Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(-c2ccccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Oc1cccc(-c2ccccn2)c1
Temperature: 190 °C
Reaction time: 8 h

Procedure:
To a 500 mL round bottom flask was added 2-(3-methoxyphenyl)pyridine (21.3 g, 115 mmol) and pyridine hydrochloride (107.5 g, 930 mmol). The reaction mixture was heated to 190° C. for 8 hours under nitrogen. The reaction mixture was cooled slightly and water was added. The mixture was stirred overnight. The pH of the solution was adjusted to 7 with 10% sodium hydroxide solution, extracted three times with dichloromethane. The organic layers were washed with 10% LiCl solution, brine, dried over magnesium sulfate, filtered, and evaporated. The residue was distilled on a Kugelrohr to remove the remaining pyridine (18 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:39]3[CH:44]=[C:43]([CH:45]([CH3:47])[CH3:46])[CH:42]=[CH:41][C:40]=3[O:48][CH3:49])[C:20]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][C:22]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:60]=[N+:61]=[N-:62])(C)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]([C:17]3[CH:18]=[C:19]([C:39]4[CH:44]=[C:43]([CH:45]([CH3:47])[CH3:46])[CH:42]=[CH:41][C:40]=4[O:48][CH3:49])[C:20]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:21][C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:62][N:61]=[N:60]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2C2CCN(C(=O)OC(C)(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 7 h
Yield: 59 %

Procedure:
A solution of 4-[(4,6-bis-benzyloxy-5′isopropyl-2′methoxy-biphenyl-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (6.1 g, 9.2 mmol), PCl5 (2.9 g, 13.8 mmol) and anhydrous dichloromethane (120 ml) was stirred at rt for 4 h. Then the TMSN3 (10.4 ml, 1.7 vols.) was charged and the mixture stirred for a further 7 h. The reaction was quenched very carefully with saturated NaHCO3 solution (100 ml) and stirred a further 1 h. The organics were then split off and aqueous washed with dichloromethane. The combined organics were then washed with brine before being dried (Na2SO4), filtered and evaporated to yield the crude product as a yellow solid. This material was purified using column flash chromatography (SiO2, ethyl acetate/hexanes), yielding 4-[5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-tetrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.7 g, 59%). M.p.: 77-81° C.; 400 MHz 1H NMR (DMSO-d) δ: 7.45-7.09 (m, 14H), 6.96 (d, J=6.4 Hz, 1H), 5.26 (s, 2H), 5.23 (s, 2H), 4.45 (br s, 1H), 3.86 (m, 2H), 3.67 (s, 3H), 2.84 (m, 3H), 1.67 (m, 4H), 1.40 (s, 9H), 1.16 (d, J=6.4 Hz, 6H); LCMS: 690 [M+H].
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH2:41]([N:43]([CH2:49][CH3:50])[CH:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)[CH3:42]>CC#N>[CH2:41]([N:43]([CH2:49][CH3:50])[CH:44]1[CH2:48][CH2:47][N:46]([C:19]([C:16]2[N:17]([CH3:18])[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)=[N:14][C:15]=2[I:22])=[O:21])[CH2:45]1)[CH3:42]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Reactant: CCN(CC)C1CCNC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N(CC)CC)C3)n2C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A solution of 0.41 g (1.0 mmol) of 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-carboxylic acid (intermediate 1) in 10 ml of MeCN was treated with 0.192 g (1.1 mmol) of 2-chloro-4,6-dimethoxy-[1,3,5]triazine and cooled down to 0° C. 0.33 ml=0.30 g (3.0 mmol) of N-methylmorpholine was added and stirring continued at 0° C. for another 2 hours. Then, a solution of 0.159 g (1.1 mmol) of (rac)-diethyl-pyrrolidin-3-yl-amine in 5 ml of MeCN was added and the reaction mixture was allowed the reach RT. After stirring at RT for 18 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.39 g (73%) of the title compound as light brown oil. MS: 537.3 (MH+).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)(O)[O-].[Na+].O.C(O[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)C>C(OCC)(=O)C.Cl(O)(=O)(=O)=O>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:7]
Reactant: CC(=O)CCCC(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 65 h
Yield: 85 %

