Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:6]([CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(O)(CC)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)(CC)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To ethyl 2-((cyclopentylamino)methyl)-2-hydroxybutanoate (2.7 g, 12 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (2.1 ml, 18 mmol) dropwise, followed by K2CO3 (5 g, 35 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 4:1) to give 2.9 g product (77%). [M+H] calc'd for C19H29NO3, 320. found 320.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5](=[O:17])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:2].[Se]=[O:22]>C(O)C>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:17])[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:15])/[CH2:14][OH:22])[CH3:20]
Reactant: CCOC(OCC)C(=O)CCC=C(C)CCC=C(C)C
Reactant: O=[Se]
Solvent: CCO
Product: CCOC(OCC)C(=O)CC/C=C(\C)CC/C=C(\C)CO
Yield: 56.2 %

Procedure:
In 70 ml of 95% ethanol was dissolved 7.4 g of 1,1-diethoxy-6,10-dimethyl-2-oxo-5,9-undecadien, and the resulting solution was, after addition of 1.7 g of selenium oxide, refluxed for 15 minutes. The ethanol was removed by evaporation, and the residue was, after addition of water, extracted with ether. The ethereal extract was washed with an aqueous sodium hydrogencarbonate solution and dried. The solvent was then removed by evaporation to leave an oil, and the oil was purified by the silica gel column chromatography to yield 3.0 g of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]I.Br[C:14]1[C:15](=[O:26])[NH:16][C:17](=[O:25])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]2[C:15](=[O:26])[NH:16][C:17](=[O:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Br
Agent: C[Mg]I
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1ccccc1
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of 4.9 g of indole in 50 ml of benzene was treated with 19 ml of a 3M solution of methylmagnesium iodide in diethyl ether and stirred under nitrogen for 15 minutes. 3.5 g of 3-bromo-4-phenyl-1H-pyrrole-2,5-dione were added and the mixture was stirred for 18 hours. The solvent was evaporated and the residue was dissolved in 250 ml of dichloromethane and 50 ml of 2M hydrochloric acid. The organic extracts were washed with water, dried and evaporated. The residue was purified on silica gel with ethyl acetate/petroleum ether. Trituration with dichloromethane and recrystallization from methanol yielded 1.40 g of 3-(3-indolyl)-4-phenyl-1H-pyrrole-2,5-dione, m.p. 256° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.N>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Brc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-bromo-4-ethynylbenzene (Alfa Aesar, 80 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (dd, J=7.7, 5.0 Hz, 1H), 7.75-8.01 (m, 5H), 8.36 (dt, J=8.0, 1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 9.14 (s, 1H) ppm; MS (DCI/NH3) m/z 303 (M+H)+, 301 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([OH:4])[CH3:3].I[CH2:17][CH2:18][CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([C:11]([CH2:10][C:7]1[CH:6]=[C:5]([C:2]([CH3:1])([OH:4])[CH3:3])[O:9][N:8]=1)([C:12]#[N:13])[C:14]#[N:15])[CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCI
Reactant: CC(C)(O)c1cc(CC(C#N)C#N)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(C#N)(C#N)Cc1cc(C(C)(C)O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
0.41 g of {[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile and 0.63 g of 4-iodo-1-butene were dissolved in 6 ml of N,N-dimethylformamide, and 0.55 g of potassium carbonate was then added under ice-cooling. The mixture was stirred at room temperature overnight. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.43 g of (3-butenyl){[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile represented by the following formula:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH2:52]1[O:54][C@H:53]1[CH2:55][OH:56]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH2:52][C@@H:53]([OH:54])[CH2:55][OH:56])[CH2:31][CH2:32]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:40])([F:42])[F:41]
Reactant: OC[C@H]1CO1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C[C@@H](O)CO)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (S)-(−)-glycidol (0.10 mL, 1.51 mmol). The reaction mixture was heated to 60° C. for 4 hours then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.36 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH3:9][O-:10].[Na+].O>CO>[CH3:9][O:10][C:5]1[N:4]=[N:3][C:2]([I:1])=[CH:7][CH:6]=1
Reactant: Ic1ccc(I)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(I)nn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86 %

