Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C=O)C.[Na+].[Cl-].CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc2c(c1)CCN2CCN1CCCC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Under a nitrogen atmosphere 700 mg (3.46 mmol) 5-bromoindoline are added to a solution of 722 mg (4.16 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride and 1.19 mL (6.93 mmol) ethyldiisopropylamine in 10 mL DMF. The reaction solution is stirred for 21 h at RT and again combined with N-(2-chloroethyl)-pyrrolidine hydrochloride. The reaction solution is heated to 70° C. and stirred for 4 h at this temperature. The solvent is eliminated i.vac. and the residue taken up in 50 mL semisaturated NaCl solution and 50 mL EtOAc. The aqueous phase is extracted twice with 50 mL DCM, the combined organic extracts are dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: [CH3:1][C:2]([S:7][CH2:8][CH2:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)([CH3:6])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:30][C:31]([C:42]1[CH:46]=[C:45]([NH2:47])[O:44][N:43]=1)([C@@H:33]([O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)[CH3:34])[CH3:32]>C(Cl)Cl.CN(C=O)C>[CH3:6][C:2]([S:7][CH2:8][CH2:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)([CH3:1])[C:3]([NH:47][C:45]1[O:44][N:43]=[C:42]([C:31]([CH3:30])([C@@H:33]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH3:34])[CH3:32])[CH:46]=1)=[O:5]
Reactant: C[C@H](OC1CCCCO1)C(C)(C)c1cc(N)on1
Reactant: CC(C)(SCC[C@H]1CCOC1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](OC1CCCCO1)C(C)(C)c1cc(NC(=O)C(C)(C)SCC[C@H]2CCOC2)on1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
Activation of 0.35 g (1.61 mmol) of 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoic acid as the corresponding acid chloride is achieved by treatment with oxalyl chloride (0.28 mL, 3.22 mmol) and DMF (cat., 0.01 mL) in DCM (15 mL) at room temperature for 3 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in THF (5 mL) and concentrated under reduced pressure. This process is repeated. Then the crude acid chloride is dissolved in anhydrous THF (10 mL) and 0.32 mL (1.81 mmol) of N,N-diisopropylethylamine are added followed by 0.17 g (0.66 mmol) of 3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-amine. After complete addition the reaction is heated to 60° C. for 17 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 solution (2×5 mL) and 1M aqueous HCl solution (2×5 mL). The organic layer is dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent heptanes, 30% ethyl acetate) to yield 133 mg of 2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanamide. Yield: 55%; ES-MS: m/z 453 [M−H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm approx 1:1 mixture of diastereoisomers: 1.00 (4H, d, J=6.24 Hz), 1.14-1.20 (4H, m), 1.22-1.39 (11H, m), 1.41-1.91 (27H, m), 1.94-2.13 (2H, m), 2.20-2.36 (2H, m), 2.48-2.67 (4H, m), 3.26-3.38 (2 H, m), 3.41-3.55 (2H, m), 3.63-3.98 (12H, m), 4.53-4.59 (1H, m), 4.74 (1H, t, J=3.12 Hz), 6.31 (1H, s), 6.35 (1H, s), 9.50 (2H, s)
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[Cl:13][C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=2)[N:15]=1.S(=O)(=O)(O)[OH:26].C(=O)(O)[O-].[Na+]>>[Cl:13][C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=2)[N+:15]=1[O-:26]
Reactant: O=S(=O)(O)O
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Product: [O-][n+]1c(Cl)cnc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Potassium persulfate (7.42 g) was slowly added to a stirred mixture of 2,6-dichloroquinoxaline (5.0 g) and concentrated sulfuric acid (25 ml) at a temperature of 10° C. On completion of the addition the mixture was allowed to warm to room temperature and the mixture was stirred for a further 24 hours. The mixture was poured into ice-water (400 ml), neutralized with aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The organic extract was washed with brine, dried (over anhydrous sodium sulfate) and the solvent was removed by distillation under reduced pressure. The residue was crystallised from ethanol to give 2,6-dichloroquinoxaline-1-oxide as brown needles, mp 185° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+].O>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Cl)nc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a solution of 1,1-dimethylethyl(4RS,5SR)-5-(6-chloro-3-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (600 mg, 1.31 mmol) in methanol (3.1 ml) was added 0.5N sodium hydroxide methanol solution (3.1 ml, 1.55 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (50 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (321 mg, 57%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH:17]2[CH2:19][CH2:18]2)[CH:10]=1.[N:20]#[C:21]Br>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:19][CH2:18]2)[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: N#CBr
