Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:21]([OH:40])[CH2:22][N:23]1[C@H:32]([C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][C@H:30]2[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:21]([OH:40])[CH2:22][N:23]1[C@H:32]([C:33]([NH:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][C@H:30]2[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Yield: 99.5 %

Procedure:
A solution of 195 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 20 ml of ethanol was hydrogenated at room temperature and atmospheric pressure for 18 hours over 10 mg of 10% palladium-on-charcoal. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give 154 mg of 2-[3(S)-[(L-asparaginyl)amino]2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N(C([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)[C@H](C(O)=O)CC1C=CC=CC=1.COC1C=CC(C[Mg]Cl)=CC=1>>[CH2:35]([O:34][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: COc1ccc(C[Mg]Cl)cc1
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
Boc-Phe 7 is converted to the allylic alcohol 8 using the same procedures reported by De Lucca et al. for the conversion of Z-Phe to the corresponding Z-allylic alcohol (J. Med. Chem. 1997, 40, 1707-1719). The allylic alcohol 8 is reacted with 4-methoxybenzylmagnesium chloride to afford the alkene 9 (J. Med. Chem. 1997, 40, 1707-1719). The 4-methoxybenzylmagnesium chloride is prepared from 4-methoxybenzylchloride according to the procedure of Van Campen et al. (J. Amer. Chem. Soc. 1948, 70 p2296). The alkene 9 is converted to the tetrahydropyrimidinone 10 using the same series of procedures reported by De Lucca et al. (J. Med. Chem. 1997, 40, 1707-1719). Treatment of the nitrile 10 with hydrogen peroxide in DMSO affords the carboxamide 11 (Synthesis, 1989, 949-950). The carboxamide 11 is treated with trimethylsilylbromide to form the phenol 12 (Green) which is then alkylated with trifluoro-methanesulfonic acid bis-benzyloxy-phosphorylmethyl ester in the presence of base (e.g. cesium carbonate) to yield the dibenzyl phosphonate 13.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11]C)=[O:9])=[N:6][CH:7]=1.[C:13](=O)([O-])[O-:14].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.CO>[CH3:13][O:14][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cn1
Temperature: 90 °C
Yield: 47.1 %

Procedure:
100 mg of ethyl 5-fluoropyridine-2-carboxylate obtained from Reference Example 18 (step 2) was dissolved in 1 ml of dimethylformamide and 1 ml of methanol, and 163 mg of potassium carbonate was added to it and stirred under heat at 90° C. for 40 minutes. This was neutralized with aqueous 10% citric acid solution, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain 46.5 mg of methyl 5-methoxypyridine-2-carboxylate as a white crystal.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:21][OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([CH:21]=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCC(CO)CCc1ccc(C#N)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCC(C=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4 g (13.18 mmol) of ethyl 8-(4-cyanophenyl)-6-hydroxymethyloctanoate in 100 ml of dichloromethane is mixed with 3.41 g (15.82 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 12 hours. After conversion is complete, the solvent is concentrated to dryness in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 2.74 g (9.09 mmol, 69% of theory) of a colorless solid are obtained.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22]>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])=[CH:10][CH:9]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COC(=O)/C=C/c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
(Bowden, et al., Tetrahedron 2000, 56, 3393-3408) Palladium(II) acetate (0.5 mg, 0.002 mmol) was added to a solution of 1 (10.9 mg, 0.0343 mmol) and methyl acrylate (15.6 mg, 0.181 mmol) in 0.18 g of 95% aqueous ethanol. The reaction mixture as stirred at room temperature for 18 h, filtered through a pad of Celite 545 with CH2Cl2, and purified by SiO2 column chromatography (6:4 hexane/CH2Cl2) to give 3 (8.4 mg, 85% yield) as colorless crystals; m.p. 80.5-81.5° C. MS (GC, EI): m/z=288 [M+], 269 [M+-F], 257, 130, 102. IR (ATR): {tilde over (v)}=1701, 1640, 1439, 1317, 1213, 1101, 999, 845, 816 cm−1. 1H NMR (500 MHz, CDCl3): δ=7.78 (d, J=8.7 Hz, 2H), 7.68 (d, J=16.1 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.61 (d, J=16.1 Hz, 1H), 3.83 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=166.7 (C), 154.6 (C), 142.5 (CH), 137.5 (C), 128.0 (2CH), 126.6 (2CH), 121.1 (CH), 52.0 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=83.7 (quint, J=150 Hz, 1 F), 62.6 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7](=[O:20])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[C:27]1(C)C=CC=C[CH:28]=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][Si:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:27]=[CH2:28])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:20]
Reactant: C[Si](C)(C)CCOCn1c(=O)ccc2cc(Br)ccc21
Reactant: Cc1ccccc1
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: [K+]
Solvent: O
Product: C=Cc1ccc2c(ccc(=O)n2COCC[Si](C)(C)C)c1
Temperature: 110 °C
Yield: 94 %