Procedure:
To 2.73 g (8.23 mmol) of 3,6-diiodopyridazine were added 80 ml of methanol and 3.17 g (16.46 mmol) of 28 wt % of sodium methylate in methanol, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica-gel column chromatography (200 ml of silica gel, hexane:ethyl acetate=8:1) to give 1.661 g (7.04 mmol) of 3-methoxy-6-iodopyridazine (yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
2,4-difluoroaniline (9.0 g, 69.71 mmol) and pyridine (5.6 mL, 69.71 mmol) were dissolved in dichloromethane (45 mL) and the solution was cooled to 0° C. A solution of cinnamoyl chloride (13.04 g, 76.7 mmol) dissolved in dichloromethane (45 mL) was added dropwise, and after the addition the reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 and the layers were separated. The organic layer was washed with 1 M HCl then dried over Na2SO4 and concentrated in vacuo to provide a white solid. The solid was slurried in dichloromethane (150 mL), stirred for 30 minutes, and then hexanes (150 mL) were added. After stirring several minutes, the white solids were collected by filtration, washed with dichloromethane and air-dried to provide 13.5 g of the desired product. MS APCI (−) m/z 258.0 (M−1) detected.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](O)(=O)CCC/C=C\CC=CCC=CCC=CCC=CCC.Cl.COC(=O)[C@H]([C@@H](C)O)N>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[C@@H:24]([CH3:33])[O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)O
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Agent: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@H](C(=O)O)[C@@H](C)OP(=O)(O)O

Procedure:
This compound was prepared as described above for (6), using 0.5 mmol (151 mg) of cis-5,8,11,14,17-eicosapentaenoic acid and 1 mmol (170 mg) of L-threonine methyl ester hydrochloride; yield 99 mg, (41%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.2-1.4 (d, 3H, CH3CHOP); 1.5-1.6 (t, 2H, CH2); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 8H, 4HC═CH—CH2—CH═CH); 4.1-4.3 (m, 2H, 2CH); 5.2-5.4 (br s, 10H, 5HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C1COCC1>[CH:15]([N:17]1[CH2:22][CH2:21][N:20]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:19][CH2:18]1)=[O:16]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=CN1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A THF (10 ml) solution of 2-naphthalenesulfonylchloride (23 g, 101 mmol) was added dropwise to a THF (100 ml) solution of 1-formylpiperazine (11.4 g, 100 mmol) and triethylamine (15 g, 150 mmol) under ice-cooling. The solution was stirred at room temperature for 30 minutes, and concentrated. The residue was washed with water and diisopropylether and dried under reduced pressure to give 1-formyl-4-(2-naphthalenesulfonyl)piperazine.
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)=[O:8])=[CH:31][N:30]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1

Procedure:
A mixture of (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1, 50 mg, 0.124 mmol), (2-aminopyrimidin-5-yl)boronic acid (26 mg, 0.187 mmol), 2 M Na2CO3 (0.124 mL, 0.249 mmol) and DME (2.5 mL) was flushed with argon and PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added. The mixture was subjected to MW irradiation 140° C. for 30 min, passed through a PL-Thiol MP SPE cartridge (StratoSpheres™), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 5) tR=1.53 min, m/z=461.1 [M+H]+, m/z=459.1 [M−H]−.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][O:19][C:20](=[O:22])[CH3:21])=O)=CC=1)([O-])=O.C(O)(=O)C.[H][H]>C(O)C.[C].[Pd]>[C:20]([OH:22])(=[O:19])[CH3:21].[C:20]([O:19][CH2:18][C@@H:13]1[CH2:14][C@@H:15]([OH:17])[CH2:16][NH:12]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-acetoxymethyl-4-hydroxypyrrolidine (1.55 g) in ethanol (23 ml), 10% palladium-carbon (233 mg) and acetic acid (330 mg) were added. The mixture was stirred at room temperature for 2 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to remove the solvent. The residue was combined with water, washed with dichloromethane and concentrated to give (2S,4R)-2-acetoxymethyl-4-hydroxypyrrolidine acetate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([NH:13][NH2:14])=[N:4][N:3]=1.[C:15](O)(=O)[CH3:16]>>[Cl:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]2=[N:13][N:14]=[C:15]([CH3:16])[N:4]2[N:3]=1
Reactant: NNc1nnc(Cl)c2c1C1CCC2C1
Reactant: CC(=O)O
Product: Cc1nnc2c3c(c(Cl)nn12)C1CCC3C1
Yield: 84 %

