Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:14]1CCN2C(=NCCC2)CC1.CI>C(#N)C.CCOC(C)=O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:14])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2(C(=O)O)CC2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C1(c2ccc(C)cc2)CC1
Yield: 64 %

Procedure:
To a solution of 1-(p-tolyl)cyclopropanecarboxylic acid (900 mg, 5.1 mmol) in acetonitrile (20 mL) was added DBU (917 μL) followed by methyl iodide (1.91 mL). The resulting solution was heated at reflux overnight, and then diluted with AcOEt. The mixture was washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated. The resulting colorless oil was purified by chromatography on silica gel (Hexane/ethyl acetate 9/1) to afford the title compound as a colorless oil (622 mg, 64%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][C:17]([Cl:22])=[CH:18][CH:19]=2)[CH:14]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[ClH:22].[Cl:22][C:17]1[N:16]=[C:15]2[CH:14]=[C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[O:21][C:20]2=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Cl)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Clc1ccc2oc([C@@H]3CCCN3)cc2n1
Temperature: 0 °C

Procedure:
A 1.5 g sample of the compound from step 11d above was dissolved in 10 mL of CH2Cl2 and cooled to 0° C. The solution was stirred under N2, 10 mL of TFA was added, and the reaction mixture was stirred for 1 hr. The reaction mixture was poured into saturated K2CO3, and the mixture was extracted with CH2Cl2. The solution was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 99:1 to 95:5 CHCl3 :MeOH. The residue was converted to the salt by treatment with HCl/ether to give 0.78 g of title compound: 1H NMR (D2O, 300 MHz) δ 2.22-2.65 (m, 4H), 3.52-3.57 (m, 2H), 5.06 (t, 1H, J=8 Hz), 7.15 (d, 1H), 7.48 (d, 1H, J=8.6 Hz), 8.1 (d, 1H, J=8.6 Hz); MS m/z: 223 (M+H)+, 240 (M+NH4)+ ; Anal. Calcd for C11H11N2OCl.1.0 HCl: C, 50.99; H, 4.67 N, 10.81. Found: C, 51.21; H, 4.79; N, 10.55.
Reaction SMILES: C(Cl)Cl.Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH:19]=[CH:20][N:21]=3)[CH:18]=2)=[C:7]([CH3:22])[N:6]=1.[CH3:23][OH:24]>>[N:21]1[CH:20]=[CH:19][N:17]2[CH:18]=[C:13]([C:8]3[CH:9]=[C:10]([C:11]#[N:12])[C:5]([O:24][CH3:23])=[N:6][C:7]=3[CH3:22])[CH:14]=[CH:15][C:16]=12
Reactant: Cc1nc(Cl)c(C#N)cc1-c1ccc2nccn2c1
Reactant: CO
Solvent: ClCCl
Product: COc1nc(C)c(-c2ccc3nccn3c2)cc1C#N

Procedure:
In a solvent mixture of 30 ml of methylene chloride and 30 ml of methanol, 0.59 g of 2-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-3-pyridinecarbonitrile described above was stirred under reflux for 3 hours. After cooling, the solvent was removed by distillation and chloroform-water was added to the residue. The chloroform was taken by fractionation. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was recrystallized from benzene-n-hexane to obtain 0.75 g of 5-(imidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-methyl-3-pyridinecarbonitrile.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[C:10]([Cl:38])[N:9]=1)=[O:7])(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCOCC1.C(Cl)Cl.CO>[Cl:38][C:10]1[N:9]=[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:12]=2[CH:11]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NNC(C)=O)c12
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3nnc(C)o3)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N′-acetyl-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide (48 mg, 0.091 mmol) was taken up in 1,4-dioxane (1.0 ml) and Burgess reagent (39.1 mg, 0.164 mmol) was added. The reaction mixture was stirred at 100° C. for 1 hour. Room temperature was attained. The reaction mixture was diluted with DCM and MeOH and was concentrated in vacuo while loading onto silica gel. The products were then purified by MPLC 0-25% EtOAc/hexanes to give 2-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-5-methyl-1,3,4-oxadiazole (43B). MS: [M+H]+ m/z 508.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH:6]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)=[O:7].Br[C:18]1[S:19][CH:20]=[CH:21][N:22]=1>O.COCCOC.C(OCC)(=O)C.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>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]=[O:7])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1nccs1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
A mixture of NaHCO3 (3.83 g, 45.6 mmol) and 4-formylphenylboronic acid (2.69 g, 18.0 mmol) in water (60 mL) was added to a solution of 2-bromothiazole (2.50 g, 15.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.43 mmol) in DME (60 mL). The reaction mixture was heated to reflux for 18 h, cooled to room temperature, diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried with Na2SO4, and concentrated in vacuo. Two consecutive recrystallizations from hexanes/ethyl acetate yielded 998 mg (35%) of the title compound. MS 190 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:21]2[C:22]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:29][CH2:28]4)=[CH:23][S:24][C:20]=2[C:19]([C:43]2[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=2)[CH:46]=O)=[CH:18][N:17]=1.[CH3:51][NH:52][CH3:53].C1COCC1.CC(O)=O>ClCCCl>[CH3:51][N:52]([CH2:46][C:45]1[CH:44]=[C:43]([C:19]2[C:20]3[S:24][CH:23]=[C:22]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([C:34](=[O:42])[CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:29][CH2:28]5)[C:21]=3[C:16]([NH2:15])=[N:17][CH:18]=2)[CH:50]=[CH:49][CH:48]=1)[CH3:53]
Reactant: Nc1ncc(-c2cccc(C=O)c2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)Cc1cccc(-c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)c1
Reaction time: 3.5 h

