Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([CH3:27])=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([N:19]([CH2:22][CH3:23])CC)=[O:18].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46]C(C#N)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:23]([C:22]3[NH:19][C:17](=[O:18])[C:16]4[C:15]([CH:27]=3)=[C:14]([Br:13])[CH:26]=[CH:25][CH:24]=4)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCN(CC)C(=O)c1cccc(Br)c1C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C#N)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4c(Br)cccc4c(=O)[nH]3)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a stirred solution of N,N-diisopropylamine (1.56 mL, 11.10 mmol) in THF (5 mL) under N2 at −78° C. was added n-BuLi (2.5M in hexanes) (4.44 mL, 11.10 mmol) and the reaction stirred at −78° C. for 20 min, after which time a solution of 3-bromo-N,N-diethyl-2-methyl-benzamide (1 g, 3.70 mmol) in THF (5 mL) was added, and the reaction stirred at −78° C. for 30 minutes. A solution of 4-(4-cyano-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (1.15 g, 3.70 mmol) in THF (5 mL) was added and the reaction stirred at −78° C. for 2 h. The reaction was quenched with ice and water, EtOAc added and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 100% EtOAc to afford 4-[4-(5-bromo-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester as a cream solid (1.22 g, 66%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH3:16][NH:17][NH2:18].[OH-].[Na+]>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=[C:2]([N:17]([CH3:16])[NH2:18])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CNN
Agent: [Na+]
Agent: [OH-]
Product: CN(N)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Chloro-4,6-bis(trifluoromethyl)pyridine (19.4 g; 0.078 mol) was treated with several portions of methyl hydrazine (4.2 g; 0.090 mol) and stirred under nitrogen at room temperature for 24 h. The oil/solid mixture was treated with 5M aqueous NaOH to basify (pHil) and extracted with ethyl acetate. The organic extracts were dried and evaporated to afford 1-[4,6-bis[trifluoromethyl]pyrid-2-yl]-1-methyl hydrazine as an oil (18.4 g; 91%). ##STR25##
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]=1[OH:22])([CH3:11])([CH3:10])[CH3:9].O.C(Cl)[Cl:25]>Cl[Ti](Cl)(Cl)Cl>[C:18]([C:14]1[CH:15]=[C:16]([C:4](=[O:5])[CH2:3][C:2]([Cl:25])([CH3:7])[CH3:1])[CH:17]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:13]=1[OH:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: ClCCl
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Product: CC(C)(Cl)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.17 h

Procedure:
In a 1 L round bottom flask, equipped with internal thermometer, magnetic stirrer and septum inlet, is placed a solution of 3,3-dimethylacryloylchloride (Aldrich Chemical Co.) (18.4 mL, 0.166 mol) in CH2Cl2) 150 mL). The stirred solution is cooled in a salt-ice bath, while TiCl4 (18.2 mL, 0.20 mol, 1.2 eq) is added dropwise via canula at a rate such that the reaction mixture does not warm above 0° C. The solution is stirred for 10 minutes after addition is complete, and then a solution of 2,6-di-tert-butylphenol (Aldrich Chemical Co.) (34.0 g, 0.166 mol, 1.0 eq) in CH2Cl2 (100 mL) is added dropwise via addition funnel. Again, the rate of addition is adjusted to maintain the reaction temperature below 0° C. The cold bath is removed, and the mixture is allowed to stir at ambient temperature for 3 hours. TLC analysis (EtOAc:hexane, 1:9) indicates the reaction to be complete. H2O (100 mL) is added, and the organic phase is separated, washed with additional H2O (2×100 mL), dried over MgSO4, filtered, and evaporated to a dark oil (49.0 g). At this stage, the reaction mixture consists of a mixture of the desired p-chloroketone and the intermediate α,β-unsaturated ketone. The oil is taken up in 1M HCl-saturated Et2O (150 mL), and stirred at ambient temperature overnight. The reaction is then extracted with H2O (3×100 mL), dried over MgSO4, filtered, and evaporated to a viscous dark oil. The crude product is crystallized from pentane to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-chloro-3-methyl-butan-1-one as a white solid, mp 101°-2° C.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Reactant: NCCCn1ccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Reaction time: 1 h
Yield: 5.2 %

