Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: Nc1ccc(F)cc1Nc1ccc(F)nc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A mixture of 4-fluoro-N2-(6-fluoropyridin-3-yl)benzene-1,2-diamine (524 mg, 2.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (493 mg, 2.61 mmol), HOAt (355 mg, 2.61 mmol), 4-methylmorpholine (575 μL, 5.21 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (500 mg, 2.61 mmol) in DCM (20 mL) was stirred at RT for 3 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (973 mg, quantitative). LCMS (Method C): RT 3.25 min [M+H]+ 393.3.
Reaction SMILES: C(OC([N:11]([C:23]1[C:24]([C:36]([O:38][CH3:39])=[O:37])=[C:25]([C:28]2[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=2)[S:26][CH:27]=1)[C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1)=[O:13])=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=[C:14]1[C:12]([NH:11][C:23]1[C:24]([C:36]([O:38][CH3:39])=[O:37])=[C:25]([C:28]2[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=2)[S:26][CH:27]=1)=[O:13]
Reactant: COC(=O)c1c(N(C(=O)OCc2ccccc2)C(=O)c2cc3ccccc3o2)csc1-c1cnc(OC)cn1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)c2cc3ccccc3o2)csc1-c1cnc(OC)cn1
Reaction time: 0.5 h

Procedure:
10% Pd/C is added to compound 160 in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 30 min. The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure to provide 161.
Reaction SMILES: [Na].[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[C:3]1C=CC=C[CH:4]=1.C1C[O:19]CC1>CCCCCC>[CH:4](=[O:19])[CH2:3][CH2:2][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C1CCOC1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CCCCCC
Product: CCCCCCCCC=O
Yield: 92 %

Procedure:
Using a Fisher-Porter bottle, 0.86 g (37.4 mmol) of solid sodium metal and 2.91 g (16 mmol) of benzophenone were added to 40 ml of dry, degassed THF under N2 flow. The reaction turned blue, characteristic of the ketyl. The Fisher-Porter bottle was then pressured up to 43 psi over atmospheric with CO and the whole reaction stirred vigorously using a magnetic stirrer at 120°. At this pressure THF can reach temperatures in excess of 100° before boiling. The reaction was cooled to 60° and 2.25 ml (16.8 mmol) of Fe(CO)5 was added. A white precipitate remained after addition of n-hexane. Washing the white precipitate and pumping to dryness gave a product that yielded 92% nonanal based on 214 MW for Na2Fe(CO)4. The product of this example was not solvated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[F:34][C:35]([F:41])([F:40])[CH2:36][NH:37][CH2:38]N.C1C=CC2N(O)N=[N:48][C:46]=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:34][C:35]([F:41])([F:40])[CH2:36][NH:37][CH2:38][CH2:46][NH:48][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCNCC(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCNCC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (95 mg, 0.19 mmol), N-(2,2,2-trifluoro-ethyl)-methanediamine (59 mg, 0.41 mmol), HOBt (41 mg, 0.3 mmol), EDAC (59 mg, 0.31 mmol) and TEA (0.06 mL) in DMF (3 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM (2×). The combined DCM was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 82 mg (69%) of the titled compound.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[Cl:59][C:60]1[C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=[C:62](C)[C:61]=1C=C.S([O-])([O-])=O.[Na+].[Na+].[C:79]([OH:83])(C)([CH3:81])[CH3:80]>ClCCl.O>[Cl:59][C:60]1[C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=[C:62]([CH3:61])[C:80]=1[C@H:79]([OH:83])[CH2:81][OH:22]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=Cc1c(C)cc2ccccc2c1Cl
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1[C@H](O)CO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A biphasic mixture of AD-mix-α (6.907 g) in tert-butanol (24.5 mL)/H2O (24.5 mL) was cooled to 0° C. and 1-chloro-3-methyl-2-vinylnaphthalene (4D) (1.00 g, 4.93 mmol) was added. The reaction mixture was stirred for 8 h at 0° C. Sodium sulfite (7.4 g) was added at 0° C. and the reaction was stirred for 40 minutes to give a white mixture. The mixture was diluted with dichloromethane and H2O. The mixture was extracted with dichloromethane (3×) and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give 4E as a white solid (0.920 g).
Reaction SMILES: [CH:1]1([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCC1CCCCCCCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCC1CCCCCCCCCCC1
Temperature: 55 °C
Yield: 25.1 %

