Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[O:22][CH2:23][C:24](O)=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:50]2[N:51]=[CH:52]C=CC=2N=N1.O>O1CCCC1.C(OCC)(=O)C>[CH3:50][N:51]([CH3:52])[C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:20]=[C:19]([S:16]([N:14]2[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])=[CH:12][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:15]2)(=[O:18])=[O:17])[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)O)c2)c1)C(=O)OC(C)(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reaction time: 3 h

Procedure:
2-(3-((4-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid 9b (170 mg, 0.33 mmol) was added to a solution of methylamine in tetrahydrofuran (2 N, 5 mL), followed by addition of 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (104 mg, 0.91 mmol) and then the reaction solution was stirred for 3 h. 20 mL of water and 20 mL of ethyl acetate were added, and the reaction solution was layered, the water phase was extracted with ethyl acetate (20 mL×1). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system C to obtain the title product tert-butyl ((1-((3-(2-(dimethylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 9c (50 mg, a white solid) in 28% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]3=[O:17])=[CH:6][N:5]2[C:18]=1[CH3:19].[Cl:20][C:21]1[S:25][CH:24]=[C:23]([CH2:26]O)[CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:20][C:21]1[S:25][CH:24]=[C:23]([CH2:26][O:16][C:13]2[CH:14]=[CH:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]4[N:5]([C:18]([CH3:19])=[C:2]([CH3:1])[N:3]=4)[CH:6]=3)[C:11](=[O:17])[CH:12]=2)[CH:22]=1
Reactant: OCc1csc(Cl)c1
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cn2c1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a solution of 1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (174 mg) and tributylphosphine (358 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (447 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (90 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:17])=[C:4]([F:18])[CH:3]=1.C1C=CC2N(O)N=[N:25][C:23]=2C=1.C(Cl)CCl.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:25][CH3:23])=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:17])=[C:4]([F:18])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cncc(F)c1-c1ccc(Cl)cc1F
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cncc(F)c1-c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To the solution of 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinic acid (530 mg, 1.966 mmol) in DMF (5 mL) cooled at 0° C., was added HOBT (602 mg, 3.93 mmol) and EDC (565 mg, 2.95 mmol), then the mixture was stirred for 5 min. Methylamine hydrochloride (531 mg, 7.86 mmol) and DIEA (1.030 mL, 5.90 mmol) were added and the resultant mixture was stirred at RT for 12 h. Ice-cold water was added to the reaction and the solid obtained was collected by vacuum filtration. The solid so obtained was washed with water (50 mL) and air dried to afford 4-(4-chloro-2-fluorophenyl)-5-fluoro-N-methylnicotinamide (350 mg, 1.238 mmol, 63% yield) as an orange oil. LC/MS (ESI) m/e 282.9 [(M+H)+, calcd for C13H10ClF2N2O 283.0]; LC/MS retention time (method D): tR=0.83 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:25])[CH2:4][CH2:3]1.[O:26]=[C:27]1[CH2:32][O:31][C:30]2[CH:33]=[CH:34][C:35]([CH:37]=O)=[N:36][C:29]=2[NH:28]1.C([BH3-])#N.[Na+]>>[O:25]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:37][C:35]3[CH:34]=[CH:33][C:30]4[O:31][CH2:32][C:27](=[O:26])[NH:28][C:29]=4[N:36]=3)[CH2:7][CH2:6]2)[C:15]2[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3ccc(OC(F)(F)F)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(OC(F)(F)F)cc54)CC3)nc2N1
Yield: 15.3 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(trifloromethoxy)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 61) (0.55 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (120 mg, 0.66 mmol) and sodium cyanoborohydride (69 mg, 1.1 mmol) were reacted as described under Example 21 to give 44 mg (15%) product as a solid.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[CH3:18][O-:19].