Procedure:
4-Anilino-2-(4-carboxyanilino)-5-chloropyrimidine (Method 1; 170 mg, 0.5 mmol) was added to 1-(3-aminopropyl)imidazole (93.9 mg, 0.75 mmol) in a reaction tube. 1-Hydroxybenzotriazole (101 mg, 0.75 mmol) was added followed by N,N-diisopropylethylamine (130 mL 0.75 mmol) in DCM (4 ml). The mixture was flushed with argon and then stirred for 1 hour. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (105 mg, 0.55 mmol) in DCM (3 ml) was added and the mixture was stirred for 16 hours. The mixture was washed with saturated sodium bicarbonate solution (10 ml), water (10 ml) and saturated sodium chloride solution (10 ml), and the organic phase was loaded on a Varian Mega Bond Elut column. Elution with 0-10% 2.0M methanolic ammonia solution in DCM gave the product (11.6 mg, 5.2%). NMR: 2.0-2.15 (m, 2H), 3.0-3.1 (m, 2H), 4.25 (t, 2H), 7.25 (t, 1H), 7.4 (t, 2H), 7.6 (d, 4H), 7.7 (s, 1H), 7.75 (d, 2H), 7.85 (d, 1H), 8.3 (s, 1H), 8.6 (br t, 1H), 9.25 (d, 1H), 9.6 (br s, 1H), 10.3 (br s, 1H); LCMS (MH+): 448; HPLC (RT, System A): 6.16.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:15].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)=[CH:36][CH2:37]O)=[CH:31][CH:30]=1>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:37][CH:36]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=2)[C:39]2[CH:40]=[CH:41][C:42]([Br:45])=[CH:43][CH:44]=2)=[CH:24][CH:25]=1)[CH3:15]
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (404 mg, 2.0 mmol), 3-(4-hydroxy-phenyl)-propionic acid ethyl ester (388 mg, 2.0 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-ol (736 mg, 2.0 mmol) in dry THF (50 ml), the mixture warmed to room temperature, and stirred for 4 h. The reaction mixture was concentrated in vacuo, and added water and ethyl acetate (75 ml each). The aqueous layer was collected and further extracted with ethyl acetate (2×75 ml). The organic layers were combined, washed with water, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica (25% ethylacetane in heptane eluent) to give 1.0 g (92%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[O:20][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Reactant: N#CCc1cccc(F)c1
Product: Fc1cccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)c1

Procedure:
The title compound, light yellow solid (73 mg, 55%), MS (ISP) m/z=374.1 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [Na+].[Na+].[F:3][C:4]([F:15])([C:12]([O-:14])=[O:13])[O:5][C:6]([F:11])([F:10])[C:7]([O-:9])=[O:8].[Br-].[C:17]1([S+:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[F:3][C:4]([F:15])([C:12]([OH:14])=[O:13])[O:5][C:6]([F:10])([F:11])[C:7]([OH:9])=[O:8].[C:30]1([S+:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[C:30]1([S+:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C([O-])C(F)(F)OC(F)(F)C(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C(O)C(F)(F)OC(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrafluorodiglycolic acid disodium salt (0.45 g, 1.8 mmol) was dissolved in 6 mL of water and added slowly to a solution of triphenylsulfonium bromide (1.25 g, 3.6 mmol, dissolved in 12 mL dichloromethane). The mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness (or to an oil stage) on a rotary evaporator. The product obtained from evaporation was washed with ethyl ether and dissolved using an excess amount of dichloromethane and filtered. After the evaporation of dichloromethane, the pure compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[C:20]([CH3:21])=[N:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=3[C:17]=2[CH3:18])=[CH:13][CH:12]=1
Reactant: Cc1cc(N)cc(O)c1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1
Temperature: 160 °C

