Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][C:7]1=[O:22].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+]>O1CCCC1>[OH:22][C@H:7]1[C@@H:6]([O:5][C:4]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:2]([CH3:1])[CH:3]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8]1
Reactant: Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2=O)cc1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.0 g (0.028 mol) of the 4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-3-piperidone described in Example 44 are dissolved in 60 ml of dry tetrahydrofurane and the solution is treated dropwise, at room temperature in a nitrogen atmosphere, with 112 ml of a 0.5 M solution of potassium tri-sec.-butylborohydride (K selectride) (0.056 mol) in tetrahydrofurane. After the addition has ended, the reaction mixture is stirred for a further 3 hours at room temperature and then concentrated to about 1/3 of the original volume under a water pump vacuum. The solution is cooled to 0° in an ice-water bath, treated dropwise with 130 ml of water and extracted by shaking with twice 150 ml of methylene chloride. The combined organic phases are washed with 0.1 N hydrochloric acid, then with 0.1 N sodium hydroxide solution and finally with water, dried over sodium sulphate and evaporated to dryness under a water pump vacuum. The oily crude product is dissolved in toluene and the solution is filtered through a layer of silica gel. cis-3-hydroxy-4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-piperidine is obtained in the form of a pale yellow oil by elution with a toluene/ethyl acetate mixture (5:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1cccs1

Procedure:
3-Thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester was prepared from 3-bromo-1H-indolecarboxylic acid ethyl ester and 2-thiopheneboronic acid followed the procedure of Example 11 Step 2 as a light yellow powder: 1H NMR (DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 4.30 (q, J=7.2 Hz, 2H), 7.12-7.16 (m, 1H), 7.17-7.20 (m, 1H), 7.31-7.34 (m, 1H), 7.36(dd, J=5.1, 1.5 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.63 (d, J=6.3 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 12.02 (br s, 1H); MS (ESI) m/z 272 (MH+); 270 ([M−H]−).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:20]1(C)C=CC=CC=1.COC(OC)OC>CO>[CH3:20][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Cc1ccccc1
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Solvent: CO
Solvent: COC(OC)OC
Product: COC(=O)CCCCCCCCCCCCCCCBr
Temperature: 55 °C
Reaction time: 16 h

Procedure:
16-Bromo-hexadecanoic acid (6.0 g) was dissolved in MeOH (35 mL), toluene (100 mL) and trimethylorthoformate (20 mL), then Amberlyst 15 from Fluka (1.4 g) was added. The mixture was stirred at 55° C. for 16 h. The mixture was evaporated to dryness and dried under vacuum for 16 h to yield 7.7 g. The residue was suspended in MeOH (ca. 50 mL) and stirred for ca ½ h. The amberlyst 15 was filtered off after stirring with DCM (30 mL) for ½ h. The filtrate was concentrated to remove the DCM, and the clear solution was cooled and more MeOH (ca 20 mL, total ca 40 mL) was added. The flask was cooled and more crystals precipitated and after stirring for 30 min, the crystals were filtered off and washed with cold MeOH. The white crystals were dried under vacuum to yield 5.61 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C.ClCCl>[C:15]1([CH2:14][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccc(O)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: OCc1ccc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(hydroxymethyl)-3-(trifluoromethyl)phenol (for a preparation see Intermediate 17)(3.86 g, 20.1 mmol) in ethanol (80 mL) was added benzyl bromide (2.4 ml, 20.2 mmol, Aldrich) and then 2 M sodium hydroxide (11 ml, 22 mmol). The mixture was stirred at ambient temperature overnight under nitrogen. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (4.68 g);
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1.[Li+].[Br-:13]>CC(C)=O>[Br:13][CH2:2][C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1
Reactant: Cn1cc([N+](=O)[O-])nc1CCl
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: Cn1cc([N+](=O)[O-])nc1CBr
Yield: 94.9 %

