Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Li]CCCC.[CH3:18][C:19]1[C:20](=O)[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]=1[CH3:24].Cl.N>C1COCC1>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:20]3[CH:19]([CH3:18])[C:23]([CH3:24])=[C:22]([CH3:25])[C:21]=3[CH3:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC1=C(C)C(C)C(C)C1=O
Reactant: Cc1ccc2cccc(Br)c2n1
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 4.4 g of 8-bromo-2-methylquinoline (20 mmol) in 50 ml of THF was cooled to −78° C., and 8.8 ml of n-BuLi (2.5 M in hexane, 22 mmol) were added dropwise with stirring. After the mixture had been stirred for 10 minutes, 3.5 g of 2,3,4,5-tetramethylcyclopentenone (25 mmol) were added dropwise, and the solution was warmed to room temperature, refluxed for one hour and cooled. Ice and hydrochloric acid were added to about pH 1, the mixture was neutralized using ammonia solution, the phases were separated, and the aqueous phase was extracted with pentane. After the combined organic extracts had been dried, the pentane was removed under reduced pressure, and the brown oil which remained was distilled under a high vacuum (b.p.: 115° C./0.01 mbar). 1-(2-Methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene was obtained as a yellow, viscous oil in a yield of 60% (3.2 g).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:35])[CH:27]=4)=[O:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.FC(F)O[C:40]1C=CC(S(Cl)(=O)=O)=C[CH:41]=1>>[CH2:40]([O:31][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([C:20]2[CH:21]=[C:22]3[C:17]([CH2:16][CH2:15][CH2:14][N:13]3[S:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:36])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:18][CH:19]=2)=[O:24])=[CH:27][C:28]=1[F:35])[CH3:41]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)F)cc1)CCC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)F)cc2)CCC3)cc1F

Procedure:
4-{[1-(4-Difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 521.17 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 4-difluoromethoxy-benzenesulfonyl chloride, yielding 4-{[1-(4-difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH:20]([C:22]1[N:23]=[CH:24][N:25]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=1)=[O:21]>>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:20]([C:22]1[N:23]=[CH:24][N:25]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:26]=1)[OH:21])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Yield: 73.2 %

Procedure:
In a similar manner to that described in Reference example 1, the reaction was carried out by using 6-bromo-2-tert-butyldimethylsilyloxynaphthalene (50.0 g) and 4-formyl-1-trityl-1H-imidazole (38.6 g) to give the titled compound (49.8 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.ClC(OCCCC)=O.Cl.[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]([NH2:35])[C:33]#[N:34]>O1CCCC1>[C:33]([CH:32]([NH:35][C:8]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:28]1[O:27][CH:31]=[CH:30][CH:29]=1)#[N:34]
Reactant: N#CC(N)c1ccco1
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: CCCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)NC(C#N)c2ccco2)s1
Reaction time: 8 h
Yield: 63.3 %

Procedure:
4.71 g of 2,4-dimethylthiazole-5-carboxylic acid was suspended in 70 ml of tetrahydrofuran, and 6.67 g of triethylamine was added. The mixture was stirred. While it was cooled to -10° to -5° C., 4.10 g of n-butyl chloroformate was added, and the mixture was stirred at this temperature for 30 minutes, and then 4.03 g of alpha-(2-furyl)-alpha-aminoacetonitrile hydrochloride was added. The mixture was stirred at room temperature for 5 hours, and then left to stand overnight. The precipitate was separated by filtration and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane/ethyl acetate gave 4.20 g (yield 53.6%) of the desired N-(alpha-cyanofurfuryl)-2,4-dimethylthiazole-5-carboxylic acid amide.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:29][CH:28]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[N:1]1([CH2:25][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=3)=[CH:31][CH:32]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: NC(=O)c1cc(-c2ccc(CN3CCCc4ccccc43)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.7 %