[Na+]>CN(C)C=O>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18](=[O:19])[CH:2]([CH3:4])[CH3:3])=[C:12]([O:17][C:8](=[O:9])[CH:10]([CH3:15])[CH3:11])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: C[O-]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of N,N-dimethylformamide under an atmosphere of nitrogen there was added 17 g. of sodium methoxide. By distillation under reduced pressure, 50 ml. of liquid was removed and the mixture was then cooled and under an atmosphere of nitrogen 25 g. of isobutyryl chloride was added rapidly at 5°-25° C. The reaction mixture was stirred at 25° C. for 1 hour and then was warmed to 70° C. and the solvent was removed by distillation. The resulting residue was slurried in 400 ml. of diethyl ether, and the slurry was filtered to remove about 10 g. of insoluble solid. The ethereal layer in the filtrate was separated, washed with dilute aqueous sodium hydroxide solution and then with water. There was thus obtained an ether solution of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone. To this solution there was added a solution obtained by adding 4 ml. of hydrochloric acid to 25 ml. of water, and the resulting mixture was shaken. The crystalline solid which formed was collected on a filter and dried at 70° C. There was thus obtained 8.5 g. of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline powder which melted at 221°-223° C. (dec.)(uncorr.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32].CN(C)C=O.C(=O)(O)[O-].[Na+]>O>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:28][CH2:29][CH2:30][C:31]#[N:32])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Reactant: N#CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCNc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
99 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) and 44 mg of 4-bromobutyronitrile were added to 0.2 mL of N,N-dimethylformamide, and stirred at 70° C. for 1.5 hour. To the reaction mixture, saturated sodium bicarbonate in water was added, extracted with ethyl acetate, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 59 mg (50%) of the title compound as a light brown powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH2:8])=[O:7])=[CH:2]1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[O:7][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccoc1
Product: ClCc1coc(-c2ccoc2)n1
Yield: 44 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-furancarboxamide was reacted with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-furyl)oxazole. The yield was 44%. Recrystallization from diethyl ether-hexane gave colorless prisms. mp 70-71° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[CH2:45][C:46](O)=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[CH2:45][C:46]([NH:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13)=[O:47]
Reactant: O=C(O)Cc1cc(F)ccc1Br
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2cc(F)ccc2Br)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 24 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.14 M and 0.40 M in N,N-dimethylacetamide, respectively, 287 μL) and 2-(2-bromo-5-fluorophenyl)acetic acid (0.4 M in N,N-dimethylacetamide, 124 μL), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.21 M in N,N-dimethylacetamide, 287 μL) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C. and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0058 g (24%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.14 (d, J=2.44 Hz, 1H), 7.68 (dd, J=8.85, 5.49 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.36 (dd, J=9.61, 3.20 Hz, 1H), 7.21 (d, J=8.54 Hz, 1H), 7.14 (td, J=8.54, 3.36 Hz, 1H), 7.04 (s, 1H), 6.82 (m, 2H), 6.49 (m, 2H), 5.02 (d, J=15.87 Hz, 1H), 4.18 (d, J=16.78 Hz, 1H), 4.03 (s, 3H), 3.92 (s, 2H). MS (APCI+) m/z 575.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CO.O1CCCC1.[OH-].[Li+].Cl>O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1

Procedure:
A solution of ethyl 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoate (35.39 g, 87.6 mmol) in 3:1 methanol/tetrahydrofuran (350 mL) was treated with lithium hydroxide (4.41 g, 183.9 mmol) in water (90 mL). The mixture was heated at reflux for 2 h., cooled, concentrated and acidified with hydrochloric acid (2M, 92.5 mL, 185 mmol). The dark precipitate was filtered, washed with water, and dried under vacuum. The solid was ground to a powder with a mortar and pestle, triturated with methanol (500 mL) then filtered again to yield 4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzoic acid as a muddy solid. This material was washed with ether, air dried overnight, and ground to a fine powder with mortar and pestle. On the basis of mass recovery (34.49 g) the yield was assumed to be quantitative. 1H NMR (300 MHz, d6-DMSO) δ 9.47 (1H, s); 8.53 (1H, d, J=5.2 Hz); 8.24 (2H, d, J=8.5 Hz); 8.08 (2H, d, J=8.8 Hz), 7.66 (2H, d, J=9.1 Hz); 7.37 (1H, d, J=5.2 Hz); 6.93 (2H, d, J=9.1 Hz); 3.73 (4H, m); 3.04 (4H, m). LC-ESI-MS (method C): rt 7.3 min.; m/z 377.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[CH:5][CH:4]=1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[NH:24][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCCCC2=O)cc1
