Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15](O)[CH:16]=2)[CH:11]=1.S(=O)(O)[O-].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([OH:9])[CH:19]=[CH:18]3)=[CH:3][CH:4]=1
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: Nc1ccc(O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3cc(O)ccc3c2)cc1
Yield: 31.1 %

Procedure:
A mixture of 300 mg (2.75 mmol, Aldrich) of 4-aminophenol, 1.5 g (90%, 8.4 mmol, Aldrich) of 2,6-dihydroxynaphthalene and 1.0 g (9.6 mmol, Aldrich) of sodium bisulfite in 30 ml of H2O was refluxed for 18 hours. The reaction mixture was cooled, added to 30 ml of H2O and extracted with two 25 ml portions of ethyl aetate. The organic extracts were combined, dried (MgSO4), and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (15×5.0 cm, 1:2 EtOAc/pet ether) followed by recrystallization (EtOAc/pet ether) to afford 215 mg (31%) of title compound as pale pink crystals, m.p. 195°-196°.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].CS(C)=O.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:30](=[S:32])=[S:31]>>[CH2:28]([O:27][C:25]([CH2:24][S:32][C:30]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:31])=[O:26])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Yield: 37.3 %

Procedure:
In the same manner as described in Example 6, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2.16 g), 10N NaOH (2 ml), dimethylsulfoxide (6 ml), carbon disulfide (912 mg) and ethyl bromoacetate (2.0 g) are reacted. The product is recrystallized from ethanol to give the title compound (1.41 g, 65%) as colorless needles, m.p. 190°-192° C.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C([N:25](CC)CC)C.N>ClCCl>[NH2:25][C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Temperature: 0 °C

Procedure:
Ethyl chloroformate (4.6 ml, 48.3 mmol) was added slowly to a solution of 1-(tert-butoxycarbonyl)4-piperidinecarboxylic acid (10 g, 43.6 mmol) in dichloromethane (100 ml) stirred at 0° C. Triethylamine (7.6 ml, 52.3 mmol) was added with stirring over two minutes. 0.88 Ammonia solution (40 ml) was added and the mixture allowed to warm to room temperature with stirring. The mixture was washed with water, 1M citric acid solution and brine, dried (MgSO4), filtered and evaporated under reduced pressure gave the title compound as white solid, 8.94 g.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]1[CH2:38]OC[CH2:35]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(Br)C=C>C(OCC)(=O)C>[CH2:38]([C:15]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:26][C:27]([CH3:32])([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:34]=[CH2:35]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: CCOC(C)=O
Product: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A solution of ethyl 2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.79 g, 6.21 mmol) in freshly distilled (THF 15 mL, 0.4 M) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (6.8 mL, 1.0 M in THF). After stirring for 10 min allyl bromide (2.25 g, 18.6 mmol) was added the reaction was warmed to room temperature and stirred for 16 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave ethyl 2-allyl-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (1.81 g, 59%). Rf 0.52 