 1190, 1120, 1050, 1030, 740, 700. ##STR8##
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:37])([F:36])[C:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])([OH:27])[CH2:21][N:22]2[CH:26]=[N:25][N:24]=[N:23]2)=[N:17][CH:18]=1>[Cu]>[N:1]1[N:2]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:36])([F:37])[C:20]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])([OH:27])[CH2:21][N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[N:17][CH:18]=2)[N:3]=[CH:4][CH:5]=1
Reactant: c1c[nH]nn1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(-n2nccn2)cn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
To a stirred solution of 1H-1,2,3-triazole (410 mg, 5.93 mmol) were added copper (Cu) powder (93 mg, 1.45 mmol), K2CO3 (160 mg, 1.15 mmol) and 1 (300 mg, 0.694 mmol) under N2 atmosphere. The reaction mixture was gradually heated to 140° C. and stirred for 4 h. The reaction mixture was cooled to 100° C., quenched with ethylenediaminetetraacetic acid (EDTA) sodium (Na) salt solution, and made basic with sodium carbonate (Na2CO3) solution. The aqueous layer was extracted with CH2Cl2 (3×50 mL); the combined organic phases were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluting with 45% EtOAc/hexane) to afford 9 (0.12 g, 0.297 mmol, 42%) as a solid. 1H NMR (500 MHz, CDCl3): δ 9.33 (s, 1H), 8.77 (s, 1H), 8.47 (dd, J=8.5, 2.0 Hz, 1H), 7.90 (s, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.34-7.29 (m, 1H), 6.78-6.73 (m, 1H), 6.67-6.64 (m, 1H), 5.64 (d, J=14.0 Hz, 1H), 5.14 (d, J=14.0 Hz, 1H). MS (ESI): m/z 420.9 [M++1]. HPLC: 99.9%.
Reaction SMILES: C1(O)C=CC=CC=1.B(O)(O)O.[CH2:12]([NH:28][C:29]1[C:42]2[C:41](=[O:43])[C:40]3[C:35](=[C:36](O)[CH:37]=[CH:38][C:39]=3[NH2:44])[C:34](=[O:46])[C:33]=2[C:32]([OH:47])=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[NH2:48]C1C2C(=O)C3C(=C(O)C=CC=3[N+]([O-])=O)C(=O)C=2C(O)=CC=1.C(Cl)CCCCCCCCCCCCCCC.O.NN.N>[N+](C1C=CC=CC=1)([O-])=O.CO.O.C1(C)C=CC=CC=1>[NH2:44][C:39]1[C:40]2[C:41](=[O:43])[C:42]3[C:33](=[C:32]([OH:47])[CH:31]=[CH:30][C:29]=3[NH:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:34](=[O:46])[C:35]=2[C:36]([NH2:48])=[CH:37][CH:38]=1
Reactant: Nc1ccc(O)c2c1C(=O)c1c([N+](=O)[O-])ccc(O)c1C2=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(O)c2c1C(=O)c1c(N)ccc(O)c1C2=O
Agent: CCCCCCCCCCCCCCCCCl
Agent: N
Agent: NN
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Solvent: Oc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(O)c2c1C(=O)c1c(N)ccc(N)c1C2=O
Temperature: 110 °C

Procedure:
120 parts of phenol, 6.1 parts (0.1 mole) of boric acid and 70 parts of toluene are refluxed, while stirring, the water of reaction formed thereby being removed from the system. The toluene is then distilled off, the mixture is cooled to 110° C. and 25.4 parts (0.05 mole) of 1-palmitylamino-8-amino-4,5-dihydroxyanthraquinone (prepared by reacting 1-amino-8-nitro-4,5-dihydroxyanthraquinone with palmityl chloride in nitrobenzene and then reducing the product with hydrazine hydrate) are added. Ammonia is then passed in at this temperature until no further starting material can be detected in the thin-layer chromatogram (duration: 3 hours). The reaction mixture is cooled to 90° C. and 240 parts of methanol are added. After cooling to room temperature, the dye precipitated is filtered off with suction and the material on the filter is washed with methanol and water and dried. 20 parts of 1,4-diamino-5-hydroxy-8-palmitylaminoanthraquinone of melting point 174° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[N:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:22]=[N:21][CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1ncc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cn1

Procedure:
The title compound was prepared from the product of Example 65A and pyrimidin-5-ylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 308.0 (M+H)+, retention time 1.45 minutes.
Reaction SMILES: CO[C:3]([C:5]1[CH2:6][CH2:7][CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)[NH:11][C:10]=12)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:3]([CH:5]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)=[CH:13][C:14](=[O:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)=[O:4])=[C:25]([O:30][CH3:31])[CH:24]=1
Reactant: COc1cc(Cl)ccc1N
Reactant: COC(=O)C1=C2NC(c3ccncn3)=CC(=O)N2CCC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1NC(=O)C1CCCn2c1nc(-c1ccncn1)cc2=O
Yield: 32.2 %

Procedure:
To a suspension of 0.150 g (0.52 mmol) of (+/−)-4-oxo-2-pyrimidin-4-yl-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic acid methyl ester in a sealed tube in 10.00 mL of toluene was added 0.825 g (5.24 mmol) of 4-chloro-2-methoxy-phenylamine and the resulting mixture was stirred under reflux for 16 hours. The mixture was dissolved in water and ethyl acetate. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 100/0/0 to 98/2/02) to afford 0.069 g (32%) of a solid.