Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].[H][H].S(=O)(=O)(O)O>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [H][H]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2ccc(CO)o2)cc1

Procedure:
To a heated suspension of 5-(4-nitrophenyl)-2-furancarboxaldehyde (176 g., 0.8 m.) and 1000 ml of ethanol was added a suspension of sodium borohydride (82 g.) in 1500 ml of ethanol. The solids dissolved and the solution turned very dark. The solution was stirred without external heating until hydrogen ceased to be evolved (22 hours). Upon stirring, the material solidified (pH 9-11). To the suspension was added a 5 percent sulfuric acid solution until the solution was just acidic (600 ml., pH 5-6). The dark mixture was dissolved upon heating at 60°-70° C. for 1 hour. After cooling, the solids were filtered and the filtrate was diluted with water to ppt. the product. The solids were extracted with boiling SDA-32 and the extracts were diluted with water. Total yield of 5-(p-nitrophenyl)-furfuryl alcohol was 150 grams (85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][O:18][CH2:19][CH2:20][C:21]1[C:26]([CH2:27]O)=[CH:25][N:24]=[C:23]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[N:22]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:27][C:26]3[C:21]([CH2:20][CH2:19][O:18][CH3:17])=[N:22][C:23]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[N:24][CH:25]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)nc4)nc3CCOC)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as yellow solid.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[CH2:11][C:12]([C:34](O)=[O:35])=[CH:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][CH:22]=3)=[CH:17][C:15]=2[N:16]=1)=O)(C)(C)C.[Si]([O:44][C@H:45]1[C@H:49]([O:50][Si](C(C)(C)C)(C)C)[CH2:48][NH:47][CH2:46]1)(C(C)(C)C)(C)C>>[NH2:9][C:10]1[CH2:11][C:12]([C:34]([N:47]2[CH2:48][C@@H:49]([OH:50])[C@H:45]([OH:44])[CH2:46]2)=[O:35])=[CH:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:28])=[CH:25][CH:26]=3)=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CNC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl
Product: NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)N2C[C@@H](O)[C@H](O)C2)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Steps H and I) with conc. HCl instead of TFA using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and (3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidin.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][CH3:20])=[N:3]3)=[CH:14][CH:15]=1
Reactant: Fc1ccc(Oc2cccc3nc(Cl)ccc23)cc1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(Oc3ccc(F)cc3)cccc2n1

Procedure:
2-Chloro-5-(4-fluoro-phenoxy)-quinoline (60 mg, 0.22 mmol) and 2-methoxybenzylamine (90 mg, 0.66 mmol) were stirred in a sealed tube at 150° C. for 16 hours. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->75:25 gradient). (5-(4-Fluoro-phenoxy)-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a yellow oil (56 mg, 68%), MS: m/e=375.4 (M+H+).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([O:9][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[C:34]([F:37])([F:36])[F:35])[CH2:22][CH2:21]3)=[N:16][N:15]2[CH:39]=1)=O)C>>[CH2:1]([NH:6][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[C:34]([F:35])([F:37])[F:36])[CH2:22][CH2:21]3)=[N:16][N:15]2[CH:39]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Reactant: CCCCCN
Product: CCCCCNC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Yield: 39 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use n-pentylamine in place of isoamylamine to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 39% yield. 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 7.76-7.66 (m, 2H), 7.33 (s, 1H), 7.27-7.18 (m, 1H), 7.09-7.03 (m, 1H), 6.89 (d, J=9.9 Hz, 1H), 4.05-3.94 (m, 1H), 3.91-3.8 (m, 1H), 3.69-3.54 (m, 2H), 3.15-3.37 (m, 4H), 3.65-3.29 (m, 2H), 1.67-1.55 (m, 2H), 1.42-1.27 (m, 4H), 0.88 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.6, 162.3, 154.8, 138.3, 136.9, 135.6, 129.7, 129.6, 129.57, 129.5, 126.3, 125.1, 125.4, 122.9, 121.4, 118.3, 116.8, 116.5, 114.9, 114.6, 111.9, 46.2, 45.6, 41.2, 39.2, 29.4, 29.1, 22.4, 14.0. MS (ES+) m/z 507 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Si](O[Cr](O[Si](C)(C)C)(=O)=O)(C)C>ClCCl>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCCCCCCCCCCCN1CCOCC1
Agent: C[Si](C)(C)O[Cr](=O)(=O)O[Si](C)(C)C
Solvent: ClCCl
Product: O=CCCCCCCCCCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A mixture of 542.9 mg (2.0 mmol) of 12-(4-morpholinyl)-1-dodecanol and 3.0 g of (5.10 mmol) of bis(trimethylsilyl)chromate (M. Heravi, Monatsh. Chem. 1998, 129(12), 1305-1308) in 10 ml of dichloromethane is stirred at room temperature overnight and filtered. After removal of the dichloromethane, the residue is purified by silica gel column chromatography to give 210 mg (39%) of 12-(4-morpholinyl)-1-dodecanal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)([OH:10])[C:26]([F:28])([F:27])[F:25])=[C:4]([Cl:24])[CH:3]=1
Reactant: CC(C(=O)c1ccc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 6-[2-(4-bromo-2-chloro-phenyl)-propionyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=475.9 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 87.5 %