Procedure:
To a solution of tetrahydroquinoline (20 μL, 0.16 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (88 mg, 0.415 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (11-20% acetone/CH2Cl2) to give 3-[4-(3,4-dihydro-2H-quinolin-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (21 mg, 45%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (br. s., 1H), 7.97 (br. s., 1H), 7.84 (d, J=8.2 Hz, 2H), 7.47-7.57 (m, 1H), 7.38 (d, J=7.8 Hz, 2H), 6.72-6.93 (m, 2H), 6.36-6.50 (m, 2H), 4.53 (s, 2H), 3.34-3.43 (m, 2H), 2.73 (t, J=6.2 Hz, 2H), 1.93 (dt, J=11.2, 5.7 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15](C(O)=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1N=C(N2CC[N:31]([CH2:34][C:35]3[CH:43]=[CH:42][C:38](C(O)=O)=[CH:37][CH:36]=3)[C:30]2=[O:44])SC=1.C(N)C1C=CC=CC=1>>[CH2:34]([NH:31][C:30](=[O:44])[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])=[CH:7][CH:6]=1)[C:35]1[CH:43]=[CH:42][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Solvent: NCc1ccccc1
Product: Cc1csc(N2CCN(Cc3ccc(C(=O)NCc4ccccc4)cc3)C2=O)n1
Yield: 60 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid to react with benzylamine, the title compound was obtained as a white powder in 60% yield: mp 185-186° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=9.0 Hz, 2H), 7.30-7.28 (m, 6H), 6.73 (t, J=6.0 Hz, 2H), 6.41 (s, 1H), 4.59 (d, J=6.0 Hz, 2H), 4.44 (s, 2H), 4.05-4.00 (m, 2H), 3.40-3.35 (m, 2H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 158.7, 155.9, 147.2, 139.6, 138.2, 134.0, 128.7, 128.3, 127.9, 127.6, 127.5, 106.9, 47.6, 44.0, 42.3, 41.9, 17.3; MS (ES+) m/z 407.2 (M+1).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30](/[CH:31]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 93.7 %

Procedure:
To a solution (100 mL) of tert-butyl diethylphosphonoacetate (13.8 g, 51.8 mmol) in tetrahydrofuran was added 60% sodium hydride (2.45 g, 61.2 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 15 min. Then, to this mixture was added dropwise a solution (138 mL) of 4-(benzyloxy)benzaldehyde (10 g, 47.1 mmol) in tetrahydrofuran with stirring at 0° C., and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, and washed with 5% aqueous potassium hydrogensulfate solution and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (13.7 g, yield 94%) as colorless crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14](=O)[NH:13][C:12]=2[CH:18]=1>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:18]=1
Reactant: O=C1COc2ccc(F)cc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)NCCO2
Yield: 88.8 %

Procedure:
LiAlH4 (14.7 mmol, 1 M solution in THF) is added to a solution of 6-fluoro-4H-benzo[1,4]oxazin-3-one (1.23 g, 7.35 mmol) in THF at rt and heated to reflux for 2 hrs. The reaction mixture is quenched with a few drops of water followed by slow addition of ethyl acetate (10 mL). The solid is filtered off, and washed with EtOAc. The filtrate is concentrated in vacuo to afford 6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine (1 g). MS: 154 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:23][C:24]([O:26]CC)=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:37][NH2:38]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][C:24](=[O:26])[NH:38][N:37]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccn1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3c3ccccn3)cc2)CC1
Yield: 54.8 %

