Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7]Br)=[CH:5][CH:4]=[C:3]([C:9]#[N:10])[CH:2]=1.[CH3:11][NH2:12]>C(#N)C>[CH3:11][NH:12][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:9]#[N:10])=[CH:2][CH:1]=1
Reactant: CN
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Product: CNCc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of a-bromo-p-tolunitrile (4.90 g, 25 mmol) in acetonitrile (50 mL) was added dropwise to a stirring solution of 40% aqueous methylamine (21.5 mL, 250 mmol) in acetonitrile (50 mL) at 0° C. The reaction mixture was stirred 0.5 h, then concentrated in vacua. Water was added to the residue and extracted 2× with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacua to give 1.41 g of 4-(methylaminomethyl)benzonitrile as a yellow oil containing ~30% of N,N-bis(4-benzonitrile)methyl-amine. The aqueous was adjusted to pH>8 and extracted 2× with 9:1 dichloromethane:methanol. The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacua to give 1.13 g of pure 4-(methylamino)benzonitrile as a colorless oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(C#Cc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
1-(trimethylsilylethynyl)-4-(4-fluorophenylethynyl)benzene (2.2 g, 7.5 mmol) was dissolved in CH2Cl2 (30 mL) diluted with MeOH (30 mL) and then treated with powdered K2CO3 (2.1 g, 15 mmol) and allowed to stir at ambient temperature for 20 h under N2. The reaction mixture was filtered to remove solids, concentrated, redissolved in CH2Cl2, washed with water (2×), brine, dried over MgSO4, filtered and concentrated to dryness to give 1.43 g (87%) product that was used as is in the next reaction. 1H NMR, (CDCl3) δ: 7.54 (m, 2H), 7.49 (m, 4H); 7.05 (t, J=8.4 Hz, 2H); 3.20 (s, 1H). 13C {1H} NMR (CDCl3): 162.6 (J=250.3 Hz), 133.6 (J=8.0 Hz), 132.1, 131.4, 123.6, 122.0, 119.1 (J=3.6 Hz), 115.7 (J=32.0 Hz), 90.3, 88.6, 83.3, 79.0 ppm.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-n2nccn2)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c(-n2nccn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A89 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460.2 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.45-6.65 (m, 8H), 4.90-2.70 (m, 5H), 2.45-0.60 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10](OCC)[CH:11]=C=O)=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1.[O:27]1CCC[CH2:28]1.[BH4-].[Na+].[Cl-].[Li+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH2:28][OH:27])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: CCOC(C=C=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CC(CO)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.0 Parts of 2-[2,4-dichloro-5-(1-ethoxy-carbonylethoxy)-phenyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A] pyridin-3(2H)-one prepared as described in Example 5 in 75 parts of tetrahydrofuran was treated with 0.3 part of sodium borohydride and 0.3 part of lithium chloride. The reaction was heated to 40° for 6 hours. After this period 0.6 part of sodium borohydride and 0.5 parts of lithium chloride were added and the reaction was then stirred for 12 hours at room temperature. The reaction was heated to reflux and an additional 3.0 parts of sodium borohydride and 2.8 parts of lithium chloride were added in small portions over 48 hours. The mixture was cooled and added slowly to 100 parts of water whereby some foaming occurred. The product was extracted three times with 200 parts of ether. The ether was then extracted twice with 100 parts of water. The ether layer was dried with sodium sulfate. The ether was stripped on a rotary evaporator at reduced pressure. The residue was triturated with methylene chloride yielding 0.35 part of a tan solid with m.p. 54°-57°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([O-])=O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)C#CC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCC(=O)c1ccccc1N
Reaction time: 72 h
Yield: 83.5 %

Procedure:
To the solution of 1-(2-nitrophenyl)-3-(trimethylsilyl)prop-2-yn-1-one (11) (294 g; 1.19 mole) in toluene (4.5 L) was added Pd/C (10% wt; 30 g) under N2. The resulting suspension was degassed under vacuum and back-filled 3-times with H2. The mixture was hydrogenated under 0.3 MPa of hydrogen at room temperature for 72 hours. The progress of the reaction was monitored by HPLC. When the HPLC analysis indicated the disappearance of compound (II), the catalyst was filtered off through a Celite pad. The filtrate was concentrated under vacuum to give the crude product as black liquid. HPLC analysis showed 90% purity. The crude product was dissolved in ethyl acetate (7.5 L) and treated with 4N hydrochloric acid (600 mL). After the phase separation, HPLC analysis showed the 92.8% purity. The organic phase was washed again with 4 N hydrochloric acid (600 mL). The organic phase was further washed with 4 N hydrochloric acid (500 mL) one additional time. The organic phase was dried over sodium sulfate (200 g), concentrated to give the crude product (3) (220 g; 84% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:31][C:9]1[C:5]2[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:11]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:10]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (16.10 g, 37.8 mmol, Intermediate 4B), potassium carbonate (17.75 g, 128 mmol) and benzyl bromide (6.3 ml, 53.0 mmol) in DMF (100 ml) was stirred at RT for 2 hr. Quenched with water and extracted into ether. Washed organics with brine, dried over MgSO4, filtered, concentrated in vacuo and triturated with hexanes to provide 3-(benzyloxy)-6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS: [M+H]+ m/z 516.
Reaction SMILES: Br[CH:2]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:3].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].CN(CCN(C)C)C>C(#N)C>[C:13]([O:16][CH:2]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(Br)c1noc2ccccc12
Reactant: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC(C)c1noc2ccccc12