Procedure:
Sodium triacetoxyborohydride (76 mg, 0.359 mmol) was added to a solution of 3-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}benzaldehyde (66 mg, 0.135 mmol), dimethylamine, 2.0 M in THF (0.10 mL, 0.200 mmol), and acetic acid (8 μL, 0.140 mmol) in 1,2-Dichloroethane (DCE) (7 mL), and the mixture was stirred at room temperature under Nitrogen for 3 days. LCMS showed only starting material, so another portion each of dimethylamine, 2.0 M in THF (0.20 mL, 0.400 mmol) and sodium triacetoxyborohydride (162 mg, 0.764 mmol) were added. Stirring continued at room temperature for another 3.5 hr, when LCMS showed complete conversion to the desired product. The mixture was poured into saturated aqueous NaHCO3 (15 mL) and extracted with methylene chloride (2×15 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson, C18, 5% to 45% CH3CN in water with 0.1% TFA, 8 minute gradient). The product fractions were combined and concentrated in vacuo, and the residue was taken up in MeOH and passed through a PL-HCO3 MP-resin cartridge, rinsing with more MeOH. The filtrate was concentrated in vacuo and dried in the vacuum oven overnight to give 7-{3-[(dimethylamino)methyl]phenyl}-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (50 mg, 0.092 mmol, 67.9% yield) as a white solid. LC/MS (ES) m/z=519 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 6H), 3.24 (t, J=8.34 Hz, 2H), 3.47 (s, 2H), 3.90 (s, 2H), 4.26 (t, J=8.46 Hz, 2H), 5.53 (br. s., 2H), 7.23-7.30 (m, 2H), 7.30-7.39 (m, 6H), 7.43-7.50 (m, 2H), 7.51-7.56 (m, 1H), 7.60 (s, 1H), 7.90 (s, 1H), 8.18 (d, J=8.34 Hz, 1H).
Reaction SMILES: [Li].[C:2]([C:6]#[CH:7])([CH3:5])([CH3:4])[CH3:3].[CH:8]([CH:10]=[CH2:11])=[O:9].C(O)(C)C>O1CCCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:6]#[C:7][CH:8]([OH:9])[CH:10]=[CH2:11]
Reactant: C#CC(C)(C)C
Reactant: C=CC=O
Agent: [Li]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CC(O)C#CC(C)(C)C
Temperature: 40 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
Under a blanket of dry nitrogen, at 0° C., metallic lithium (0.667 gr., 0.096 mole) was added to a mixture of t-butylacetylene (9.94 gr., 0.121 mole) and tetrahydrofuran (75 ml). The mixture was heated to 40° C. for 5 hours and kept at room temperature for 24 hours. The lithium was almost completely consumed. A second amount of t-butylacetylene (9.94 gr., 0.121 mole) was added and the reaction mixture was stirred for 21 hours. The mixture was cooled to 0° C. and a solution of freshly distilled acrolein (6.634 gr., 0.118 mole) in tetrahydrofuran (10 ml) was added gradually during 30 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. Isopropanol (6 ml) was added to quench the remaining lithium. The mixture was quenched using saturated ammonium chloride aqueous solution (30 ml) at 0° C. The pH was brought to 6 by 10% sulfuric acid (ca. 45 ml). The tetrahydrofuran and excess t-butylacetylene were evaporated and the mixture was extracted 3 times by dichloromethane (70 ml each time). The organic phase was washed with water (2×20 ml), dried and the solvent evaporated to give 10.2 gr. of an almost pure 6,6-dimethylhept-1-en-4-yn-3-ol (73.9% yield).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:16]([NH2:18])=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C@@H:8]([OH:19])[CH2:7][C:5]=2[CH:6]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl.C(OCC)(=O)C>[CH3:36][C:35]([O:19][C@@H:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]([C:16]([NH2:18])=[O:17])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:37]
Reactant: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 37.5 °C
Reaction time: 5.5 h