Procedure:
In a procedure similar to that of Example 5, 1-chloro-4-hydrazino-5,6,7,8-tetrahydro-5,8-methanophthalazine (25.0 grams, 0.119 mol) was mixed with 150 milliliters of acetic acid, and the mixture was heated at the boiling temperature under reflux for two hours. The reaction mixture was concentrated and the residue taken up in aqueous sodium bicarbonate. The resulting precipitate was collected, washed with water and air-dried to yield 23.4 grams (84 percent yield) of 6-chloro-7,8,9,10-tetrahydro-3-methyl-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine. After recrystallization from benzene-hexane this product melted at 137°-138° C. Infrared spectroscopy and elemental analysis were consistent with the named structure.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][CH:8]=2)[N:3]=1.[N:24]12CCN(CC1)C[CH2:25]2.[C-]#N.[Na+]>CS(C)=O>[N:18]1([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:25]#[N:24])=[N:3]3)=[CH:8][CH:7]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Clc1nc(N2CCCCC2)c2ccc(N3CCOCC3)cc2n1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nc(N2CCCCC2)c2ccc(N3CCOCC3)cc2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
0.20 g (0.60 mmol) of 2-chloro-7-morpholin-4-yl-4-piperidin-1-ylquinazoline and 0.067 g (0.60 mmol) of 1,4-diazabicyclo[2.2.2]octane were dissolved in 3.0 ml of dimethyl sulfoxide. After 1.0 h, 0.03 g (0.60 mmol) of sodium cyanide were added, and the reaction mixture was subsequently stirred at 80° C. for 24 h. Conventional work-up gave 0.17 g of 7-morpholin-4-yl-4-piperidin-1-ylquinazoline-2-carbonitrile (No. 58).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].I[CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1.O>CN(C)C=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCI)O2
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCOCCN(C)C)O2
Temperature: 50 °C

Procedure:
210 mg of 2-dimethylaminoethanol were dissolved in 3 ml of dimethylformamide, and then 100 mg of a 50% w/w oily suspension of sodium hydride were added to the solution. This reaction mixture was then heated for 1 hour at 50° C. The reaction mixture was then cooled with ice, and a solution of 900 mg of 2-(3-iodopropyl)-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 86) in 2 ml of dimethylformamide was added dropwise, while stirring. After completion of the dropwise addition, the temperature of the reaction mixture was gradually raised, and then the mixture was heated for a further 2 hours at 50° C. The reaction mixture was then poured into water, and the resulting precipitate was extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The residual crude oily reaction product was separated by silica gel column chromatography. The fraction eluted with benzene was removed, while the fraction eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine was subjected to silica gel Lobar column chromatography, eluted with the same eluent, to give the title compound.
Reaction SMILES: CN(C)C=[O:4].C1(N2C(C3C=CC=CC=3)CC(=O)N2)C=CC=CC=1.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:31]([NH:30][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:4]
Reactant: CN(C)C=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C1CC(c2ccccc2)N(c2ccccc2)N1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Into 100 ml of dimethylformamide, 23.8 g of Compound (A), 30.1 g of Compound (B) and 0.8 g of 4-dimethylamino-pyridine were dissolved, and thereto an ethyl acetate 20 ml solution containing 20.6 g of dicyclohexylcarbodiimide was added dropwise in an ice bath. After the dropwise addition, the solution was allowed to react at room temperature over night. Into the reaction solution, 200 ml of ethyl acetate was poured, and dicyclohexylurea obtained was separated by filtration. Into the filtrate, 300 ml of water was poured to perform liquid separation operation. Water washing was performed twice, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the oily product obtained was subjected to silica gel column chromatography. As a result, from the methylene chloride/ethyl acetate=10/3 fraction, 43 g of Compound (C) was obtained as a pale yellow oily product. ##STR16## Synthesis of Compound (D):
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.S1C=CC=C1.N.[H][H]>CO.[Pd]>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccccc2[N+](=O)[O-])o1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: c1ccsc1
Product: Cc1ccc(CNc2ccccc2N)o1
Yield: 95 %