Procedure:
A mixture of 5.6 g of 3-(1-bromoethyl)-1,2-benzisoxazole, 2.4 g of potassium acetate, 2.1 g of N,N,N,N-tetramethylethylenediamine and 50 ml of acetonitrile are refluxed for 14 h. After cooling and filtering the mixture, the filtrate is concentrated under vacuum and diluted with diethyl ether. The ether phase is washed once with water, then twice with a 10% solution of hydrochloric acid and finally washed once with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated. The crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:3) to give 3-(1-acetoxyethyl)-1,2-benzisoxazole having a refractive index nD20 of 1.5229.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:20])[CH2:4][CH2:5][CH2:6][CH:7]1[CH:13]2[O:14][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][O:8]1.[CH2:21](Cl)Cl>>[CH3:21][C:7]1([CH2:6][CH2:5][CH2:4][CH:3]([CH3:20])[CH:2]=[O:1])[CH:13]2[O:14][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][O:8]1
Reactant: ClCCl
Reactant: COC(=O)CC12CCC(O1)C(CCCC(C)CO)OC2
Product: COC(=O)CC12CCC(O1)C(C)(CCCC(C)C=O)OC2
Reaction time: 4 h

Procedure:
A mixture of methyl (1RS,4SR,5RS)-4-(5-hydroxy-4-methyl-pentyl)-3,8-dioxabicyclo [3.2.1] octane-1-acetate (420 mg, 1.4 mM) and methylene chloride (5 ml) is added to a mixture of chromium trioxide-pyridine complex (10 mM), methylene chloride (20 ml) and Celite (2 g) at 0° C. and stirred for four hours under nitrogen. The resulting mixture is filtered and washed with ether (100 ml). The filtrate is treated with ether (200 ml) and washed with saturated sodium bicarbonate solution (3×100 ml), saturated cupric sulfate solution (2×100 ml) and dried (sodium sulfate). The solvent is removed in vacuo to give methyl (1RS,4SR,5RS)-4-methyl-4-(4-methyl-5-oxopentyl)-3,8-dioxabicyclo [3.2.1] octane-1-acetate as a colorless oil. This material is homogeneous by thin layer chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1.Cl>C(O)(C)C>[CH3:23][N:24]1[CH:28]=[C:27]([NH:29][C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=[CH:10][C:5]3=[CH:4][N:3]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(N)cn1
Reactant: CS(=O)(=O)Nc1ccccc1Cn1ncc2cnc(Cl)nc21
Agent: Cl
Solvent: CC(C)O
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4NS(C)(=O)=O)c3n2)cn1
Temperature: 140 °C

Procedure:
A suspension of N-(2-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)methanesulfonamide (53 mg, 0.16 mmol), 1-methyl-1H-pyrazol-4-amine (0.24 mmol) and HCl (0.26 mmol, 4M in dioxane) in isopropanol was heated in the microwave at 140° C. for 1 h. After cooling to rt the mixture was washed with H2O, extracted with DCM then dried using a hydrophobic frit. The organic phase was concentrated in vacuo. Purification was performed by prep. HPLC. The desired fractions were concentrated in vacuo to afford the title compound. 1H NMR (d6-DMSO) δ 9.88 (s, 1H), 9.44 (s, 1H), 8.94 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.13 (t, 1H), 6.71 (s, 1H), 5.71 (s, 2H), 3.79 (s, 3H), 3.06 (s, 3H); LC-MS method B, (ES+) 399, RT=7.14 min
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])([O:3]CC)=O.[OH:16][CH2:17][CH2:18][NH2:19]>>[OH:16][CH2:17][CH2:18][N:19]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:15])[C:8]=2[CH2:7][CH2:6][C:1]1=[O:3]
Reactant: NCCO
Reactant: CCOC(=O)CCC1C(=O)CCCC1=O
Product: O=C1CCCC2=C1CCC(=O)N2CCO

Procedure:
Prepared analogously to Example 27 from 2-(2-carbethoxy-ethyl)-cyclohexan-1,3-dione and 2-hydroxy-ethylamine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH2:27][OH:28])=[CH:26][C:4]=2[N:3]=1>CS(C)=O.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH:27]=[O:28])=[CH:26][C:4]=2[N:3]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(CO)ccc4c3c2)c(C)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Reaction time: 2.5 h