Procedure:
To a solution of 7.6 g (30 mmol) of methyl 3-cyclododecylpropanoate in 100 ml of methanol is added 2.4 g of sodium hydroxide. The mixture is heated to 55° C. and is maintained for 4 hours. The reaction mixture is diluted with water and is extracted with hexane. The aqueous phase is acidified with 1N hydrochloric acid and is extracted (2 times) with ethyl ether. The combined ethereal extracts are washed with 1N hydrochloric acid and are dried over magnesium sulfate. Filtration and evaporation gives 7.48 g of crude title compound. Recrystallization of a portion of the product from hexane gives 1.81 g of the title compound: m.p. 72°-74° C.; IR (KBr) 1715 cm-1 ; NMR (CDCl3) δ 1.34 (m, 23 H), 1.57 (q, 2 H, J=8 Hz), 2.36 (t, 2 H, J=8 Hz).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH:23]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:26]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:23]([C:26]2[NH:25][C:33]3[C:28]([C:27]=2[CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccccc1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Product: CC(=O)NCCc1c(C(CCc2ccccc2)C2=C(O)C(Cc3ccccc3)OC2=O)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with 3-phenyl-propionaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide) to give the title compound as a yellow solid. MS: 507.2 ([M−H]−).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](=[O:14])(O)[O-:12].[Na+]>C(OCC)(=O)C.O>[C:4]([O:12][C:11](=[O:14])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[Br:2])([CH3:7])([CH3:5])[CH3:3]
Reactant: O=C([O-])O
Reactant: NCc1ccccc1Br
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 2-bromobenzylamine hydrochloride (5.00 g) and di-tert-butoxycarbonyl (5.39 g) in ethyl acetate (30 ml) was added saturated sodium bicarbonate solution (30 ml), and stirred at room temperature for 16 hours. The obtained reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a colorless liquid (6.48 g, 95%).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:11]1)=[O:3].[OH:28]O>C(O)(=O)C>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:11]1)(=[O:28])=[O:3]
Reactant: OO
Reactant: CS(=O)c1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
To a solution of 1-[2-(methylsulfinyl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (60% purity, 300 mg, 0.80 mmol) in 20 mL of acetic acid was added 30% H2O2 aqueous solution (362 mg, 3.19 mmol), and the mixture was stirred at 40° C. for 18 h. The solvents were removed under reduced pressure, water was added, extracted with AcOEt, washed with water, Na2CO3 aqueous solution and brine, dried over Na2SO4, and then concentrated. The residue was purified by prep.-HPLC to give the title compound (20 mg, 6% yield) as a red solid: 1H NMR (400 MHz, CDCl3): δ 2.89 (3H, s), 6.60 (1H, d, J=8.0 Hz), 6.96 (1H, d, J=2.0 Hz), 7.24-7.35 (4H, m), 7.41-7.43 (2H, m), 7.70-7.77 (3H, m), 7.92 (1H, d, J=8.0 Hz), 8.16-8.18 (1H, m); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >90%, Rt=3.073 min; MS Calcd.: 392; MS Found: 393 [M+H]+.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=C([CH:15]=[CH:16][CH:17]=2)C#N)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.[OH-:18].[Na+].Cl.[CH3:21][CH2:22][OH:23]>O>[N:1]1[C:2]([C:10]2[CH:11]=[C:21]([CH:15]=[CH:16][CH:17]=2)[C:22]([OH:18])=[O:23])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: N#Cc1cccc(-c2cn3ncccc3n2)c1
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(-c2cn3ncccc3n2)c1
Yield: 60 %