Procedure:
A mixture of 2-(chloromethyl)-1-methyl-4-nitro-1H-imidazole (485 mg, 2.76 mmol) and LiBr (4.80 g, 55.2 mmol) in acetone was heated at reflux for 5 hours before all the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate twice. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was recrystallised from DCM/hexane to give 2-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (105) (576 mg, 95%) as an off-white solid, m.p. 130-132° C. 1H NMR (CDCl3, 400 MHz) δ 7.74 (s, 1H), 4.50 (s, 2H), 3.83 (s, 3H). Analysis found: C, 27.81; H, 3.27; N, 19.05. C5H6BrN3O2.0.04hexane requires: C, 28.16; H, 2.96; N, 18.80. HRMS (FAB+) found: 219.97220, 221.97018 (M+1), calcd. for C5H779/81BrN3O2: 219.97216, 221.97012.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1[O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][C:30]2[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:34]([CH2:41][CH3:42])[N:33]=[CH:32][N:31]=2)=[CH:23][CH:22]=1>C(O)C>[OH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][C:30]2[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:34]([CH2:41][CH3:42])[N:33]=[CH:32][N:31]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCO)cc1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
p-Toluenesulfonic acid (0.10 g) was added to a solution of ethyl 4-(2-(4-(2-(tetrahydropyran-2-yloxy)ethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (4.20 g, 9.82 mmol) in ethanol (40 ml). The mixture was heated under reflux for 4 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. Water (40 ml) was added to the residue. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=1/1) to give the desired ethyl 4-(2-(4-(2-hydroxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (2.60 g, 77%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].[C:14]([O:17][CH2:18][CH2:19]Cl)(=[O:16])[CH3:15]>CN(C)C=O>[C:14]([O:17][CH2:18][CH2:19][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCCl
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A suspension of sodium hydride (3.0 g, 60% in mineral oil) and dimethyl formamide (100 mL) was kept at 15-18° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (10.0 g) in dimethyl formamide (150 mL). The resulting mixture was stirred at room temperature for 60 min followed by the addition of a solution of 2-chloroethyl acetate (10.0 g) in dimethyl formamide (50 mL) at a temperature of 20° C. The resulting mixture was heated at 80° C. for 2½ h, cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one (10.2 g). A mixture of crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one, sodium methanolate (2.5 mL, 30% in methanol) and methanol (250 mL) was stirred at room temperature for 16 h and subsequently concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the corresponding alcohol as a red crystalline compound (4.9 g). This alcohol was dissolved in tetrahydrofuran (100 mL) followed by the addition of triethylamine (8.2 mL). The resulting mixture was cooled to 5-6° C. followed by the addition of a solution of methane sulfonic acid chloride (2 mL) in tetrahydrofuran (25 mL). The mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in dimethyl formamide (50 mL) followed by addition of lithium chloride (4.9 g), and the resulting mixture was heated at 70° C. for 5 min. The mixture was poured onto brine, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a red oil (2.9 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:30][C:31](O)=[O:32]>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[CH2:30][C:31]([NH:17][CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:14][CH2:15][CH3:16])=[O:32])[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1ccc(CC(=O)O)c(OC)c1
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC)cc1OC)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 2-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(O)ccc3c2)o1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC(=O)OC)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A mixture of 6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthol (306 mg, 0.792 mmol), prepare in step 5 of Example 2, methyl bromoacetate (75 μL, 0.792 mmol) and potassium carbonate (556 mg, 4.02 mmol) in 35 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated and extracted three times with water. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give methyl ({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (364 mg, 96%) as a yellow solid, mp 149-151° C. Elemental Analysis for C28H25NO5 Calc'd: C, 73.83; H, 5.53; N, 3.07. Found: C, 73.55; H, 5.72; N, 3.08.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][N:8]1C[CH2:23][CH2:22][C:11]2[N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:10]=2[C:9]1=[O:25])[CH2:15][CH2:14][CH2:13]3.[CH3:26]O>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][N:8]1[CH2:23][CH2:22][C:11]2[N:12]3[C:21]4[C:20](=[CH:19][CH:18]=[CH:17][C:16]=4[CH2:15][CH2:14][CH2:26][CH2:13]3)[C:10]=2[C:9]1=[O:25]
Reactant: CO
Reactant: Cc1[nH]cnc1CN1CCCc2c(c3cccc4c3n2CCC4)C1=O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc4c3n2CCCC4)C1=O

Procedure:
11-{(5-methyl-1H-imidazol-4-yl)methyl}-5,6,9,10,11,12-hexahydro-4H, 8H-azepino[3',4':4,5] pyrrolo[3,2,1-ij]quinolin-12-one; melting point 215°-216° C. C-13-NMR (SLV: CDCl3, Ref.: TMS, ADT: MeOH)
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29]I.[Cl-].[NH4+]>C(COC)OC.CCCCCC>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:16]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: ClCCCCI
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCl)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57M hexane solution, 3.52 ml) was added to a dimethoxyethane solution (30 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.52 g, 5.02 mmol) obtained in Example 5. The temperature of the reaction mixture was elevated to room temperature, at which stirring was conducted for 15 minutes. After cooling the reaction mixture to −78° C., 4-chloro-1-iodobutane (672 μl, 5.52 mmol) was added thereto and the mixture was stirred at room temperature for 24 hours. A saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water, a saturated aqueous solution of sodium thiosulfate and brine, dried over MgSO4, and then distilled under reduced pressure to remove the solvent. The residue thus obtained was recrystallized from hexane, whereby the title compound (1.64 g, 83%) was obtained as colorless needle crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][NH2:13])[C:5]=2[O:4][CH2:3][CH2:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: NCCc1cccc2c1OCCO2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1cccc2c1OCCO2