Reactant: NNc1nnc(Cl)cc1C1CC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc2c(C3CC3)cc(Cl)nn12
Temperature: 55 °C
Reaction time: 6 h

Procedure:
(6-Chloro-4-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.010; 400 mg) was converted and worked up analogously to W2.009. However, one further equivalent of cyanogen bromide was added and the mixture was additionally stirred at 55° C. for 6 h. 252 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([CH3:13])([NH2:12])[CH3:11])[CH2:4][CH2:3]1.[C:15](ON1C(=O)CCC1=O)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]([NH:12][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:13])[CH3:11])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)CCN1CCC(C)(C)CC1
Solvent: C1CCOC1
Product: CC1(C)CCN(CCC(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.9 %

Procedure:
Crude 4-(4,4-dimethylpiperidin-1-yl)-2-methylbutan-2-amine (5.80 g, 29.2 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (7.29 g, 1 equiv, 29.2 mmol) in one portion. The reaction was left to stir at room temperature for 3 d. The solvent was removed and the residue was taken up in a mixture of diethyl ether (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1M HCl (50 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 10-80% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a white solid (4.75 g, yield: 49.0%). 1H NMR (CDCl3, 400 MHz): δ 0.92 (s, 6H), 1.35-1.40 (bm, 10H), 1.58-1.63 (t, J=10.8, 2 H), 2.40 (bs, 4H), 2.44-2.52 (t, J=10.8, 2H), 5.03 (s, 2H), 7.27-38 (m, 5H). LRMS (ESI+) for C20H32N2O2 (332.2); Found: 333 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:19](N1CCOCC1)C.CN(C1C=CC=CN=1)C.ClC(OCC(C)C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN1CCOCC1
Reactant: COc1ccc(C2(CN)CCCCC2)cc1OC
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: CNCC1(c2ccc(OC)c(OC)c2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 7.73 g (0.031 mol) of 1-(3,4-dimethoxyphenyl)-1-cyclohexanemethanamine, 4.3 ml (0.00348 mol) of N-ethylmorpholine and 0.3 g of dimethylaminopyridine in 100 ml of abs. tetrahydrofuran was cooled to -10° and treated within 10 minutes with 4.4 ml (0.0348 mol) of isobutyl chloroformate. The mixture was then stirred at room temperature for 18 hours and filtered, and the solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the organic solution was washed first with 1N hydrochloric acid and then with a saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. The residual oil was treated with 100 ml of abs. tetrahydrofuran and 2.35 g (0.062 mol) of lithium aluminium hydride and the mixture was heated to reflux for 2 hours, thereafter cooled and treated with a saturated sodium sulphate solution. After filtering the mixture and evaporating the solvent there was obtained an oil which was distilled at 153° /260 Pa, whereby there was obtained 1-(3,4-dimethoxyphenyl)-N-methyl-1-cyclohexanemethanamine as a colourless oil which was used directly in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[CH:9]1([C:18]#[N:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:9]1([C:18]#[N:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: BrCCC1OCCO1
Reactant: N#CC1CCc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CCC2OCCO2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2(2-bromoethyl)-1,3-dioxolane (14.09 ml, 120.1 mmole) was added to a solution of 1-indanecarbonitrile (15.63 g, 109.2 mmole) in 100 ml of THF and cooled to 0° C. After the dropwise addition of 1M LHMDS (120 ml) the solution was stirred at 0° C. for 20 min then at room temperature for 20 min. After the removal of solvent the residue was flashed of silica using 15% EtOAc and Hexanes to afford 1-[2-(1,3-dioxolan-2-yl)ethyl]-1-indanecarbonitrile as a thick oil.