Procedure:
To a solution of 5-oxohexanoic acid (25 g, 192 mmol) in t-butyl acetate (600 mL) was added perchloric acid (500 μL, 8.31 mmol) and the resulting pale yellow solution was allowed to stir at room temp, with a drying tube in place, for 65 h. The reaction was diluted with ethyl acetate (400 mL) and then quenched with a mixture of sodium bicarbonate (50 g, 595 mmol) and water (100 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (5×150 mL), water (1×100 mL), brine (1×75 mL), dried over sodium sulfate, and filtered. The solvent was removed in vacuo to give the title compound (30.55 g, 85%) as a light oil. 1H NMR (500 MHz, chloroform-d) δ 2.50 (t, J=7.2 Hz, 2H), 2.25 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.89-1.83 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2.Cl[CH2:34][C:35](=[O:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:35]([CH2:36][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27]([CH3:32])=[CH:26]5)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:17][CH2:18]1)(=[O:37])[CH3:34]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCNCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(CC(C)=O)CC1
Temperature: 70 °C

Procedure:
A mixture of 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]quinazoline (0.15 g), chloroacetone (0.036 ml), potassium carbonate (0.05 g) and DMA (1.3 ml) was stirred and heated to 70° C. for 1.5 hours. The mixture was cooled to ambient temperature, the precipitate was filtered off and the residue was purified by preparative LCMS (Hypersil C18-β-Basic column using a solvent gradient consisting of acetonitrile and water buffered with a 5% ammonium carbonate solution (100 g/L, pH 8.9). Evaporation of the solvents gave 7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline as a pale yellow solid (0.10 g), which was dried under vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:18][N:19](C(C)C)[CH:20](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:19]([CH3:20])[CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 11.2 g of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid in 50 ml of DCM is cooled to 0° C., 8.45 ml of DIPEA and then 21.2 g of BOP are added and the resulting mixture is stirred for 10 minutes. Dimethylamine gas is then added by sparging and the mixture is stirred for 3 hours at RT. The reaction mixture is partially concentrated under vacuum to a volume of 20 ml and an insoluble material is filtered off. The filtrate is chromatographed on silica gel, eluting with a DCM/MeOH mixture (94/6; v/v) and the product obtained is re-chromatographed on alumina, eluting with a DCM/MeOH mixture (96/4; v/v). 11.1 g of the expected product are obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.Br[C:20]1[S:24][C:23]([C:25]2[S:26][C:27](Br)=[CH:28][N:29]=2)=[N:22][CH:21]=1.[F-].[K+]>CN(C)C=O.CCOCC.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>[CH2:9]([O:8][C:6]([C:20]1[S:24][C:23]([C:25]2[S:26][C:27]([C:6]([O:8][CH2:9][CH3:10])=[CH2:7])=[CH:28][N:29]=2)=[N:22][CH:21]=1)=[CH2:7])[CH3:10]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc(-c2ncc(Br)s2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cnc(-c2ncc(C(=C)OCC)s2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.425 mL, 1.26 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (21.5 mg, 0.031 mmol) were added to a stirred solution of 5,5′-dibromo-2,2′-bithiazole (200 mg, 0.613 mmol) in dimethylformamide (4 mL) under nitrogen. The reaction mixture was heated at 100° C. for 2 h. The reaction was cooled, diluted with ether and aqueous potassium fluoride (0.5 g in 5 mL of water). The mixture was vigorously stirred for 1 h at room temperature, both phases were filtered through CELITE® and then separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0 to 30% ethyl acetate in hexanes) to yield 5,5′-bis(1-ethoxyvinyl)-2,2′-bithiazole (181 mg, 0.587 mmol, 96% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=1.[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26]>>[C:14]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:29]3[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=3)=[O:41])=[C:3]([C:16]3[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)#[N:15]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 1-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-cyclohexanecarbonitrile (as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) according to the procedure of Example 1, step (f). Mass spectrum (ESI, m/z): Calcd. for C32H43N5O2Si, 558.3 (M+H), found 557.8.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:48][CH2:47][CH2:46][CH2:45][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[C:15]1=[O:38]
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 3-(4-morpholinyl)-1-propanamine (0.357 mL, 2.44 mmol) for 15 min. (150° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68-1.76 (m, 2 H), 2.31-2.38 (m, 7 H), 2.78 (t, J=6.81 Hz, 2 H), 3.35-3.46 (m, 3 H), 3.55-3.62 (m, 5 H), 4.16 (s, 2 H), 4.22 (t, J=6.81 Hz, 2 H), 7.10-7.17 (m, 2 H), 7.38 (ddd, J=9.02, 5.79, 3.02 Hz, 2 H), 8.15 (s, 1 H), 8.50 (d, J=1.26 Hz, 1 H), 10.41 (d, J=3.93 Hz, 1 H); ES+ MS: 484 (M+H+).
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:10](N1C(=O)C2C(=CC=CC=2)C1=O)(=[S:12])[CH3:11]>C(O)C.N1C=CC=CC=1.[Pd]>[C:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[S:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OCCN
Reactant: CC(=S)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=S)NCCOC(C)(C)C
Reaction time: 23 h