Procedure:
A solution of 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile (1 mmol) and 6M NaOH (2 ml) in EtOH was heated to reflux for 2 h. Then the mixture was diluted with water and acidified with HCl. The precipitate was filtered to give 3-(imidazo[1,2-b]pyridazin-2-yl)benzoic acid with a yield of 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].[CH:12](=O)[CH:13]([CH3:15])[CH3:14].C1C(=O)N(Br)C(=O)C1.[C:25](#[N:29])[CH2:26][C:27]#[N:28].CC[O-].[Na+]>C(O)C.CN(C=O)C.O>[NH2:28][C:27]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([CH:13]([CH3:15])[CH3:14])[C:26]=1[C:25]#[N:29]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)C=O
Reactant: N#CCC#N
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Part A: To a stirred solution of 106 g (500 mmol) of 2,4,6-trichlorophenyl hydrazine in 600 mL of absolute ethanol was added 48.1 mL (530 mmol) of isobutyraldehyde. The solution was stirred 2 h at RT and concentrated under reduced pressure to afford an oil. The crude oil was dissolved in 450 mL of dry DMF and cooled to 0° C. This solution was treated with 94.3 g (530 mmol) of NBS in four portions over 10 min. The solution was stirred 1 h at 0° C. and poured onto ice. The mixture was diluted with water and extracted with 800 mL of ether. The organic extract was washed twice with water and once with brine, dried (MgSO4), and concentrated under reduced pressure to afford an oil. In a separate flask, 44.3 g (670 mmol) of malononitrile in 140 mL of EtOH was cooled to 0° C. and treated with 252 mL (670 mmol) of 2.66 M NaOEt in EtOH over 6 min. This solution was added in four portions over 5 min. to a rapidly stirred solution of the crude bromohydrazone in 350 mL of absolute EtOH. Using a heat pistol, this solution was maintained at reflux for 10 min. further. The reaction was cooled, quenched with 5% aq. HOAc, and extracted twice with ether. The combined organic extracts were washed (brine), dried (MgSO4) and filtered over activated charcoal and celite, and concentrated under reduced pressure. The product was chromatographed on silica gel (gradient elution with 1:3 ether-hexanes and 2:1 ether-CH2Cl2) to afford 93.5 g (57%) of 5-amino-4-cyano-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.51(s, 2H); 4.28(br. s, 2H); 3.05(septet, 1H, J=7.0 Hz); 1.36(d, 6H, J=7.0 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[NH2:12])=[CH:2]1.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C(O)CCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:12][C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[CH:2]1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: Brc1ncccn1
Solvent: CCCCO
Product: c1ccc(-c2c[nH]c([C@@H](Cc3c[nH]c4ccccc34)Nc3ncccn3)n2)cc1
Temperature: 80 °C
Yield: 20 %

Procedure:
(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine (2 g; 0.0066 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 10 ml n-butanol. 2-bromopyrimidine (1 g; 0.0066 mol) and then diisoethylamine (1.15 ml; 0.0066 mol) were added dropwise. The mixture was then heated to around 80° C. for about 16 hours. The n-butanol was evaporated and the residue taken up in water and ethyl acetate. The organic phase was washed with water and then with a saturated solution of sodium chloride before being dried over magnesium sulfate and concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/7-3, followed by CH2 Cl2—MeOH—NH4OH/95-4.5-0.5 and ethyl acetate). A white powder was obtained (yield of 20%). Free base. Melting point: 138-140° C. MH+=381.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[O:34][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc2cc[nH]c2cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Yield: 46.6 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (222 mg, 0.662 mmol), (prepared as described for the starting material in Example 67), and 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.993 mmol) was heated at 95° C. for 3.5 hours. After cooling the mixture was poured onto water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (139 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:23])[O:3]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32](C)C=O>ClCCl>[CH3:1][C:2]1([CH3:24])[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:32][CH3:31])=[O:19])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:23])[O:3]1
Reactant: CON(Cc1ccc(C(=O)O)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of 4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoic acid (0.150 g, 0.45 mmol) in dichloromethane (2 ml) was treated at 22° C. with oxalyl chloride (0.08 ml) and a trace (capillary) of N,N-dimethylformamide and the resulting mixture was stirred for 2 h. The solvent and excess reagent were evaporated in vacuo and the residue was dissolved in dichloromethane (2 ml). This solution was added dropwise to a cold (5° C.) solution of methylamine (0.5 mmol, 0.25 ml of a 2M solution in tetrahydrofuran) and pyridine (0.01 ml) in dichloromethane (2 ml). After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution ethyl acetate and acetonitrile, 0 to 5%) yielded 0.060 g (38% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.69 (6H, s, CH3), 2.77 (3H, d, J=4.5 Hz, NCH3), 3.72 (2H, s, OCH3), 4.85 (2H, s, NCH2), 6.18 (1H, s, CH), 7.35 (2H, d, J=8.2 Hz, aromatics), 7.79 (2H, d, J=8.2 Hz, aromatics), 8.41 (1H, broad q, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:33][C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CC1(N)CCCC1
Reactant: CC(C)(C)CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CC(NC(=O)OC(C)(C)C)C(=O)NC1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a stirred solution of 2-tert-butoxycarbonylamino-4,4-dimethyl-pentanoic acid (5 g, 20.3 mmol) and N-methyl morpholine (4.46 mL, 40.6 mmol) in THF (40 mL) at 0° C. was added isobutyl chloroformate (2.64 mL, 20.3 mmol) and, after 10 min, the solution of 1-amino-cyclopentanecarbonitrile (3.35 g, 30.5 mmol) in THF (40 mL). The mixture was allowed to warm to room temperature and stirred overnight. It was diluted with water, extracted with dichloromethane, washed with brine, dried (sodium sulfate) and concentrated to give the crude product. Chromatography on silica gel (dichloromethane:MeOH=30:1) gave [1-(1-cyano-cyclopentylcarbamoyl)-3,3-dimethyl-butyl]-carbamic acid tert-butyl ester (6.15 g, 89.6%).
Reaction SMILES: Cl.[S:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[C:7](=[S:9])=[S:8].C([O-])(=O)C.[Zn+2:14].C([O-])(=O)C>N1C=CC=CC=1>[S:2]1[CH2:6][CH2:5][N:4]([C:7]([S-:9])=[S:8])[CH2:3]1.[S:2]1[CH2:6][CH2:5][N:4]([C:7]([S-:9])=[S:8])[CH2:3]1.[Zn+2:14]
Reactant: C1CSCN1
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: c1ccncc1
Product: S=C([S-])N1CCSC1