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.58-7.53 (m, 2H), 7.39-7.22 (m, 6H), 7.16-7.12 (m, 2H), 5.89-5.74 (m, 1H), 5.07 (dd, J1=15.3 Hz, J2=2.1 Hz, 1H), 5.05 (dd, J1=8.7 Hz, J2=2.1 Hz, 1H), 3.70 (q, J=7.5 Hz, 1Hdiasterotopic), 3.69 (q, J=7.2 Hz, 1Hdiasterotopic), 2.70 (dd, J1=7.2 Hz, J2=1.2 Hz, 2H), 1.92-1.83 (m, 2H), 1.44-1.35 (m, 2H), 1.35-1.23 (m, 2H), 1.19 (s, 12H), 1.10 (t, J=7.2 Hz, 3H), 0.78 (t, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C.C(Cl)Cl>[CH3:33][N:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:15][CH2:16]2)[C:21]1=[O:29]
Reactant: CI
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a stirred suspension of 1-[1-(1-phenylcycloheptyl)-4-piperidyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one (116 mg, 0.298 mmol) in DMF (1 ml) was added NaH (60% oil suspension, 18 mg, 0.447 mmol) at rt. After 30 min stirring at rt, iodomethane (22.3 μl, 0.358 mmol) was added to the reaction mixture at rt. After 15 min stirring at rt, the reaction mixture was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4), filtered, and concentrated to give pale yellow solid, which was purified by column chromatography (silica gel:5 g, hexane/ethyl acetate:5/1-3/1) to give 83 mg (69%) of white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@:7]1([NH2:19])[CH2:12][C:11](=[O:13])[C@@H:10]2[C@H:8]1[C@H:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>O1CCCC1.C(OCC)(=O)C.O>[CH2:30]([O:29][C:27]([NH:19][C@@:7]1([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:12][C:11](=[O:13])[C@@H:10]2[C@H:8]1[C@H:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](N)(C(=O)OCC)[C@@H]21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](NC(=O)OCc3ccccc3)(C(=O)OCC)[C@@H]21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Suspend diethyl-(1S,2S,5R,6R)-2-amino-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate-hydrochloride (55.0 g, 188.5 mmol) in tetrahydrofuran (220 mL), then add water (220 mL) and potassium carbonate (92.1 g, 659.9 mmol). Stir the resulting mixture for 30 minutes. Add benzyl chloroformate (26.7 mL, 175.3 mmol) to the mixture over 45 minutes, keeping the reaction temperature below 25° C. Stir reaction mixture for 30 minutes, then dilute with ethyl acetate (550 mL) and water (275 mL). Separate the phases and back extract the aqueous layer with ethyl acetate (250 mL). Combine the organics and wash it sequentially with aqueous HCl (0.5N, 100 mL), saturated NaHCO3 (100 mL) and brine (100 mL). Dry the organic solution over Na2SO4, filter and concentrate in vacuo to afford the title compound as a clear oil (67.6 g, 92.1%). 1H NMR (CDCl3) δ 1.24-1.26 (m, 6H), 2.36 (bs, 1H), 2.47 (dd, 1H), 2.78 (dd, 1H), 2.90 (dd, 1H), 4.09-4.19 (m, 4H), 5.08 (s, 2H), 5.73 (s, 1H), 7.24-7.36 (m, 5H).
Reaction SMILES: C1([C@@H](N[C:14]([CH3:28])=[CH:15][C:16]([O:18][C@@H:19]([C:24]([Cl:27])([Cl:26])[Cl:25])[CH:20]=[C:21]([CH3:23])[CH3:22])=[O:17])C)C2C(=CC=CC=2)C=CC=1.Cl.[O:30]1CCCC1>>[C:16]([O:18][C@@H:19]([C:24]([Cl:27])([Cl:26])[Cl:25])[CH:20]=[C:21]([CH3:23])[CH3:22])(=[O:17])[CH2:15][C:14]([CH3:28])=[O:30]
Reactant: CC(C)=C[C@@H](OC(=O)C=C(C)N[C@@H](C)c1cccc2ccccc12)C(Cl)(Cl)Cl
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 62 h
Yield: 85 %