Procedure:
A mixture of 3-amino-5-methylphenol (1.0 g), 3-(4-chlorobenzyl)pentane-2,4-dione (1.7 g) and toluene-4-sulfonic acid (0.30 g) was heated at 160° C. under nitrogen for 3 hours. The mixture was cooled to room temperature and the residue triturated with methanol to give title compound, 1.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:12]([CH3:18])[C:13](=O)[CH2:14][CH2:15]Cl.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[CH3:18][N:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]=2[N:1]=[C:13]1[CH2:14][CH2:15][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CN(C(=O)CCCl)c1ccc2ccccc2c1N
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: c1ccccc1
Product: Cn1c(CCN2CCN(c3ccccc3)CC2)nc2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A solution of 5.25 g (0.02 mole) of N-(1-amino-2-naphthyl)-3-chloro-N-methyl-propanamide in 150 cc of anhydrous benzene is gradually added to a solution of 9.73 g (0.06 mole) of 1-phenylpiperazine in 25 cc of anhydrous benzene under argon atmosphere over a period of time of twenty minutes. The reaction mixture is then refluxed for 21 hours. Further, 11.73 g (0.0724 mole) of 1-phenylpiperazine is added and reflux is continued for an additional 24 hours. After cooling to room temperature, the mixture is diluted with 350 cc of benzene, poured into a separatory funnel and washed with 100 cc of water containing 7.8 cc of acetic acid. The benzene phase is extracted four times with 40 cc portions of 8% HCl. The pH of the aqueous acid phase is brought to 9 by addition of concentrated NH4OH and this aqueous solution is extracted with methylene chloride. The organic extracts are combined, dried over Na2SO4 , filtered and evaporated to dryness yielding 4.03 g of raw compound which is recrystallized from 25 cc of ethanol. M.p. 153°-155° C.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].Cl.[S:8]1[CH:12]=[CH:11][C:10]2[CH:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH2:17][C:9]1=2.C(N(CC)CC)C>O1CCCC1>[CH:1]([NH:4][C:5]([NH:18][CH:13]1[C:10]2[CH:11]=[CH:12][S:8][C:9]=2[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: NC1CCCCc2sccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)NC1CCCCc2sccc21

Procedure:
In dry tetrahydrofuran, stoichiometric quantities of isopropyl isocyanate, 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride, and triethylamine are stirred at room temperature for 2 hours and then heated at reflux for half an hour. The title product is then collected and washed with water.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:3]=1[NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[N:37]=[C:36]([C:38]([NH:41][C:42]2[C:47]([CH:48]([CH3:50])[CH3:49])=[CH:46][CH:45]=[CH:44][C:43]=2[CH:51]([CH3:53])[CH3:52])([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CO>[CH:51]([C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH:48]([CH3:50])[CH3:49])[C:42]=1[NH:41][C:38]([C:36]1[N:37]=[C:32]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH2:5][NH:4][C:3]2[C:2]([CH3:1])=[CH:28][C:27]([CH3:29])=[CH:26][C:25]=2[CH3:30])[CH:33]=[CH:34][CH:35]=1)([CH3:40])[CH3:39])([CH3:53])[CH3:52]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C(C)(C)Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.26 g (5.64 mmol) of 2,4,6-trimethyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 2.11 g (6.00 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,6-diisopropylaniline, 4.03 g (14.1 mmol) of Na2CO3×10H2O, 63 ml of water, 18 ml of methanol, and 76 ml of toluene was purged with argon for 30 min. To the obtained solution 0.32 g (0.30 mmol) of Pd(PPh3)4 was added. In argon atmosphere, this mixture was stirred for 12 h at 80° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 2.60 g (81%) of yellow oil. Anal. calc. for C40H47N3: C, 84.31; H, 8.31; N, 7.37. Found: C, 84.50; H, 8.51; N, 7.22. 1H NMR (CDCl3): δ 7.88 (m, 1H, 8-H in naphtalene), 7.85 (d, J=8.4 Hz, 1H, 4-H in naphtalene), 7.80 (t, J=7.7 Hz, 1H, 4-H in pyridine), 7.67 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 5-H in naphtalene), 7.37-7.49 (m, 4H, 3, 5, 6, 7-H in naphtalene), 7.24 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 7.04-7.06 (m, 3H, 3, 4, 5-H in 2, 6-iPr2C6H3), 6.76 (s, 2H, 3, 5-H in mesityl), 4.14 (br.s, 1H, NH), 4.00 (m, 2H, CH2N), 3.48 (br.s, 1H, NH), 3.23 (sep, J=6.7 Hz, 2H, CHMe2), 2.22 (s, 3H, 4-Me in mesityl), 2.06 (s, 6H, 2, 6-Me in mesityl), 1.57 (s, 3H, CMeMe′), 1.45 (s, 3H, CMeMe′), 1.04 (d, J=6.7 Hz, 6H, CHMe2), 1.02 (d, J=6.7 Hz, 6H, CHMe2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([OH:22])[CH2:17]1.CCN(C(C)C)C(C)C>C(O)C>[OH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([NH:15][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)[CH2:17]1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N[C@@H]1CCC[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: 60 °C
Yield: 85.3 %