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=2)[C:11]1=[O:23])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:24][C:25]([O:28][C:29]([N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1)=[O:30])([CH3:27])[CH3:26].S1C=CC=C1B(O)O>>[C:6]([O:5][C:3](=[O:4])[C@@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]([C:34]3[CH:33]=[N:32][N:31]([C:29]([O:28][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:30])[CH:35]=3)[CH:19]=[CH:20][CH:21]=2)[C:11]1=[O:23])[OH:1])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2cccc(I)c2)C1=O
Agent: OB(O)c1cccs1
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2cccc(-c3cnn(C(=O)OC(C)(C)C)c3)c2)C1=O
Yield: 62.7 %

Procedure:
According to the Step 22-1 in synthetic method for EXAMPLE 22, compound 107-1 (0.2 g) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid 1,1-dimethylethyl ester (0.27 g) were used instead of 14-4 and 2-thiopheneboronic acid to obtain compound 107-2 (137 mg) as a pale yellow amorphous solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=[CH:18][C:12]=3[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]=1[OH:32])=[O:24]>>[C:23]([C:25]1[C:26]([OH:32])=[C:27]([NH:31][C:19]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:14][C:13]=3[CH:15]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:22]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1ccc2c(c1)CC(CCCc1ccccc1)O2
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CC(CCCc2ccccc2)O3)c1O
Yield: 60 %

Procedure:
Following the process described in example 1 (point K), starting from 2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared (60% yield).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:37])=O>O>[Cl:37][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(O)nc1NCc1ccc(OC)c(Cl)c1
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 92) 500 mg, diethylaniline 2 ml and phosphoryl chloride 4 ml is stirred at 80° C. for 30 minutes and then at 100° C. for 5 hours. After cooling, the reaction solution is poured into water in ice and the mixture is stirred at room temperature for 30 minutes. The product is extracted with ethyl acetate and the organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (silica gel 7 g, solvent; chloroform) to give 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a slightly yellow crystalline powder, 375 mg. mp 114-115° C. MS(m/z): 356(M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])C.[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:27][C@H:22]([C:21]([O:20][CH3:19])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C1Oc2cccc(Cl)c2C=C1CN[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 55.9 %

Procedure:
To a solution of 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.5 g, 5.62 mmol) (from Example 1, Step 1) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-4-methyl-pentanoic acid methyl ester (1.2 g, 5.62 mmol) and N,N′-diisopropylethylamine (2 mL, 11.24 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.706 g, 11.24 mmol) and acetic acid (0.70 mL, 11.24 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo and the residue was purified using flash column chromatography over neutral alumina (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.7) to afford 5-chloro-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-2H-chromene-2-carboxylic acid methyl ester (1.2 g, 54.5%) as an oil.