Procedure:
Dissolve (2-tert-butoxyethyl)dicarbamic acid benzyl ester (387.8 mg, 1.01 mmol) and 5% Pd/C (0.212 g) in absolute ethanol and expose it to 60 psi of H2 for 18 hours. Filter the reaction mixture over a pad of celite. Acidify the filtrate with 5N HCl and concentrate in vacuo to obtain 139.4 mg of a crude residue containing the HCl salt of 2-tert-butoxyethylamine. Dissolve this crude material (139.4 mg, 0.852 mmol) in 10 mL pyridine at 25° C. To this add 2-thioacetylisoindole-1,3-dione (180.53 mg, 0.88 mmol) and allow to stir for 23 hours. Concentrate the reaction mixture in vacuo and dissolve the residue in methylene chloride and wash it with 1N HCl (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 266.9 mg of crude product. Triturate this crude material in diethyl ether and remove the solids by filtration. Concentrate the filtrate in vacuo to afford 176.2 mg of a crude solid. Purify via Biotage chromatography to afford 74.1 mg of N-(2-tert-butoxyethyl)thioacetamide. Dissolve this thioacetamide (74.1 mg, 0.423 mmol) in 20 mL methylene chloride and add methyl trifluoromethanesulfonate (76.3 mg, 0.465 mmol). Allow the reaction mixture to stir for an additional 21 hours. Decant the diethyl ether from the oil and triturate the oil with diethyl ether (3×). Remove any excess diethyl ether from the oily residue in vacuo to obtain 60.3 mg of crude triflic acid salt of N-(2-tert-butoxyethyl)thioacetimidic acid methyl ester as an oil. Dissolve this crude product (60.3 mg, 0.62.5 mmol) in 10 mL pyridine and add N-(R)-(6-amino-2(R)-hydroxyindan-1-yl)-4-bromobenzamide (62.5 mg, 0.180 mmol). Allow the reaction to stir at 25° C. for 22 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 31.4 mg of crude product. Purify via Biotage chromatography (10% MeOH/EtOAc) to afford 6.6 mg of the titled product (8% yield). MS (ES): m/z 488.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][N:19]([CH3:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[CH:21]=1>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:22]3[CH:21]=[C:20]([N:19]([CH3:28])[CH3:18])[CH:25]=[CH:24][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cccc(N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(N(C)C)c2)CCN(C)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was in NMP (1 mL) were added powdered KOH (196 mg, 3.5 mmol) and dimethyl-(3-vinyl-phenyl)-amine (147 mg, 1.0 mmol) and the reaction mixture stirred at 100° C. for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0-3% MeOH-DCM) to yield {3-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-phenyl}-dimethyl-amine. 1H NMR (CDCl3, freebase) δ (ppm): 7.21 (m, 2H), 7.18 (dd, 1H), 7.0 (d, 1H), 6.6 (d, 1H), 6.43 (d, 1H), 6.21 (s, 1H), 4.2 (t, 2H), 3.71 (s, 2H), 2.90 (t, 2H), 2.85 (s, 3H), 2.80 (m, 4H), 2.57 (s, 6H), 2.41 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=O)C.[I:8]I.OS(O)(=O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[O-]S([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([I:8])=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(I)ccc1Cl
Temperature: 64 °C
Yield: 62 %