Reactant: NCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCCCC2NCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-methoxyphenyl)-cyclohexanone (prepared following the procedure described in W. E. Bachmann et al., J. Am. Chem. Soc., 1950, 72, 1995) (2.0 g, 9.79 mmol), phenethylamine (1.19 g, 9.79 mmol), toluene (40 ml) and a catalytical amount of p-toluenesulfonic acid was refluxed in a Dean-Stark apparatus overnight. After removal of the solvent, the residue was dissolved in MeOH (25 ml) and sodium borohydride (excess) was added. After stirring for 1 h at RT, the solvent was evaporated, H2O was added to the residue. Extraction with CH2Cl2, drying of the organic layer over Na2SO4, evaporation of the solvent and chromatography of the residue over SiO2 (Merck 230-400 mesh) eluting with AcOEt gave (1RS,2RS)-[2-(4-methoxy-phenyl)-cyclohexyl]-phenethyl-amine (1.5 g, 50%, light yellow oil, MS: m/e=310.2 (M+H+)) and (1RS,2SR)-[2-(4-methoxy-phenyl)-cyclohexyl]-phenethyl-amine (0.95 g, 31%, light yellow oil, MS: m/e=310.2 (M+H+)).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[N:10][CH:11]=2.[C:14]1([CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:13]=[C:5]1[C:6]2[C:7](=[N:8][CH:9]=[N:10][CH:11]=2)[N:12]=[C:3]([CH2:2][NH:1][S:22]([CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:24])=[O:23])[NH:4]1
Reactant: O=S(=O)(Cl)CCc1ccccc1
Reactant: NCc1nc2ncncc2c(=O)[nH]1
Product: O=c1[nH]c(CNS(=O)(=O)CCc2ccccc2)nc2ncncc12

Procedure:
In analogy to the procedure described in example 20.4, 2-aminomethyl-3H-pyrimido[4,5-d]pyrimidin-4-one (example 20.3) was treated with 2-phenyl-ethanesulfonyl chloride [4025-71-2] to obtain 2-phenyl-ethanesulfonic acid (4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-ylmethyl)-amide as light brown solid. MS: m/e=346.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([CH2:31][CH2:32]O)=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[Br:54][CH2:32][CH2:31][C:29]1[CH:28]=[CH:27][C:26]2[C:19]3[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)=[N:23][CH:22]=[N:21][C:20]=3[S:24][C:25]=2[CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(CCBr)ccc5c34)cc2Cl)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino) [1]benzothieno[2,3-d]pyrimidin-7-yl]ethanol (700 mg, 1.46 mmol, 1 equiv) in THF (10 mL) were added triphenylphosphine (0.82 g, 3.12 mmol, 3 equiv) and carbon tetrabromide (1.03 g, 3.12 mmol, 3 equiv). The resulting solution was stirred at rt for 14 h and the solvent was evaporated under reduced pressure. The resulting crude material was purified by flash chromatography eluting with 9:1 CH2Cl2/EtOAc yielding a light yellow solid (688 mg, 1.27 mmol, 87%). 1H-NMR (CDCl3) δ 8.60 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.50-7.44 (m, 3H), 7.39-7.34 (m, 1H), 7.23 (m, 2H), 7.03 (td, 1H), 7.00 (d, J=9.0 Hz, 1H), 5.12 (s, 2H), 3.68 (t, 2H), 3.36 (t, 2H); LCMS RT=4.26 min, [M+H]+=541/544
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([O:31][CH3:32])=[O:30])=[CH:14][C:15]=3[N:16]3[C:23]=2[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[NH:20][C:19](=[O:28])[CH2:18][CH2:17]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38].ClCCN(C)C.N1C2C(=CC=CC=2)C=C1>CN(C=O)C>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([O:31][CH3:32])=[O:30])=[CH:14][C:15]=3[N:16]3[C:23]=2[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[C:19](=[O:28])[CH2:18][CH2:17]3)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)Nc1ccccc1-3
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)N(CCN(C)C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (1.4 eq, 60% dispersion in mineral oil) was added to a solution of methyl 14-cyclohexyl-6-oxo-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate in DMF (0.1 M) and the solution allowed to stir at RT for 1 h. In the meantime, a 1:1 equimolar mixture of (2-chloroethyl)dimethylamine hydrochloride and NaH (60% dispersion in mineral oil) in solution in DMF (0.5 M) was prepared. After 30 mins, this mixture (2.5 eq of (2-chloroethyl)dimethylamine) was slowly added to the solution of indole anion and the mixture was stirred at RT overnight. DMF was removed in vacuo and the residue taken up in EtOAc. The organic phase was washed with H2O (twice) and then brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo. The crude compound was used in the next step without further purification; MS (ES+) m/z 474 (M+H)+.