Reaction SMILES: C(N(CC)CC)C.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.Br[C:30]1[CH:31]=[CH:32][C:33]([C:36]#[C:37][CH2:38][OH:39])=[N:34][CH:35]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44](OB(O)O)=[CH:43][CH:42]=1>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:30]2[CH:31]=[CH:32][C:33]([C:36]#[C:37][CH2:38][OH:39])=[N:34][CH:35]=2)=[CH:43][CH:42]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: OCC#Cc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: OCC#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 1 mL (7.22 mmol) triethylamine, 23 mg (0.1 mmol) Pd(OAc)2 and 57.5 mg (0.19 mmol) biphenyl-2-yl-di-tert-butyl-phosphane are added to a solution of 500 mg (2.36 mmol) 3-(5-bromo-pyridin-2-yl)-prop-2-yn-1-ol and 600 mg (3.72 mmol) 4-chlorophenyl-boric acid in 10 mL DMF and 2.5 mL water and the reaction mixture is stirred for 8 h at 60° C. Then 400 mg (2.48 mmol) 4-chlorophenyl-boric acid are added and the mixture is stirred for a further 19 h at 60° C. The mixture is evaporated down i. vac., the residue is combined with 10 mL water and 10 mL EtOAc, the aqueous phase is saturated with NaCl, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc3 2:1).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:18]([CH:19]=2)=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)[CH:15]=2)[CH:10]=3)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Agent: Cl
Product: CN1CCN(CCOc2ccc3cc4ccc(OCCN5CCN(C)CC5)cc4nc3c2)CC1
Temperature: 100 °C

Procedure:
The compound is prepared from 3,6-bis(2-chloroethoxy)acridine hydrochloride and N-methylpiperazine as described in Example 15, except that the mixture is heated at 100° C. for 24 hours to attain reaction and that the free base is isolated.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[CH2:4]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C@@H:18]([OH:22])[C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[Na+]>C(Cl)Cl.CO.C(OCC)C.C(OCC)(=O)C.C(N(CC)CC)C>[OH:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][C@@H:3]([NH:2][C:19](=[O:20])[C@@H:18]([C:17]3[CH:23]=[CH:24][CH:25]=[C:15]([Cl:14])[CH:16]=3)[OH:22])[CH2:4]2)=[CH:9][CH:8]=1
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: N[C@@H]1CCc2ccc(O)cc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H]1CCc2ccc(O)cc2C1)[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.6 g of (R)-2-amino-7-hydroxytetralin hydrochloride (PREPARATION II), 2.4 g of (R)-3-chloromandelic acid (Bull. Soc. Chim. Fr., 1973, 12, 3330) and 5.2 g of BOP in 60 ml of anhydrous methylene chloride, there is added 3.6 ml of triethylamine slowly, then the solution thus obtained is stirred at room temperature for 3 hours. After addition of 50 ml of a saturated sodium chloride solution, the reaction mixture is stirred for 30 minutes at room temperature, then 200 ml of ethyl acetate are added thereto and the phases are separated. The organic phase is washed twice with 30 ml of a 2N hydrochloric acid solution, then twice with 30 ml of a saturated sodium chloride solution. The organic solution is dried over sodium sulfate, filtered and evaporated to dryness. The oil thus obtained is purified by flash chromatography (eluent 55/45 mixture of ethyl acetate/cyclohexane). A doughy solid is obtained that is taken up with 20 ml of ethyl ether from which the product crystallizes. After addition of 10 ml of cyclohexane, the solution is filtered, washed with a 2/1 mixture of cyclohexane/ethyl ether and dried under reduced pressure at 50° C. to give 2.4 g (55%) of a stereoisomer that is pure according to 13C RMN at 60 MHz; m.p. 132°-134° C., [alpha]=+24.9° (methanol, c=1%). In TLC this product has the same shift of the product of Example 1(c), SR 58536 (RR,SS) and no impurity corresponding to the Rf of SR 58535 (RS,SR) of Example 1(b) (elution with 1/1 ethyl acetate/cyclohexane). After a further purification by chromatography, there is obtained the enantiomerically and chemically pure N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chloromandelamide; m.p. 143°-147° C., [alpha]=+35.1° (methanol, c=1%). This product is identical with the compound SR 58533 of Example 8(c), the R,R configuration of which is thus confirmed.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 7) (18 g, 63.6 mmol) was dissolved in dry NMP (90 mL). 6-chloronicotinonitrile (13.21 g, 95 mmol) and DIPEA (22.20 ml, 127 mmol) were added, the mixture was stirred at 150° C. under a nitrogen atmosphere for 8 h, then allowed to stand overnight at room temperature. The solution was added to water (1 L) and the mixture extracted with EtOAc (2×400 mL). The organic layer was washed with water (2×500 mL), dried and evaporated in vacuo to give a brown foam. This brown foam was purified by silica gel column chromatography (750 g column, eluting with 0-100% EtOAc/cyclohexane). The appropriate fractions were combined and evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (18.7 g, 48.5 mmol, 76% yield) as a pale yellow solid.