Procedure:
In close analogy to the procedure described above, 2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][NH:15][C:12]2=[CH:13][N:14]=1.[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[C:28]([CH2:33][CH3:34])[N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[Cl:25][C:26]1[N:31]=[C:30]([N:15]2[C:12]3=[CH:13][N:14]=[C:9]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:8])[CH:10]=[C:11]3[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16]2)[CH:29]=[C:28]([CH2:33][CH3:34])[N:27]=1
Reactant: CCC(CC)C(=O)c1c[nH]c2cnc(-c3c(C)cccc3C)cc12
Reactant: CCc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(-n2cc(C(=O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-[5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (200 mg, 0.62 mmol), 2,4-dichloro-6-ethyl-pyrimidine (221 mg, 1.25 mmol), Cs2CO3 (305 mg, 0.93 mmol), and DMF (3 mL) is stirred for 4 h at room temperature. The mixture is diluted with EtOAc (10 mL), and the obtained solution is washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 337 g of 4-nitro-3-(4-chlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(4-chlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([OH:30])=O)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])=[O:30])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCCO
Reactant: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 44.5 %

Procedure:
8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol) was reacted with 2-(methylamino)ethanol (0.028 mL, 0.35 mmol) using a procedure similar to the one described in Example 2.00 to afford 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (65.0 mg, 44.3%) as a white solid. Mass Spectrum: M+H+ 504. NMR Spectrum: (DMSOd6) 1.57 (d, 3H), 2.76 (s, 1.5H), 2.94 (s, 1.5H), 3.07 (bs, 1H), 3.27 (bs, 1H), 3.45 (bs, 1H), 3.51-3.64 (m, 5H), 3.70-3.78 (m, 4H), 4.69 (bs, 0.5H), 4.78 (ns, 0.5H), 5.08 (bs, 1H), 5.60 (s, 1H), 6.33-6.47 (bs, 2H), 6.65 (ddd, 1H), 6.83 (dd, 1H), 7.60 (bs, 0.5H), 7.61 (bs, 0.5H), 7.79 (bs, 0.5H), 7.81 (bs, 0.5H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([C:41]2[CH:42]=[CH:43][C:44]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[CH:22][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: OB(O)c1ccc(C2CCCC2)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclopentylphenylboronic acid (38 mg, 0.2 mmol) to give 5-{-4-[2-(4′-cyclopentyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:38]1[C:46]2[C:41](=[C:42](B3OC(C)(C)C(C)(C)O3)[C:43]([F:47])=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)(C(C)(C)C)(C)C>>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:17]([CH:15]2[CH2:16][N:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:2]([C:42]5[C:43]([F:47])=[CH:44][CH:45]=[C:46]6[C:41]=5[CH:40]=[CH:39][NH:38]6)[N:3]=[C:4]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:5]=4[N:11]=3)[CH2:14]2)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: FC1(F)CCN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CC1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)(F)CC4)C3)ccc2n1

Procedure:
4-(2-chloro-6-((3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 24.7 mg of 125 following reverse phase HPLC purification. MS (Q1) 538.3 (M)+
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([C:18]#[N:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29]Br>C1(C)C=CC=CC=1>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][C:8]1([C:18]#[N:19])[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][CH2:12][C:13]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: N#CC1c2ccccc2CCc2ccccc21
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(CCCOC2CCCCO2)c2ccccc2CCc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
In a 50 ml roundbottom flask equipped with magnetical stirring, thermometer and addition funnel, sodium hydride (0.8 g, 0.02 mol, 60% dispersion in oil) was suspended in dry toluene under an atmosphere of nitrogen. A solution of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (3.0 g, 0.014 mol, prepared in a similar way as described in J. Med. Chem., 6, (1963), 251) in dry toluene (15 ml) was added. The reaction mixture was heated to reflux temperature in 30 minutes and then heated at reflux temperature for 150 minutes. After cooling to about 50° C., a solution of 3-bromopropyl tetrahydropyranyl ether (4.5 g, 0.02 mol) in dry toluene (6 ml) was added dropwise. The reaction mixture was heated at reflux temperature for 5 h and then left stirring at room temperature overnight. After filtration of precipitated salts, the solution was washed with 1N HCl (100 ml), diluted with more toluene (100 ml) and finally washed with water. After drying (MgSO4), the organic phase was evaporated in vacuo affording 7.2 g (99%) of 5-(3-(tetrahydropyran-2-yloxy)-1-propyl)-10,11-dihydro-5 H-dibenzo[a, d]cycloheptene-5-carbonitrile.