Procedure:
To a solution of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (1 g, 2.82 mmol) in toluene (20 mL) and water (20.00 mL) were added trivinylboraxin (0.684 g, 4.23 mmol), K2CO3 (0.780 g, 5.64 mmol). The reaction mixture was purged with N2 for 15 min, then Tetrakis (0.652 g, 0.564 mmol) was added and the reaction mixture was heated to 110° C. for 12 h. The reaction mixture was concentrated and dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and concentrated to get the 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylquinolin-2(1H)-one (0.8 g, 94%), used without further purification. LCMS (ES-API), RT: 2.17 m/z 302.2 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]2[CH:13]3[C:14]([CH3:16])([CH3:15])[C:10]([CH3:17])([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:8]2[CH:13]3[C:14]([CH3:16])([CH3:15])[C:10]([CH3:17])([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC12CCC(C(=Cc3ccc(O)cc3)C1=O)C2(C)C

Procedure:
A mixture of 172 g of 3-(p-methoxybenylidene)-bornan-2-one and 344 g of dry pyridine hydrochloride is heated under gentle reflux for 2 hours. After cooling, the reaction mixture is poured into 1 liter of water; the resulting solid precipitate, which is beige in colour, is filtered off, washed copiously with water and drained; it is then crystallised from 700 ml of isopropanol. 136 g of compound no. 2, which melts at 220°, are thus collected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C(OC([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[C:31](B(O)O)=[CH:30]1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:41][O:40][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][C:35]=1[O:38][CH3:39])[NH:29][CH:30]=[C:31]2[C:9]1[N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[CH:10]=1
Reactant: COc1cc2c(B(O)O)cn(C(=O)OC(C)(C)C)c2cc1OC
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3cc(F)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2[nH]cc(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Temperature: 110 °C
Yield: 76.7 %

Procedure:
A mixture of 3.1 g of 5-fluoro-2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 2.4 g of 1-tert-butyloxycarbonyl-5,6-dimethoxy-1H-indole-3-boronic acid and 20.3 ml of a saturated aqueous sodium hydrogen carbonate solution in 100 ml of dimethylformamide is degassed with argon for approximately 15 minutes and then 0.43 g of tetrakis(triphenylphosphine)palladium is added. The mixture is heated at around 110° C. for approximately 2 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 500 ml of water, and extracted with three times 250 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue is taken up with 100 ml of diisopropyl ether, filter-dried, washed with three times 20 ml of diisopropyl ether, and dried under reduced pressure (13 kPa) in the presence of potassium hydroxide chips at a temperature in the region of 20° C. 2.66 g of 2-(5,6-dimethoxy-1H-indol-3-yl)-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[N:9]=[C:8]2[N:10]([CH3:19])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]2=[CH:6][CH:5]=1.Cl>CS(C)=O>[CH3:19][N:10]1[C:8]2[NH:9][C:4](=[O:1])[CH:5]=[CH:6][C:7]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11]1
Reactant: Cn1nc(-c2ccccc2)c2ccc(Cl)nc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1nc(-c2ccccc2)c2ccc(=O)[nH]c21
Temperature: 100 °C
Yield: 95.7 %

Procedure:
A mixture of aqueous NaOH (0.64 g, 16.00 mmol in 2.0 mL H2O) and 6-chloro-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine (0.39 g, 1.6 mmol) in DMSO (2.0 mL) was heated at 100° C. for 10 h. The reaction mixture was cooled to rt and neutralized with diluted HCl. A white solid was obtained. The solid was collected by filtration, washed with diethyl ether and dried under vacuum to yield the title compound as white solid (0.345 g, 96%). [1H-NMR (DMSO-d6, 300 MHz) δ 8.27 (d, 1H), 7.92 (m, 2H), 7.55-7.35 (m, 3H), 6.46 (d, 1H), 3.9 (s, 3H); HPLC RtA=6.802 min (99.7%); LCMS RtA=0.360 min; [M+H]+=226.0]
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:25]4[CH2:31][CH2:30][NH:29][CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N1([O:53][C:54](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:23]=[C:24]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:25]4[CH2:31][CH2:30][N:29]([CH:54]=[O:53])[CH2:28][C:26]=4[N:27]=3)=[CH:20][CH:21]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCNC2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(C=O)C2
Reaction time: 1 h