Procedure:
To a solution of (R)-3-methyl-1-trichloromethylbut-2-en-1-yl (S)-3-[N-(1-(1-naphthyl)ethyl)amino]but-2-enoate (10 g, 0.023 mole) in tetrahydrofuran (200 ml) at room temperature was added, in one portion, 0.5 N aqueous hydrochloric acid (250 ml, 0.125 mole). Upon addition of the acid, a white precipitate formed immediately, then slowly disappeared. The mixture was stirred at room temperature for a total of 62 hours and then extracted three times with 200 ml of hexane, after which the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The pale yellow oily residue was distilled to yield (R)-1-trichloromethyl-3-methyl-2-butenyl acetoacetate (5.57 g, 85% yield); bp, 90°-92° C. (0.05 mmHg); [α]D25 =+13.00° (CHCl3).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH3:13])=[N+:9]([O-])[CH:10]=1)=[N+:2]=[N-:3].[CH3:14][N:15](C)C(Cl)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[N:1]([CH2:4][C:5]1[C:10]([C:14]#[N:15])=[N:9][C:8]([CH2:12][CH3:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: CCc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1ccc(CN=[N+]=[N-])c(C#N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 90.5 %

Procedure:
After dissolving 5-(azidomethyl)-2-ethyl-1-pyridiniumolate (2.16 g, 12.1 mmol) in acetonitrile (25 ml), 1.77 ml of trimethylsilylnitrile (13.3 mmol) and 1.23 ml of dimethylcarbamoyl chloride (13.3 mmol) were added under a nitrogen stream and the mixture was stirred at room temperature for 66 hours. Saturated aqueous sodium hydrogencarbonate was added for treatment and extraction was performed with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.05 g) as a colorless oil. (90.4% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: CCCCOCCCC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCc1ccccc1
Yield: 61.1 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8-nitro-5-(8-phenyloctoxy) quinoline (2.1 g, 0.005 mol), degreased 40 mesh Fe filings (5 g), H2O (20 ml), HOAc (4 ml) and n-Bu2O (4 ml) was heated at 80° C. to 1.5 h, cooled and filtered. The solid was thoroughly extracted with Et2O and the filtered extract was dried (Na2SO4), treated with carbon and concentrated to an oil. Trituration with pet ether gave 1.2 g (61%) of 8-amino-6-methoxy-4-methyl-5-(8-phenyloctoxy) quinoline as yellow-green solid, mp 33°-34° C. Crystallization from pet ether (Darco) gave the analytical sample as yellow green crystals, mp 39°-40° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[NH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=3)[O:24][CH:25]=1>CN(C)C=O>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[N:22]=[C:23]([C:26]4[NH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:30][CH:29]=5)[O:24][CH:25]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc2[nH]c(-c3nc(COc4ccc(CCCCn5ccnn5)cc4)co3)cc2c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (7 mg, 0.28 mmol) was given at 0° C. to a solution of 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol (55 mg, 0.25 mmol) in 2.0 ml N,N-dimethyl formamide and stirred for 30 min. 2-(4-Chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole (80 mg, 0.25 mmol) dissolved in 1.0 ml N,N-dimethyl formamide was added at 0° C. and stirring continued at 0° C. for 1 h and 12 h at room temperature thereafter. The mixture was quenched with water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (10 ml), dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (ethyl acetate) yielded 2-{4-[4-(4-[1,2,3]Triazol-1-yl-butyl)-phenoxymethyl]-oxazol-2-yl}-5-trifluoromethoxy-1H-indole as off white solid. Yield 50 mg (40%)
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:11]=[CH:10][O:9][N:8]=1.C(N(CC)CC)C>C(OCC)C>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:11]=[CH:10][O:9][N:8]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Nc1ccon1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CBr)Nc1ccon1
Reaction time: 3 h

Procedure:
To a stirred solution of bromoacetylbromide (5.36 ml, 61.6 mmol) in diethylether (100 ml) at −40° C. is added, dropwise over 20 minutes, a solution of 3-aminoisoxazol (5.0 ml, 67.0 mmol) and triethylamine (8.5 ml, 61.4 mmol) in diethylether (20 ml). Additional diethylether (50 ml) is added and stirring continued for 3 hours. The reaction mixture is filtered and the solution then washed with 1 M sodium carbonate solution, 1 M hydrochloric acid and brine. Concentration followed by purification by flash silica column chromatography (ethyl acetate/iso-hexane 4:7) gives the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[C:10](=[O:19])[NH:11][C:12]=2[C:16]([OH:18])=O)[C:7]1=[O:22].[CH2:27]([O:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:27]([O:34][CH2:35][CH2:36][N:37]([CH2:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[C:16]([C:12]1[NH:11][C:10](=[O:19])[C:9]([O:20][CH3:21])=[C:8]2[C:13]=1[CH2:14][CH2:15][N:6]([CH2:5][C:4]1[CH:23]=[CH:24][C:25]([F:26])=[C:2]([Cl:1])[CH:3]=1)[C:7]2=[O:22])=[O:18])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1c2c(c(C(=O)O)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCNCCOCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c2c(c(C(=O)N(CCCCO[Si](C)(C)C(C)(C)C)CCOCc3ccccc3)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (0.19 g, 0.49 mmol), N-[2-(benzyloxy)-ethyl]-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-amine (0.19 g, 0.55 mmol), EDC (0.10 g, 0.55 mmol), HOAt (75 mg, 0.55 mmol) and diisopropylethylamine (0.35 mL, 1.99 mmol) in DMF (2 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between methylene chloride and water. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title compound. This material was used in the following step without further purification.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6]CC)=O.CO[C:16](OC)([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17].C1(OC2C=CC=CC=2)C=CC=CC=1>O>[CH3:17][C:16]1[N:1]=[CH:2][CH:3]([C:4](=[O:6])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: COC(C)(Cc1ccccc1)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: CCOC(=O)C1C=NC(C)=C(c2ccccc2)C1=O

Procedure:
25 g. of diethyl aminomethylenemalonate, 18 g. of phenylacetone dimethylketal, 300 ml. of dry diphenyl ether and 1.0 g. of TSA.H2O were mixed and heated under a nitrogen atmosphere at 135°-145° C. for three hours. The mixture was then brought to reflux. After 30 minutes the solution was cooled and extracted with 200 ml. of 21/2% aqueous NaOH solution. The basic extracts were acidified yielding a precipitate of ethyl 6-methyl-5-phenyl-4-oxonicotinate. Recrystallization of this material from methylene chloride/ether provided 12.3 g. of white solid, m.p.=178°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18][CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31]>>[F:27][C:28]([F:34])([F:33])[CH2:29][C:30]([NH:20][CH2:19][CH2:18][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:31]
Reactant: NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: O=C(O)CC(F)(F)F
Product: O=C(CC(F)(F)F)NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 97 %