Procedure:
A solution of the product from step 3 (4.0 g, 8.3 mmol) and hydrazine hydrate (0.83 g, 16 mmol) in 30 mL of EtOH was stirred at 90° C. overnight. The yellow suspension was reduced to ˜15 mL of EtOH. The solid was collected and washed with cold EtOH to give the product (2.05 g, 55%): Mp 213-214° C.; MS m/z 395 (M-tBu+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([CH2:30][OH:31])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]I.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([CH2:30][O:31][CH3:32])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC(CO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
1.37 g (3.04 mmol) of the above prepared (rac)-4-[3-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and 0.95 ml (15.20 mmol) of methyl iodide were dissolved in 4.8 ml of N,N-dimethylformamide. After cooling (0° C.), 0.16 g (3.65 mmol) of NaH (55% in oil) was added. The reaction was stirred for 3 h at this temperature, then poured onto crushed ice/10% aq. potassium hydrogensulfate solution and extracted with diethyl ether (3×). The organic layers were washed with 10% aq. potassium hydrogensulfate solution and 10% aq. sodium chloride solution, dried over Na2SO4 and evaporated to dryness to yield 1.36 g (96%) of the title compound as light yellow oil. MS: 465.3 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:27]([C:29]1[NH:30][CH:31]=[CH:32][N:33]=1)[CH3:28]>>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:25]=[N:24][C:23]([N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[CH2:27][CH3:28])=[N:22][CH:21]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Reactant: CCc1ncc[nH]1
Product: CCc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 2-ethyl-1H-imidazole following procedures analogous to those described in Intermediate 16 and Intermediate 17. LC (method 10): tR=0.56 min; Mass spectrum (ESI+): m/z=341 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:18])[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(OCC)C>CO.O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][O:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H](CBr)c1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(COc2ccc([C@H]3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
2.8 g of (S)-1-(4-benzyloxyphenyl)-2-bromoethanol was dissolved in a mixed solvent of 20 ml of methanol and 10 ml of tetrahydrofuran. To the solution was added a solution of 0.8 g of potassium hydroxide dissolved in 4 ml of water, with ice cooling. The mixture was stirred for 5 minutes at the same temperature and further for 10 minutes at room temperature. The reaction mixture was added to a mixture of 50 ml of diethyl ether and 50 ml of ice water. The organic layer was separated. The aqueous layer was extracted with 25 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.4 g of (S)-2-(4-benzyloxyphenyl)oxirane.
Reaction SMILES: [C:1]1([N:10]=[C:11]=[O:12])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[N:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH3:27][N:25]([CH3:26])[C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:8]([NH:7][C:4]3[CH:3]=[CH:2][C:1]([NH:10][C:11]([NH:13][C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]5[N:25]([CH3:26])[CH3:27])=[O:12])=[CH:6][CH:5]=3)=[O:9])[CH:15]=2)[N:20]=[C:19]([CH3:24])[CH:18]=1
Reactant: O=C=Nc1ccc(N=C=O)cc1
Reactant: Cc1cc(N(C)C)c2cc(N)ccc2n1
Solvent: CN(C)C=O
Product: Cc1cc(N(C)C)c2cc(NC(=O)Nc3ccc(NC(=O)Nc4ccc5nc(C)cc(N(C)C)c5c4)cc3)ccc2n1
Temperature: 20 °C
Reaction time: 17 h
Yield: 48.3 %

Procedure:
A solution of 25 mg of 1,4-phenylene diisocyanate and 62.8 mg of 6-amino-4-dimethylamino-2-methylquinoline in 1 mL of dimethylformamide is stirred at a temperature in the region of 20° C. for 5 hours. 2 mL of dimethylformamide, 218 mg of polystyrene-isocyanate resin (Argonaut, 1.49 mmol/g) and 42 mg of polystyrene-trisamine resin (Argonaut, 3.75 mmol/g) are then added to the reaction mixture. The suspension obtained is stirred at a temperature in the region of 20° C. for 17 hours, filtered on sintered glass, and then the solid residue is washed with 10 mL of a dichloromethane-methanol (90-10 by volume) mixture. The filtrate obtained is concentrated under air stream at a temperature in the region of 50° C. 42.4 mg of 1-(4-dimethylamino-2-methylquinolin-6-yl)-3-{4-[3-(4-dimethylamino-2-methylquinolin-6-yl)ureido]phenyl}urea are thus obtained in the form of a yellow solid.
Reaction SMILES: [C:1]([CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH2:2][CH3:3].O.[NH2:17][NH2:18]>C(O)(=O)C.C(OCC)C>[CH2:9]([O:8][C:6]([C:5]1[C:1]([CH2:2][CH3:3])=[N:17][NH:18][C:11]=1[OH:13])=[O:7])[CH3:10]
Reactant: CCOC(=O)C(C(=O)CC)C(=O)OCC
Reactant: NN
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(CC)n[nH]c1O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To diethyl propionylmalonate (3.63 g, 16.8 mmol) in glacial acetic acid (8 ml) at RT, is added hydrazine hydrate (55% hydrazine, 1.4 ml, 25.2 mmol). The reaction mixture is heated at 100° C. for 2 hrs and allowed to cool to ambient temperature whereupon crystallization occurs. The mixture is diluted with diethyl ether (approx. 25 ml) and stirred for 20 minutes and filtered to obtain the title compound as a white solid. This is washed with diethyl ether and dried in vacuo. A second crop of product is obtained by cooling the filtrate liquor, the precipitated solid is washed with diethyl ether and dried in vacuo. 1H NMR (400 MHz, DMSO-d6) δ 12.0 (1H, br s), 9.8 (1H, br s), 4.16 (2H, q, J 7.1), 2.73 (2H, q, J 7.5), 1.24 (3H, t, J 7.1), 1.14 (3H, t, J 7.5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:21])([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24](=O)[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][N:14]([CH2:24][CH3:25])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:21])[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(C)(CNc2ccccc2)COC1(C)C
Reactant: CC=O
Product: CCN(CC1(C)COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1