Procedure:
To a stirring solution of ethyl 4-chloro-2-(methylthio)-pyrimidine-5-carboxylate (4.38 g, 18.82 mmol) and (1S,3R)-3-aminocyclohexanol (2.276 g, 19.76 mmol) in ethanol (75 ml) was added DIEA (4.93 ml, 28.2 mmol). The reaction mixture was heated to 60° C. for 2 h, was removed from heat and concentrated, then purified by silica gel chromatography (20-100% ethyl acetate/hexane). The desired product fractions were combined and concentrated to afford ethyl 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylate (5 g, 16.06 mmol, 85% yield) as a white foam. MS (ESI) m/z 312.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][CH2:6][S:7]2.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]([OH:17])[CH2:5][CH2:6][S:7]2
Reactant: COC(=O)c1cc(C)c2c(c1C)C(=O)CCS2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(C)c2c(c1C)C(O)CCS2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.40 g (0.04 mol) of methyl 5,8-dimethyl-4-oxo-6-thiochromanecarboxylate were dissolved in 200 ml of ethanol and, a little at a time, admixed with 0.89 g (0.023 mol) of sodium borohydride. The mixture was subsequently stirred at room temperature for another 1 h and then concentrated using a rotary evaporator. The residue was taken up in 200 ml of ethyl acetate, washed with sat. NaCl solution (2×100 ml), dried over MgSO4 and concentrated using a rotary evaporator.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(CN3CCC(O)CC3)cc2)cc1
Yield: 58.8 %

Procedure:
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (2.50 g) in dimethyl formamide (25 mL) were added 4-hydroxypiperidine (1.74 g) and acetic acid (2.5 mL), and the solution was stirred. To the reaction solution was added sodium triacetoxyborohydride (2.18 g) and the solution was stirred for 2 days. After finishing the reaction, the reaction solution was neutralized with 2N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride:methanol=10:1) to give the title compound (1.90 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:27]([O:29]CC)=[O:28])[CH2:26][CH2:25][CH2:24]3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24]3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C3(C(=O)O)CCC3)ccc2n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1.0 g of ethyl 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylate are dissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 50° C. for 4 h and subsequently evaporated in vacuo. The mixture is then adjusted to pH2 using 3 ml of 25% hydrochloric acid with ice-cooling, with yellow crystals precipitating. The precipitate obtained is filtered off and dried in vacuo. Yield: 800 mg (86%) of 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclobutanecarboxylic acid; LC-MS retention time: 1.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=C(S(Cl)(=O)=O)C=CC=1Cl>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)CCC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 539.18 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3,4-dichloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.