Procedure:
(S)-6-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine (0.2684 g, 0.5277 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.226 g, 0.704 mmol) and Formic acid (0.0294 mL, 0.779 mmol) were combined then added dry N,N-Dimethylformamide (2.20 mL, 28.4 mmol) followed by N,N-Diisopropylethylamine (0.507 mL, 2.91 mmol). The reaction mixture stirred for 1 hour then concentrated and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). 1H NMR (500 MHz, DMSO) δ 9.33 (s, 1H), 8.20 (dd, J=7.4, 5.2, 2H), 7.70-7.65 (m, 2H), 7.54 (t, J=7.9, 1H), 7.47 (d, J=7.7, 2H), 7.39 (t, J=7.5, 2H), 7.32 (t, J=7.2, 1H), 6.47 (d, J=7.9, 1H), 6.27 (d, J=7.7, 1H), 5.39 (s, 2H), 4.58 (dt, J=18.2, 12.9, 2H), 4.41 (d, J=19.0, 1H), 4.08 (s, 1H), 3.89 (d, J=11.5, 1H), 3.80-3.51 (m, 5H), 3.44 (s, 1H), 2.73 (s, 1H), 2.69 (s, 1H), 1.30-1.18 (m, 3H). LC/MS-m/z+537.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19].[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu](I)I.CC(C)=O.CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([C:32]#[C:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(I)cc3Cl)c2c1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(C#Cc4ccccc4)cc3Cl)c2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(2-chloro-4-iodobenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole (0.91 g), phenylacetylene (1.02 g), palladium acetate (II) (0.045 g), triphenylphosphine (0.105 g), tri n-butylamin (1.12 g), copper iodide (I) (0.038 g), and N,N-dimethylformamide (5 ml) was stirred for 1 hour at 70° C. and for 30 minutes at 100° C. After cooling the reaction solution, acetone was added thereto and the solution was filtrated with celite. The filtrate was concentrated and the resulting residue was dissolved in ethyl acetate followed by washing with 1N hydrochloric acid and a 10% aqueous solution of sodium hydroxide. The organic layer was dried and concentrated to obtain crude 1-(2-chloro-4-(phenylethynyl) benzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole. This product was immediately subjected to the next step.
Reaction SMILES: CC[N:3](CCCC(NC1C=C(/C=C/C2C=CC=CC=2Cl)N=C2C=C(Cl)C=CC=12)C)CC.Cl[C:33]1[C:34]2[CH2:42][N:41](C3C=CC=CN=3)[CH2:40][CH2:39][C:35]=2[N:36]=[CH:37][N:38]=1>>[N:36]1[C:35]2[CH:39]=[CH:40][N:41]=[CH:42][C:34]=2[C:33]([NH2:3])=[N:38][CH:37]=1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Reactant: Clc1ncnc2c1CN(c1ccccn1)CC2
Product: Nc1ncnc2ccncc12

Procedure:
Appropriate 6-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[4,3-d]pyrimidin-4-amine derivatives are prepared starting from 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline. The nitroquinoline derivate is reacted with appropriate alkylating agent to give the N-substituted nitroquinoline, which is reduced using standard procedures known in the art to yield 7-aminoquinoline derivative. The resulting aminoquinoline derivated is then condensed with the appropriate 4-chloro-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine to give the desired 6-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[4,3-d]pyrimidin-4-amine derivative. As a representative example, preparation of the N-morpholionethyl derivative is depicted in Scheme 6.
Reaction SMILES: C([N:8]([CH2:21][CH2:22][C:23]#[CH:24])[S:9]([CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])(=[O:11])=[O:10])(OC(C)(C)C)=O.CN(C=O)C.[CH:30]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1I)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.[Cu](I)I.CN(C)C(=O)C.O.C1(C)C=CC=CC=1>[CH:30]([N:43]1[C:44]2[C:49](=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)[CH:24]=[C:23]1[CH2:22][CH2:21][NH:8][S:9]([CH2:12][C:13]1[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19])(=[O:10])=[O:11])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#CCCN(C(=O)OC(C)(C)C)S(=O)(=O)Cc1c(C)cccc1C
Reactant: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C)c1CS(=O)(=O)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 55 °C
Yield: 105.3 %