Reaction SMILES: Cl.C[O:3][CH:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12]2)[CH2:7][CH2:6]1>O>[CH2:16]([CH:13]1[CH2:14][CH2:15][CH:11]([CH:8]2[CH2:9][CH2:10][CH:5]([CH:4]=[O:3])[CH2:6][CH2:7]2)[CH2:12]1)[CH2:17][CH3:18]
Reactant: CCCC1CCC(C2CCC(=COC)CC2)C1
Agent: Cl
Solvent: O
Product: CCCC1CCC(C2CCC(C=O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
Hydrochloric acid (1 M) (30 ml) was added to 1-methoxymethylene-4-(3-propylcyclopentyl)cyclohexane (17.0 g) obtained in the first step, which was dissolved in (200 ml), and the mixture was stirred at room temperature for 2 hours. Water (100 ml) was added to the mixture, which was extracted with toluene. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (200 ml) and toluene (50 ml) was added to the residue, and a NaOH aqueous solution (20%) (30 ml) was added under ice-cooling, and the mixture was stirred at room temperature for another 3 hours. A saturated aqueous solution of ammonium chloride was added to neutralize and the mixture was extracted with toluene. The combined organic layer was washed with water, dried over anhydrous magnesium sulfate, and the toluene was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/20 by volume) to give 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (15.0 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19].[K+].[Br-]>C(O)C>[CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Clc1ncnc2c1ncn2OCc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Nc1ncnc2c1ncn2OCc1ccccc1

Procedure:
A solution of 9-benzyloxy-6-chloropurine (38.4 g; 0.147 mmol) in ethanol (300 ml) saturated with ammonia was heated at 100° C. in an autoclave for 16 hours. After cooling the suspension was evaporated to dryness and the residue partitioned between chloroform (750 ml) and water (500 ml). The separated aqueous phase was washed with chloroform (200 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated, affording an orange solid homogeneous on t.l.c. (31.1 g, 87%). IR: υmax (KBr) 3372, 3300, 3187, 3038, 1660, 1637, 1600, 1581 cm-1 ; 1H NMR: δH [(CD3)2SO] 5.3(2H, s, CH2Ar), 6.8(2H, br.s, D2O exchangeable, NH2), 7.3(6H, s, H-8, Ar), 7.7(1H, s, H-2). Found: C, 59.39; H, 4.60; N, 29.07%; m/e 241.0949. C12H11N5O requires: C, 59.73; H, 4.60; N, 29.03%; m/z 241.0964.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([OH:28])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1cncc(Cl)c1)CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(CC(O)CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a stirred solution of 1-{[4-(4-chlorophenyl)piperazin-1-yl]sulfonyl}-4-(5-chloropyridin-3-yl)butan-2-one (228 mg, 0.51 mmol) in a mixed solvent system of CH2Cl2/MeOH (1:1, 5 mL) at RT was added solid sodium borohydride in one portion. The reaction was stirred for 40 minutes before being quenched with aqueous hydrochloric acid (1 M, 2 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried, (MgSO4), filtered and concentrated in vacuo. The crude product was then filtered through a plug of silica gel, eluting with 50% ethyl acetate in hexane to give the title compound (111 mg, 0.25 mmol).