Procedure:
A solution of eslicarbazepine (15.0 gm), pyridine (8 mL), dimethylaminopyridine (0.17 gm) in dichloromethane (150 mL) was cooled to 5-10° C. Added acetyl chloride (7.6 mL) at about 5-10° C. followed by stirring at 35-40° C. for about 5-6 h. Washed the reaction mass with 0.5N HCl solution (45 mL) and followed by washing the organic layer with water (100 mL). Distilled out the solvent completely under vacuum to obtain crude eslicarbazepine acetate. The residue was dissolved in a mixture (60 mL) of dichloromethane and ethyl acetate (1:1) at 35-40° C. then cooled to 25-30° C. Reaction mass was filtered, washed with ethyl acetate and dried to obtain the title compound (m. p. 186.0-187.2° C.).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH:22](=[O:26])[CH2:23][CH2:24][CH3:25]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:3][C@H:2]([C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CCCC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21
Yield: 80 %

Procedure:
A solution of N-propionyl-2-benzoxazolone (100.0 g) in anhydrous CH2Cl2 (1100 mL) was cooled to 3° C. with mechanical stirring under N2 atmosphere. TiCl4 (58.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting yellow slurry was stirred vigorously for 40 minutes, then triethylamine (87.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting deep red solution was stirred for 80 minutes. Butyraldehyde (58.9 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 20 minutes), and the reaction was followed by thin-layer chromatography (4:1 hexanes/ethyl acetate). After stirring for 90 minutes, the reaction was quenched by addition of 450 mL of 2 N HCl. The phases were separated, and the aqueous phase was extracted 3 times with 750-mL portions of ether. The organic phases were combined and washed three times with 200-mL portions of 2 N HCl. The acidic washes were combined and back-extracted 3 times with 150-mL portions of ether. The combined organic extract was washed once with 300 mL of sat. aq. NaHCO3, and once with 300 mL of sat. aq. NaCl. The organic phase was then dried over MgSO4, filtered, and concentrated under vacuum to a yellow slurry. The product was collected by vacuum filtration and rinsed with hexanes to yield a colorless solid. Concentration of the filtrate yielded a second crop of product, which was collected in the same manner, giving a combined 103 g (80% yield) of crystalline product; mp=123–4° C. The mother liquor can be chromatographed (4:1 hexanes/ethyl acetate) to yield additional product. 1H-NMR (CDCl3, 400 MHz): δ 8.10 (1H,m), 7.23–7.32 (3H,m), 4.12 (1H,m), 3.98 (1H,dq,J=3, 7), 2.26 (1H, br s), 1.38–1.64 (4H,m), 1.34 (3H,d,J=7), 0.98 (3H,t,J=7). 13C-NMR (CDCl3, 100 MHz): δ 176.4, 151.1, 142.2, 127.8, 125.5, 124.9, 116.3, 109.9, 71.3, 43.7, 36.2, 19.2, 13.9, 10.1.
Reaction SMILES: [OH:1][CH:2]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([CH3:25])[CH:17]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=1[CH3:26].Cl.[NH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:12]([C:11]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:21])=[C:18]([CH3:25])[CH:17]=1)([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[C:27]([CH3:30])([CH3:28])[CH3:29])=[C:6]([CH3:26])[CH:7]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)c(C)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoic acid, Example 1, (0.53 g, 1.29 mmol), 2-aminoethylmethylsulfone hydrochloride (0.21 g, 1.29 mmol), HOBt (0.19 g, 1.43 mmol), Et3N (0.72 mL, 5.19 mmol) and CH2Cl2 (10 mL) is added EDCI (0.249 g, 1.29 mmol) and stirred overnight. The reaction is diluted with CH2Cl2 (50 mL), washed with 1M HCl (2×30 mL), H2O (20 mL), satd NaHCO3 (2×20 mL), and brine (20 mL). The organic layer is MgSO4 dried, concentrated, and chromatographed (75% EtOAc/Hex) to give the title compound (0.51 g, 76%).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)=[CH:49][CH:48]=2)=CC=1)([O-])=O>>[N:53]1([C:50]2[CH:51]=[CH:52][C:47]([NH:46][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[O:27])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:5])=[CH:48][CH:49]=2)[CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCC(=O)N4CCOCC4)ccc23)CC1
Agent: Cl
Product: O=C(COc1ccc2c(C3CCN(C(=O)Nc4ccc(N5CCCC5)cc4)CC3)ncnc2c1)N1CCOCC1