Procedure:
A warm (40-45° C.) solution of N-Boc-N-but-3-ynyl-(2,6-dimethylphenyl)-methanesulfonamide (44.4 g, 0.106 mol), dichlorobis(triphenylphosphine)palladium (II) (0.50 g, 0.713 mmol), and DMF (125 mL) was added slowly over 7 h to a warm (55° C.), stirred mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (50 g, 0.119 mol), dichlorobis(triphenylphosphine)palladium (II) (0.50 g, 0.713 mmol), copper (I) iodide (3.0 g, 15.7 mmol), triethylamine, (42.2 g, 0.418 mol), and DMF (75 mL). Toluene (250 mL) and water (250 mL) were added to the reaction mixture. The aqueous phase was separated and washed with toluene (2×100 mL). The combined organic phases were filtered through a celite pad. The filtrate was washed with an 8.3% aqueous solution of N-acetylcysteine (2×150 mL), then again with water (150 mL). The organic phase was washed with 5% aqueous sodium bicarbonate (150 mL), then again with water (150 mL). The organic phase was concentrated to a heavy oil under reduced pressure. The oil was dissolved in N,N-dimethylacetamide (DMA, 175 mL). This DMA solution was added over 1 hour to a stirred mixture of copper iodide (2.26 g, 11.8 mmol) and DMA at 150° C. The reaction mixture was stirred at 150° C. for an additional 2.25 hours. The reaction mixture was cooled to room temperature and filtered through a celite pad with a DMA wash (2×25 mL). 2-Propanol (400 mL) was added to the warmed (45-40° C.), stirred filtrate. Then water (600 mL) was added to the stirred, warm (45-50° C.) mixture over 1 hour. The mixture was cooled to room temperature and stirred for a minimum of 12 hours. The solid was collected by filtration and washed with 2-propanol (2×50 mL). The solid was vacuum dried at 50° C. to give N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide (60.6 g, 94%) with 98% purity (as determined by HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>CN(C)C=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH3:10]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(C(=O)OCC)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a stirred solution of 2-(pyrrol-1-yl)malonic acid diethyl ester (53.0 g) in anhydrous dimethylformamide (300 ml) was added portionwise sodium hydride (63% dispersion in mineral oil, 10.0 g) under ice cooling. The resulting mixture was stirred at 25° C. for 30 minutes and thereto was added benzyl bromoacetate (70.1 g). After stirring at 25° C. for 15 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (10:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure to give the title compound (80.0 g, 91.0%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][C:8]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][CH2:17][C:18](Cl)=[O:19].Cl>[Cl-].[Zn+2].[Cl-].N1C=CC=CC=1>[C:18]([C:9]1[C:10](=[O:13])[CH2:11][CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[OH:14])(=[O:19])[CH2:17][CH2:16][CH3:15]
Reactant: O=C1CCC(c2ccccc2)C(=O)C1
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccncc1
Product: CCCC(=O)C1=C(O)C(c2ccccc2)CCC1=O
Yield: 34.1 %

Procedure:
Zinc chloride (7.1 g) was added to pyridine (50 ml) followed by 4-phenylcyclohexane-1,3-dione (5 g). n-Butyryl chloride (2.6 g) was then added dropwise and the mixture heated to reflux for 4 hours. After cooling, the mixture was poured into 5N hydrochloric acid (200 ml) and the aqueous phase extracted with methylene chloride. The extracts were dried over magnesium sulphate, filtered and evaporated to give a red oil. Purification on a silica gel column using methylene chloride as eluent gave the title compound as an orange oil (2.15 g).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH:48]=[CH2:49].Cl[C:57]1[N:62]=[CH:61][C:60]([O:63][S:64]([C:67]2[CH:72]=[CH:71][C:70]([CH:73]([CH3:75])[CH3:74])=[CH:69][CH:68]=2)(=[O:66])=[O:65])=[CH:59][CH:58]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:47]([N:50]1[CH2:55][CH2:54][N:53]([C:57]2[N:62]=[CH:61][C:60]([O:63][S:64]([C:67]3[CH:68]=[CH:69][C:70]([CH:73]([CH3:75])[CH3:74])=[CH:71][CH:72]=3)(=[O:66])=[O:65])=[CH:59][CH:58]=2)[CH2:52][CH2:51]1)[CH:48]=[CH2:49]
Reactant: CC(C)c1ccc(S(=O)(=O)Oc2ccc(Cl)nc2)cc1
Reactant: C=CCN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C=CCN1CCN(c2ccc(OS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 50 °C
Yield: 21 %

Procedure:
A flask containing 45 mg of palladium(II) acetate (0.2 mmol), 126 mg of BINAP (0.20 mmol) and 0.233 mg of sodium tert-butylate in dry toluene (15 mL) was flushed with nitrogen 1.275 g of 1-allylpiperazin (10 mmol) were added and the reaction mixture was heated to 50° C. 630 mg of 4-isopropyl-benzenesulfonic acid 6-chloro-pyridin-3-yl ester (2.0 mmol) were dissolved in toluene and the solution was slowly added over a period of 10 minutes into the reaction mixture with stirring. The mixture was heated to reflux with stirring for 7 h. Thereby 4-isopropyl-benzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester was obtained in 21% yield.