Procedure:
To a jacketed reactor, acetic acid (450 mL) and acetic anhydride (225 mL) is charged at 10° C. Then, to the above mixture, NalO4 powder (97.2 g) and Iodine (77.2 g) is added under stirring. While keep internal temperature at below 30° C., conc. H2SO4 (720 mL) is added dropwise. Then, 2-chloro-nitrobenzene (Rt=11.11 min) is added in one portion, and heat the mixture gradually to 64° C. The resulting mixture continues to be stirred for usually at least 2 hours until process monitor shows almost complete conversion. Then, the mixture is cooled down to room temperature, and transferred slowly into another jacketed reactor with pre-cooled cold Na2SO3 solution (250 g Na2SO3 in 2000 mL water). Collect the wet cake by filtration and wash the cake with water (450 mL×2), then purification of the cake with n-heptane crystallization to afford 2-chloro-5-iodonitrobenzene in 62% yield and 98% HPLC purity (Rt=15.75 min).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18](B(O)O)[CH:19]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[F:23])[CH:11]=1
Reactant: Clc1cc(Cl)c2cccnc2n1
Reactant: OB(O)c1cc(Cl)ccc1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 9.95 g (50.0 mmol) 2,4-dichloro-[1,8]naphthyridine (described by Koller, Chemische Berichte 60: 407 (1927)), 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid und 5.04 g (60.0 mmol) sodium hydrogencarbonate in 100 ml DMF und 50 ml water was heated to 80° C. under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80° C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol. This yielded 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as yellowish crystals; HPLC-MS: 2.49 min, [M+H] 293.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19]([NH:11][C:5]1[C:6](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])=[O:20]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)Nc2ccc(Cl)cc2C(=O)O)cc1OC
Yield: 43.2 %

Procedure:
In a mixture of 30 ml of chloroform and 3 ml of triethylamine is dissolved 3.4 g of 5-chloroanthranilic acid. To this solution is added a solution of 4.5 g of 3,4-dimethoxycinnamoylchloride in chloroform, and the mixture is heated under reflux for 2 hours. The reaction mixture is concentrated under a reduced pressure, and to the residue is added water and hydrochloric acid then added to make the mixture weakly acidic. The precipitated crystals are collected by filtration and recrystallized from ethanol to obtain 3.1 g of N-(3,4-dimethoxycinnamoyl)-5-chloroanthranilic acid as pale yellow needles.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1>>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1)=[O:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Product: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 56.6 %

Procedure:
26.5 g of N-benzyloxycarbonyl-DL-isoleucine and 10 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 3(i) to obtain 19.5 g (yield: 56%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 149° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[Cl:30][CH2:31][C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22])=[O:33]
Reactant: O=C(Cl)CCl
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCNC(=O)CCl
Reaction time: 0.5 h
Yield: 53 %

Procedure:
1.68 Grams of 1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone was suspended in 100 ml of chloroform, then 5 ml of triethylamine was added thereto and stirred for 30 minutes. Under ice-cooling condition, 2 ml of chloroacetyl chloride was added little by little and stirred for 5 hours. The reaction mixture was washed with water, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate, then concentrated under reduced pressure, there was obtained 1 g (53%) of 1-(3-chloroacetylaminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone. White powdery crystals (recrystallized from ethyl acetate-n-hexane). Melting point: 152°-154° C.