Procedure:
The title compound was prepared from 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester as synthesized in the previous step, using (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (preparation given in Example 74a), essentially as described in Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.10 (d, 1H), 7.38 (dd, 1H), 7.29 (d, 1H), 7.18 (m, 2H), 6.51 (m, 2H), 6.34 (s, 1H), 4.88 (s, 2H), 4.26 (m, 2H), 3.75-3.61 (m, 7H), 3.55 (m, 2H), 3.25 (m, 4H), 3.10 (td, 2H), 2.16-2.04 (m, 2H), 2.02-1.90 (m, 6H). LC/MS (ESI): calcd mass 544.3, found 545.3 (MH)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (76%).
Reaction SMILES: N1C=CC=CC=1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH2:29].CC(C)N=C=NC(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH:29][C:21]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([I:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1)=[O:23]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CN1CCC(C(=O)O)(c2ccc(I)cc2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1CCC(C(=O)NCc2cc(Cl)cc(Cl)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a solution of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid pyridine salt (0.44 g, 1.04 mmol, see Example 6) and 3,5-dichlorobenzylamine (0.22 g, 1.24 mmol, 1.2 eq) in anhydrous DMF (5 mL) was added DIC (0.326 mL, 2.08 mmol, 2 eq) followed by DMAP (0.006 g, 0.052 mmol, 5%). The mixture was stirred at room temperature for 16 h and then it was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with H2O (3×40 mL) and saturated brine (50 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude material was purified by silica gel chromatography by eluting with 10% MeOH/EtOAc to give 60 mg (11%) of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid. MS(ESI): 503.1/505.1. To a flask containing 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide (60 mg, 0.12 mmol) was added Pd(PPh3)4 (3.2 mg, 0.012 mmol, 10 mol %), 3-cyanophenylboronic acid (26.4 mg, 0.18 mmol, 1.5 eq.) and Na2CO3 (0.21 g, 2 mmol). The mixture was suspended in toluene (2 mL), EtOH (1 mL) and H2O (1 mL) and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by HPLC to give 4-(3′-cyano-biphenyl-4-yl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid (0.05 g, 0.0105 mmol, 10%). 1H NMR (300 MHz, CDCl3): δ 7.88 (m, 2H), 7.71 (m, 3H), 7.52 (d, 2H), 7.31 (t, 1H), 7.00 (dd, 2H), 6.55 (t, 1H), 4.55 (br, 1H), 4.44 (d, 2H), 3.76 (m, 2H). 3.32 (m, 2H), 2.94 (s, 3H), 2.86 (m, 2H). 2.52 (t, 2H). MS (ESI): 478.1/480.1.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O-:23])=[O:22])=[CH:15][CH:14]=2)(C(C)(C)C)(C)C.[F-].[CH2:25]([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21]([O:23][CH3:25])=[O:22])=[CH:15][CH:14]=2
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2cc(CC(=O)[O-])ccc2[nH]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-(2-(t-butyldimethylsilyl-oxyethyl)-indole-5-acetate (400 mg; 1.15 mmol) in ca. 4 ml of THF was added a 1 M tetrabutylammonium fluoride in THF (1.2 mL; 1.05 eq) at 0° C. After 15 minutes, the reaction was allowed to warm to room temperature and stirred for an additional 3 hours. It was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), concentrated and chromatographed (silica gel, hexane:ethyl acetate 4:1) to yield 241 mg of the title compound as a colorless oil.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[NH3:7].[CH:8]1([CH2:11][C:12]2[NH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1.Cl>C(OCC)C>[CH:8]1([CH2:11][C:12]2[NH:13][C:14]([CH:3]([C:2]([OH:6])=[O:5])[NH2:7])=[CH:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: O=CC(=O)O
Reactant: c1c[nH]c(CC2CC2)c1
Reactant: N
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: NC(C(=O)O)c1ccc(CC2CC2)[nH]1
Reaction time: 2 h

Procedure:
Glyoxylic acid hydrate (8.3 g., 0.09 mole) was dissolved in 0.880 sp. gr. ammonia solution (50 ml.) and the solution heated to 50°-60°. 2-Cyclopropylmethyl pyrrole (10.9 g., 0.09 mole) was added dropwise and the resulting mixture stirred at 50°-60° for 2 hours. Diethyl ether (50 ml.) was added to the cool reaction mixture. Filtration gave a solid which was washed with diethyl ether (50 ml.). The filtrate was shaken and the aqueous phase separated and combined with the filtered solid to give a slurry whose pH was adjusted to ca. 5 with concentrated hydrochloric acid. The mixture was filtered and the resulting solid thoroughly washed with water, acetone, and with diethyl ether, affording, after drying in vacuo, DL-2-(5-cyclopropylmethyl-2-pyrrolyl)glycine (9.65 g., 55%), M.P. 203°-205° (decomp.).