Procedure:
To a solution of (5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)methanol (2-1), 1.0 equiv. in DMSO (0.15 M) at room temperature was added IBX (1.5 equiv.). The reaction was stirred for 2.5 hours and then diluted with water. The aqueous layer was extracted with 2% MeOH/DCM (4×). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:20])[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]=3[N:14]([CH3:23])[CH:15]=2)=[O:9])=[CH:21][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno-[2,3-b]pyridine-5-carboxamide (Example No. 2) (2.00 g) in DMF (14 mL) are added K2CO3 (1.76 g) and iodomethane (0.79 mL). The reaction is heated to 90° C. and stirred for 18 h. The reaction mixture is concentrated in vacuo. The resulting residue is partitioned between H2O (100 mL) and CH2Cl2 (200 mL). The aqueous layer is extracted with CH2Cl2 (3×150 mL). The combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting off-white solid is recrystallized from ethanol to yield 1.78 g (92%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[O:26][C:25]3[C:16](=[CH:17][C:18]4[CH2:19][C@@H:20]([C:36](O)=[O:37])[N:21]([C@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28][CH3:29])[CH2:22][C:23]=4[CH:24]=3)[N:15]([CH3:39])[C:14]2=[O:40])=[CH:9][CH:8]=1.[CH3:45][O:46][C:47](=[O:65])[C@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:65])[C@H:48]([NH:64][C:36]([C@@H:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[C:25]([O:26][C@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([Cl:44])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[C:14](=[O:40])[N:15]3[CH3:39])=[CH:24][C:23]=2[CH2:22][N:21]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:37])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid was coupled to (R)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester following general procedure O to provide (R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester. Title compound was prepared from (R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (267 mg) following general procedure B. LC-MS (m/z): 880.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4]1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4]1
Reactant: COC1CN(Cc2ccccc2)CCC1(OC)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC1CN(Cc2ccccc2)CCC1=O
Yield: 98.6 %

Procedure:
A mixture of 38.1 parts of 3,4,4-trimethoxy-1-(phenylmethyl)piperidine and 1200 parts of sulfuric acid solution 1% was stirred and refluxed for 7 hours. The reaction mixture was allowed to cool overnight to room temperature and treated with sodium carbonate till a turbid solution was obtained. The product was extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated, yielding 28.8 parts (98.6%) of 3-methoxy-1-(phenylmethyl)-4-piperidinone as an oily residue (intermediate 60).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11](Cl)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:32]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=3[NH:30][C:29]2=[O:38])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:32]5[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=5[NH:30][C:29]4=[O:38])[CH2:26][CH2:27]3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: Fc1ccc(C2(c3ccc(F)cc3)C=CC(Cl)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C2C=CC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
A mixture of 6.1 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene (m.p. 39°-42° C), 5.0 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone, 2.8 g of potassium carbonate, 3.3 g of potassium iodide and 50 ml of dimethylformamide is stirred at 65°-70° C for 3 hours. The reaction mixture is poured into water, and the precipitated powder is collected by filtration, dried and dissolved in a mixture of chloroform and methanol (9:1). The solvent is then removed, and the precipitate is collected by filtration and purified in the same manner to give 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystalline powder, melting at 153°-157° C. This white crystalline powder, when recrystallized from a mixture of ethanol and methanol (7:3), turns into white crystals showing a melting point of 217°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH2:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: Clc1cccc(Cl)c1CBr
Product: CCOP(=O)(Cc1c(Cl)cccc1Cl)OCC
Temperature: 150 °C

Procedure:
2,6-Dichlorobenzyl bromide (1.20 g, 5 mmol) was mixed with triethyl phosphite (1.66 g, 10 mmol) and heated at 150° C. for 2 h. The resulting mixture was then distilled at 160° C. under reduced pressure (10 mm Hg) to remove the excess triethyl phosphite. (2,6-Dichloro-benzyl)-phosphonic acid diethyl ester was obtained as a colorless liquid (1.46 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.15-7.07 (m, 1H), 4.14-4.02 (m, 4H), 3.60 (d, 2H, J=22.4 Hz), 1.27 (t, 6H, J=7.0 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=4)[C:20]#[N:21])[O:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[C:20]([C:19]1[CH:22]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:2]=[CH:3]4)[N:14]=2)[CH:16]=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])#[N:21]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21

Procedure:
Prepared in a similar fashion to (D44) from 5-[3-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D43) and ethyl bromoacetate. The crude material was purified by trituration with diethyl ether to give the title compound as a yellow solid. MS (ES) C23H21N5O4 requires 431; found (MH+) 432.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cnc2cc(O)ccc2c1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc2cc(C=O)cnc2c1
Temperature: 60 °C
Yield: 30 %

Procedure:
To a solution of 7-hydroxyquinoline-3-carbaldehyde (1.3 g, 7.5 mmol) in DMF (30 mL) was added 1-bromo-heptane (5.37 g, 30 mmol, 4 eq.) and K2CO3 (2.0 g, 15 mmol, 2 eq.). The mixture was warmed to 60° C. over 3 h. Then, the reaction mixture was diluted (water), extracted (ethyl acetate), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (pet. ether:ethyl acetate, 10:1) to give 7-(heptyloxy)quinoline-3-carbaldehyde as yellow solid (610 mg, yield 30%). ESI-MS: 272 (M+H)+.