Procedure:
A solution of 2-chloro-5-nitro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 29a, 0.50 g) and ammonium chloride (0.5 g) were dissolved in 50% aqueous ethanol. Iron powder (0.5 g) was added and the mixture stirred at reflux temperature for 3 h before being cooled and the solids removed by filtration. The mother liquors were treated with 10% sodium hydroxide solution and the product extracted into ethyl acetate. The organic solution was washed with brine, dried over sodium sulphate (Na2SO4) and concentrated to give a residue which was purified by silica gel chromatography to give the sub-title compound as a white solid (0.4 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:24][OH:25].CCN(CC)CC>ClCCl.ClCCl.C(Cl)(Cl)Cl>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH:24]=[O:25]
Reactant: Cc1ccc(-c2nc(CO)c(C)o2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc(C=O)c(C)o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
At −78° C., 22.2 ml of DMSO in 30 ml of dichloromethane are added dropwise to a solution of 12 ml of oxalyl chloride in 150 ml of dichloromethane such that the temperature does not exceed −70° C. The solution is then stirred at this temperature for 30 min. 24 g of 5-methyl-2-p-tolyloxazole-4-methanol in 120 ml of dichloromethane/chloroform (2/1) are then added dropwise, the temperature not exceeding −70° C. The solution is stirred at this temperature for 30 min. 80 ml of NEt3 are then added dropwise such that the temperature does not exceed −70° C. After the addition has ended, the cooling bath is removed and the solution is, with stirring, warmed to 0° C. At this temperature, 100 ml of water are added and the mixture is stirred vigorously at room temperature. The aqueous phase is separated off and extracted with chloroform. The combined organic phases are washed with saturated NH4Cl solution, dried over MgSO4 and concentrated, giving 23.8 g of 5-methyl-2-p-tolyloxazole-4-carbaldehyde as a yellow solid. C12H11 NO2 (201.23), LCMS(ESI): 202.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17]O)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:53]I>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][I:53])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CI)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Yield: 688.4 %

Procedure:
To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (500 mg, 0.98 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), PPh3 (3.0 g, 7.3 mmole) and imidazole (650 mg, 9.5 mmole) in 50 mL of dichloromethane (DCM) was added iodine (2.4 g, 9.5 mmole) at 0° C. and refluxed for 18 hrs. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 3.5 g of (2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:17](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:17][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2ccn3cccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc2ccn3cccc3c(=O)c2c1
Reaction time: 2 h