Procedure:
Prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropan-1-amine (25 mg, 0.05 mmol) and 3,3,3-trifluoropropionic acid using General Coupling Method A to give 24 mg (97%) of 3,3,3-trifluoro-N-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropyl)propanamide. MS found: (M+H)+=456.
Reaction SMILES: [F:1][C:2]1[C:25]([CH3:26])=[CH:24][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]4([C:22]#N)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C[Mg]Br.[Cl-].[NH4+].[Cl:32]CCl>O1CCCC1.O>[ClH:32].[F:1][C:2]1[C:25]([CH3:26])=[CH:24][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]4([CH3:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C2(C#N)CCOCC2)CC1
Reactant: ClCCl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C2(C)CCOCC2)CC1
Product: Cl
Reaction time: 1 h

Procedure:
4-[4-(5-Fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]tetrahydro-2H-pyran-4-carbonitrile (D72, 300 mg) in tetrahydrofuran (10 ml) was treated with methylmagnesium bromide 3M solution in tetrahydrofuran (1.4 ml) over 5 minutes and stirred for 1 hours then treated with saturated ammonium chloride solution (5 ml). The mixture was treated with dichloromethane and water. The dichloromethane layer was separated, dried by passing through a hydromatrix cartridge and the solvent was removed. The white solid from Et2O was dissolved in a mixture of methanol and dichloromethane and treated with hydrogen chloride in ether. The solvent was removed and the title compound as a white solid (211 mg) from ether. M+ 348
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:10]([CH3:31])[C:11]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:12].[OH:32]O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:10]([CH3:31])[C:11]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:12])=[O:32]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(C)Sc3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Reactant: OO
Solvent: CC(=O)O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(C)S(=O)c3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A suspension of 250 mg of 5'-[2(RS)-(2,4-dichlorophenylthio)propionamido]-2',5'-dideoxy-5-ethyluridine in 10 ml of acetic acid was cooled to 0° C. and 60 mg of 30% hydrogen peroxide were added. The mixture was stirred at 0° C. for 0.5 hour and then at room temperature overnight. An additional 60 mg of 30% hydrogen peroxide were added and the mixture was stirred for 24 hours. An additional 30 mg of 30% hydrogen peroxide were added and the mixture was stirred for an additional 4 hours and then evaporated to dryness. The residue was triturated with methanol and the resulting solid was removed by filtration and recrystallized from methanol to give 90 mg of 5'-[2(RS)-(2,4-dichlorophenylsulphinyl)propionamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 208°-209° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1.[CH2:22]([C:26]1[CH:37]=[CH:36][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1)[CH2:23][C:24]#[CH:25].O>CN(C=O)C.[Cu]I>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[N:10][C:9]([C:25]#[C:24][CH2:23][CH2:22][C:26]3[CH:37]=[CH:36][C:29]([CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:28][CH:27]=3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: C#CCCc1ccc(CN2CCCC2)cc1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCCC4)cc3)nn2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere 0.1 mL (0.72 mmol) triethylamine, 3 mg (0.02 mmol) CuI and 8 mg (0.01 mmol) bis-triphenylphosphane-palladium(II)-chloride are added to a solution of 77 mg (0.34 mmol) 3-chloro-6-(4-chloro-phenyl)-pyridazine and 73 mg (0.34 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine (Example 2e) in 4 mL DMF and the reaction mixture is stirred for 20 min at 100° C. and at 300 W in the microwave. The reaction mixture is combined with 10 mL water, extracted with 10 mL EtOAc and the organic phase is washed with water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([NH:13][C@@H:14]([C:19]([OH:21])=[O:20])[C:15]([SH:18])([CH3:17])[CH3:16])(=[O:12])[CH3:11]>Cl>[C:10]([N:13]1[C@@H:14]([C:19]([OH:21])=[O:20])[C:15]([CH3:17])([CH3:16])[S:18][C@@H:6]1[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)(C)S
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Product: CC(=O)N1[C@@H](c2ccc(Cl)cc2)SC(C)(C)[C@@H]1C(=O)O
Reaction time: 0.2 h
Yield: 88.4 %

Procedure:
4.2 g (30 mmoles) of 4-chlorobenzaldehyde are given to the suspension containing 5.73 g (30 mmoles) of N-acetyl-D-penicillamine in 18 ml of ethereal hydrogen chloride solution under stirring for 12 minutes. After dissolution, a product is precipitated which is filtered out and washed with ether to give 8.32 g (88.4%) of the title compound, m.p.: 197°-198° C. after recrystallization from ethyl acetate, [α]D =+230.5° (c=0.59, methanol).