Procedure:
While cooling and stirring 250 g. of pyridine, 175 g. (1.40 moles) of thiazolidine hydrochloride [preparation described by S. Ratner and H. Clarke, J. Am. Chem. Soc. 59, 200 (1937)] was added. After it had dissolved, 106.4 g. (1.40 mole) of carbon disulfide was added dropwise, followed by 128.5 g. (0.70 mole) of anhydrous zinc acetate. The resulting reaction mixture was stirred at 40° - 50°C for 2 hours. The precipitate was filtered at 5° - 10°C. The crude solid was water-washed and finally freed of pyridine by vacuum-drying at 120°C. to give 147.8 g. of the desired product. It gradually decomposed starting at ca. 200°C without a definite final decomposition point. A small sample washed with hot benzene had the following analysis:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:15]([NH2:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].[OH-:24].[K+]>C(Cl)CCl>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:23][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6]([O:24][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: NCCCCCCCN
Agent: [K+]
Solvent: ClCCCl
Product: CCCCOc1ccc(C(=O)NCCCCCCCNC(=O)c2ccc(OCCCC)cc2)cc1

Procedure:
m.p. 151°-152° C., 20.0 g., was prepared as in Example 1 using 4-n-butoxybenzoyl chloride (prepared from 27.2 g. of 4-n-butoxybenzoic acid as in Example 6) in 200 ml. of ethylene dichloride, 6.5 g. of 1,7-heptanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from ethanol using decolorizing charcoal.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:33]([C:35]([CH3:38])([CH3:37])[CH3:36])#[C-:34]>CO.O>[C:35]([NH:33][C:34]1[N:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][C:5]2=[N:9][C:16]=1[C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: [C-]#[N+]C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1c(-c2cccc(Cl)c2)nc2cc(C(F)(F)F)ccn12
Temperature: 25 °C
Yield: 52.6 %

Procedure:
4-(trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol, Eq: 1.00), 3-chlorobenzaldehyde (182 mg, 147 μl, 1.3 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (70.4 mg, 370 Eq: 0.3) were dissolved in MeOH (2.00 mL). The resulting colorless solution was stirred at rt. To this solution was added dropwise 2-isocyano-2-methylpropane (103 mg, 140 μL, 1.23 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. To the yellow clear solution was added dropwise water until the mixture got turbid and the product precipitated from the MeOH/water mixture. The solid was filtered off, washed with MeOH/water (1:1) and hexane and dried under vacuum, to give a yellow solid (238 mg, 52.5%). MS: 367.0 [M]+; 1H-NMR (D6-DMSO): δ 8.63 (d, 1H), 8.29 (s, 1H), 8.18 (d, 1H), 8.00 (s, 1H), 7.49 (t, 1H), 7.40 (d, 1H), 7.15 (d, 1H), 4.95 (s, 1H), 1.04 (s, 9H).