Procedure:
In analogy to example 1.b (RS)-2,2,4-trimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with acetaldehyde to give (RS)-4-[(ethyl-phenyl-amino)-methyl]-2,2,4-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. Colourless oil. MS (ISP): 349.5 ([M+H]+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:28])[CH2:13][CH:14]([NH:20]C(=O)OC(C)(C)C)[C:15]3[CH:19]=[CH:18][S:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:29]>C(Cl)Cl>[ClH:29].[ClH:29].[NH2:20][CH:14]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)[CH2:13][C:12]([NH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:28]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)Nc1ccc2cnccc2c1)c1ccsc1
Agent: Cl
Solvent: ClCCl
Product: NC(CC(=O)Nc1ccc2cnccc2c1)c1ccsc1
Reaction time: 8 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5) in CH2Cl2 was added HCl (4N in dioxane), and the solution was stirred for 8 hours. The solvents were evaporated to give 3-amino-N-(isoquinolin-6-yl)-3-(thiophen-3-yl)propanamide dihydrochloride (E6).
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[O:4][C:3]1([CH3:15])[CH3:14].[S:16]([O-])([O-])(=O)=S.C([N+](CC)(CC)CC)C.C([N+](CC)(CC)CC)C>C(O)C.C(OCC)C.C(Cl)Cl>[CH3:14][C:3]1([CH3:15])[C:2](=[S:16])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[O:4]1
Reactant: O=S([O-])([O-])=S
Reactant: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1Br
Agent: CC[N+](CC)(CC)CC
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flask are placed 5.44 g (0.020 mole) of 3-bromo-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran (prepared by the method of Example 2, Step A) and 7.45 g (0.020 mole) of tetraethylammonium thiosulfate (prepared by the method of B. Hahn et al., Liebigs Ann. Chem. 1981, 10-19) in 100 mL of absolute ethanol. This mixture is heated at reflux for 24 hours after which the solvent is removed under reduced pressure, leaving a residue. This residue is taken up in 60 mL of diethyl ether which is then filtered to remove inorganic salts. Slowly, 20 mL of a 2N aqueous sodium hydroxide solution is added to the rapidly stirred filtrate. This mixture is stirred for 30 minutes at room temperature after which the aqueous phase is separated from the organic phase. The latter is washed with water, dried over anhydrous sodium sulfate, and filtered. The solvent is evaporated under reduced pressure, leaving a residue which is dissolved in methylene chloride. This solution is passed through a column of silica gel, eluting with methylene chloride. Product-containing fractions are combined, and the solvent is evaporated under reduced pressure, yielding 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-thione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](I)[CH3:26]>>[CH2:25]([N:13]1[C:12](=[O:24])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14]1)[CH3:26]
Reactant: CCI
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Product: CCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)c(F)c2)cc1=O
Yield: 97.8 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethyl iodide as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 97.8%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:26]3[C:21]([O:20][CH3:19])=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncccc1C1=CCC2(CC1)OCCO2
Temperature: 100 °C

Procedure:
To a mixture of trifluoro-methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-7-en-8-yl ester (prepared according to JOC, 69, 3943, 2004, 1.27 g, 3.47 mmol) and 2-methoxypyridine-3-boronic acid (Aldrich, 637 mg, 4.17 mmol) was added tetrakistriphenylphosphine palladium (120 mg, 0.10 mmol), dioxane (10 mL) and aqueous sodium carbonate (4.00 mL, 8.00 mmol, 2N). The reaction mixture was heated to 100° C. under argon for 16 hours and then cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) to afford 3-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-2-methoxy-pyridine as a colorless oil.