Procedure:
A mixture of 62 parts of 5-methyl-N-(2-nitrophenyl)-2-furanmethanamine, 2 parts of a solution of thiophene in methanol 4% and 400 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperaure with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 50.5 parts (95%) of N1 -[(5-methyl-2-furanyl)methyl]-1,2-benzenediamine as a residue (intermediate 8).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42](=[O:52])(=[O:51])[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:38][CH:37]=3)[N:30]=2)=[CH:27][N:26]=[C:25]1[CH3:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[CH:38][C:39]([S:42](=[O:52])(=[O:51])[N:43]([C:44]([O:46][C:47]([CH3:49])([CH3:50])[CH3:48])=[O:45])[CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:40][CH:41]=3)[N:30]=2)=[CH:27][N:26]=[C:25]1[CH3:53]
Reactant: COCCOCCO
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc3)n2)n1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
2-(2-Methoxyethoxy)ethanol (50 μl, 0.4 mmol) followed by diisopropyl azodicarboxylate (0.1 ml, 0.4 mmol) was added to a stirred solution of 4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(t-butoxycarbonyl)sulphamoyl]anilino}pyrimidine (Example 36; 90 mg, 0.2 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in anhydrous THF (4 ml) under nitrogen at 0° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was poured directly on to an Isolute SCX-2 column, eluted first with MeOH (8×15 ml) and then the product was eluted with 2% methanolic ammonia (6×15 ml). The solvent was evaporated and the residue dissolved in EtOAc (25 ml), washed with saturated aqueous sodium hydrogen carbonate solution (2×25 ml), dried and the solvent evaporated to give the title compound (77 mg, 71%) as a yellow oil. NMR 1.38 (s, 9H), 2.49 (s, 3H), 3.38 (s, 3H), 3.56 (m, 2H), 3.68 (m, 2H), 3.76 (t, 2H), 3.96 (s, 3H), 4.06 (t, 2H), 7.03 (d, 1H), 7.49 (s, 1H), 7.58 (s, 1H), 7.78 (d, 2H), 7.93 (d, 2H), 8.40 (d, 1H); m/z 547.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([CH3:9])[NH:4][C:3]1=[N:10]C(=O)[O-].[C:14](O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:9]([CH:5]1[NH:4][C:3](=[NH:10])[N:2]([CH3:1])[C:7](=[O:8])[CH2:6]1)[CH3:14]
Reactant: CC1CC(=O)N(C)C(=NC(=O)[O-])N1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1CC(=O)N(C)C(=N)N1

Procedure:
(S)-tert-butyl 4-(3-3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo. The residue was redissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of the crude product as a yellow solid. The crude product was purified via reverse phase HPLC to provide 10 mg (60%) of (S)-6-(3-3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4 (1H)-one (CF4; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): 11.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H), 3.68 (br s, 1H), 5.18 (br s, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H), 2.95 (d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH+=344.1. HPLC (A) Rt=5.07 min.