Procedure:
A solution of 9-amino-11H-pyrrolo[2,1-b] [3]-benzazepin-11-one in triethyl orthoformate (2.17 g., 10 mmoles in 80 ml.) is refluxed for 5 hrs. The volatiles are removed under vacuum and the residue, dissolved in 100 ml. absolute ethanol is stirred in an ice bath as sodium borohydride (0.88 g., 0.024 moles) is added over a period of 10 minutes. The mixture is stirred for a period of 2 hrs. After concentration of the ethanol, the residue is dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-11H-pyrrolo[2,1-b] [3]benzazepin-11-one as a brown amorphous solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][N:2]1[CH2:10][C:11]1[S:19][C:18]2[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:16][C:15]([C:26]3[C:34]([F:35])=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][NH:30]4)=[N:14][C:13]=2[CH:12]=1.C[Si]([N:40]=[C:41]=[O:42])(C)C>C(Cl)Cl>[F:35][C:34]1[C:26]([C:15]2[N:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:18]3[S:19][C:11]([CH2:10][N:2]4[CH2:3][C:4]5([CH2:9][CH2:8][N:7]([C:41]([NH2:40])=[O:42])[CH2:6][CH2:5]5)[CH2:1]4)=[CH:12][C:13]=3[N:14]=2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2
Reactant: C[Si](C)(C)N=C=O
Reactant: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2sc(CN3CC4(CCNCC4)C3)cc2n1
Solvent: ClCCl
Product: NC(=O)N1CCC2(CC1)CN(Cc1cc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 6-(2,7-diaza-spiro[3.5]non-2-ylmethyl)-2-(5-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (125 mg, 0.254 mmol) in anhydrous DCM (10 mL) was added trimethylsilyl isocyanate (35 μL, 0.254 mmol). The reaction mixture was stirred at RT for 1 h, then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC to give the title compound as a white solid (41 mg, 30%).
Reaction SMILES: C([N:4]1[CH2:27][CH2:26][C:7]2[N:8]([CH2:16][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)([OH:19])[CH3:18])[C:9]3[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:16][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)([OH:19])[CH3:18])[C:7]3[CH2:26][CH2:27][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CC(O)(Cn1c2c(c3cc(Cl)ccc31)CNCC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a degassed solution of 1-(2-allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol (300 mg, 0.78 mmol) in DCM (20 mL) were added 1,3-dimethyl barbituric acid (368 mg, 2.3 mmol) and Pd(PPh3)4 (18 mg, 0.015 mmol). After stirring at RT for 30 min, the reaction mixture was diluted with DCM and washed with saturated potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 1-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol. 1H NMR (CD3OD, formate salt) δ (ppm): 8.4 (d, 2H), 7.48 (d, 2H), 7.4 (s, 1H), 7.18 (d, 1H), 6.98 (d, 1H), 4.6 (bs, 1H), 4.4 (s, 2H), 4.3 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 3.1 (m, 2H). Separation by chiral HPLC provides enantiomers II-62a-b.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20]1>N1C=CC=CC=1.CN(C)C=O>[CH2:30]([N:29]([CH2:28][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:20]1)[CH2:32][CH3:33])[CH3:31]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CCN(CC)CC1CNc2ccccc21
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 44.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 150 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 238 mg of (2,3-dihydro-1H-indol-3-ylmethyl)diethylamine and 140 mg of N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride in a mixture of 0.1 ml of pyridine and 3 ml of N,N-dimethylformamide. 108 mg of 2-(2-{3-[(diethylamino)methyl]-2,3-dihydro-1H-indol-1-yl}-2-oxoethyl)-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a cream solid, the characteristics of which are the following:
Reaction SMILES: [Pt:1].[C:2]([O:19]C(=O)CCCCCCCCCCCCCCC)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(=O)(O)[O-].C([NH+](CC)CC)C.C(O)(C)C.O>[C:2]([Pt:1])(=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [Pt]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCC
Agent: CC[NH+](CC)CC
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCC(=O)[Pt]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An estimated 30 nmol of the amino-derivatized 2-3 nm platinum cluster dissolved in 0.6 M triethylammonium bicarbonate in 20% isopropanol/water was evaporated to dryness five times from methanol, then dissolved in 3 mL of diclhoromethane, and treated with 200 nmol of palmitic anhydride. The mixture was stirred for one hour at room temperature, then washed three times with 0.1 M sodium phosphate buffer at pH 6.5. The remaining reaction mixture was evaporated to dryness, redissolved in 2:1 methanol/chloroform, then separated by gel filtration (GH25, Amicon eluted with 2:1 methanol:chloroform); the first species to elute is the dark brown palmitamido-platinum cluster. After evaporation to dryness, lipid conjugation was demonstrated by the extraction of the cluster into the chloroform layer when the palmitoyl cluster was shaken in a chloroform/water mixture with a small amount of methanol as a phase transfer agent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.C([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(OC(C)(C)C)=O.Cl.O1CCOCC1>CC(O)C>[N:28]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: c1ccc2c(N3CCNCC3)ncnc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.6 %

Procedure:
To a solution of 4-chloroquinazoline (2.0 g, 12.2 mmol) (Tobe, Masanori, et al., Bioorg. Med. Chem. 2003, 11(3), 383) and DIEA (3.2 mL, 18.2 mmol) in 40 mL IPA was added Boc-piperazine (1.96 g, 12.81 mmol). The reaction mixture was heated to reflux and stirred for 20 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was dissolved in 25 mL dioxane, and 4M HCl/dioxane (46 mL, 182 mmol) was added dropwise. The suspension was sonicated for 2 minutes and stirred 13 hours at room temperature, after which the reaction mixture was concentrated to dryness by rotary evaporation. The resulting amine HCl salt was dissolved in 2N NaOH and extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified on silica (9:1:0.02 DCM/MeOH/NR4OH) to give 4-piperazinylquinazoline as a yellow oil (2.5 g, 96%). 1H NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 7.92-7.86 (m, 2H), 7.76-7.70 (m, 1H), 7.48-7.42 (m, 1H), 3.75 (t, J=4.9 Hz, 4H), 3.09 (t, J=4.9 Hz, 4H), 1.89 (br s, 1H). Rt 0.70. MS (ESI+) [M+H]+ 215.