Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:27](Br)[C:28]#[CH:29]>O1CCCC1>[CH:1]([S:14][C:15]1[N:19]=[N:18][N:17]([CH2:29][C:28]#[CH:27])[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(Sc2nnn[nH]2)c2ccccc2)cc1
Reactant: C#CCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCn1nnc(SC(c2ccccc2)c2ccccc2)n1
Reaction time: 2.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-benzhydrylthio-1H-tetrazole (29 g) in tetrahydrofuran (145 ml) were added triethylamine (12.0 g) and 2-propynyl bromide (19.3 g) at room temperature. The resulting mixture was stirred for 2.5 hours at 40° to 45° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was shaken with a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residual oil (27.7 g) was subjected to column chromatography on silica gel, and eluted with a mixture of n-hexane, chloroform and ethyl acetate (5.5:4.5:0.5), to give 5-benzhydrylthio-2-(2-propynyl)-2H-tetrazole (14.2 g), mp 85° to 86° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h
Yield: 7.6 %

Procedure:
To a stirred solution of 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg, 0.68 mmol) and 4-chloro-6,7-dimethoxyquinazoline (153 mg, 0.68 mmol) in DMF (4 mL) at rt, was added potassium carbonate (188 mg, 1.36 mmol). The reaction mixture was stirred at 35° C. for 15 h. The mixture was poured into water, and the resulting brown solid was filtrated, washed with water, and dried to afford the crude product. Purification via reverse-phase preparative HPLC afforded 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (25 mg, 8%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (brs, 1H), 8.85 (brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.55 (s, 1H), 7.40-7.44 (m, 2H), 7.16 (m, 1H), 6.50 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 482 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl>C1COCC1>[C:23]([O:22][C:20](=[O:19])[NH:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
To a solution of 3-amino-2-chloropyridine (5 g 38.9 mmol) in THF (35 mL) is added 2 M NaHMDS in THF (38.9 mL, 77.8 mmol). After stirring at rt for 15 min, BOC2O (7.7 g, 35.6 mmol) in THF (20 mL) is added in one portion and then stirred for 5 h at rt. 0.1% aqueous HCl is added. The mixture is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-50% EtOAc in heptane to afford (2-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (7.18 g, 89%). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.52 (d, 1H), 8.05 (dd, 1H), 7.23 (dd, 1H), 7.02 (broad s, 1H), 1.55 (s, 9H)).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:9][CH:10]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=O)[CH:17]=[CH:16]2)[CH3:11])[CH3:8].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([O:9][CH:10]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[CH2:1])[CH:17]=[CH:16]2)[CH3:11])[CH3:8]
Reactant: CCOC(C)Oc1ccc2cc(C=O)ccc2c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc2cc(OC(C)OCC)ccc2c1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
In a 1 L three neck flask, equipped with an overhead mechanical stirrer, was added 45 g of methyltriphenylphosphonium bromide (0.126 mol) under nitrogen atmosphere. To this were added anhydrous 300 mL of THF and 16.02 g of potassium tert-butoxide (0.1428 mol). After 1 h of stirring, 20 g of 6-(1-ethoxy ethoxy)-2-naphthaldehyde (0.0819 mol), dissolved in 50 mL of THF, was added dropwise using a cannular and the reaction mixture was stirred overnight. After overnight stirring, deionized water (200 mL) was added with a syringe and the phases were separated. The aqueous phase was extracted with ether (2×100 mL) and the combined extracts were dried over MgSO4. After filtration and concentration, the crude product was purified by column chromatography (silica gel, hexane/CH2Cl2 40/60˜10/90) to yield 19.12 g of pure 6-(1-ethoxy ethoxy)-2-vinylnaphthalene (96%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[CH2:6].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>C1COCC1.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([OH:20])([CH2:6][CH2:5][CH:4]=[CH2:3])[C:16]([F:19])([F:17])[F:18]
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: C=CCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a 300 mL oven dried 3 necked, round bottomed flask with a stirring bar, argon inlet, addition funnel and a reflux condenser was added magnesium (turnings, 3.03 g, 125 mmol) and dry THF (75 mL). To this well stirred mixture was added 4-bromo-1-butene (12.0 mL, 118.21 mmol) at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was aged 30 min then cooled to 0° C. in an ice bath. To this well stirred solution was added a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (5.00 g, 22.36 mmol) in THF (35 mL), dropwise over 30 min. The cooling bath was allowed to expire and the mixture was stirred 20 h at ambient temperature. The reaction was diluted with EtOAc and 10% aqueous citric acid. This mixture was stirred for 4 h. The layers were separated and the organic phase was washed with aqueous NaHCO3 and brine. Drying (MgSO4), filtration, removal of the solvent in vacuo, and chromatography on 300 g of silica gel using 15% EtOAc in hexane as eluantas eluant gave 4.80 g of (+/-) 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-5-hexen-2-ol as a yellow solid.
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[C:15](Cl)[CH:16]=[CH:17][C:12]=3[N:11]3[C:19](C#N)=[N:20]N=[C:10]3[CH2:9][N:8]=2)C=CC=CC=1.Cl.C[OH:26]>[OH-].[Na+]>[N:11]1([C:19]([NH2:20])=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)N1C=CN=Cc2ccccc21
Reaction time: 0.17 h

Procedure:
A solution of 1.60 g (0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carbonitrile in a mixture of 50 ml of methanol and 50 ml of 1N sodium hydroxide solution is allowed to stand for ca. 10 minutes at 25°. The reaction mixture is then neutralised with 2N hydrochloric acid, and concentrated to about half its volume. The concentrate is extracted in methylene chloride, the organic solution washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is crystallised from methanol/ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4benzodiazepine-1-carboxamide, M.P. 285°-289°.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][CH:13]([CH3:15])[CH3:14])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: CC(C)N
Product: CSc1nc(Cl)c(C=O)c(NC(C)C)n1

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and isopropylamine to give the title compound 4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.31 (d, 6H, J=5.7 Hz), 2.60 (s, 3H), 4.47 (m, 1H), 9.16 (br s, 1H), 10.25 (s, 1H). LC MS (m/e)=246 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44]1[CH:56]=[CH:55][C:47](CN2C=CC(N)=N2)=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:47]3[CH:55]=[CH:56][C:44]([O:43][CH3:42])=[CH:45][CH:46]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COc1ccc(Cn2ccc(N)n2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-(4-methoxy-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methoxy-benzyl)-1H-pyrazol-3-yl]-propionamide (92 mg, 59%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O4S [M+] 515.2, found 516.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.21 (m, 2H, CH2), 1.41-1.91 (m, 8H, 4×CH2), 2.10-2.26 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.54 (t, J=7.6 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 5.05 (s, 2H, NCH2), 6.66 (d, J=2.3 Hz, 1H, Ar), 6.83 (d, Jo=8.5 Hz, 2H, Ar), 7.09 (d, Jo=8.5 Hz, 2H, Ar), 7.25 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.30 (s, 1H, NH).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:34])[N:18]([CH3:33])[C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:33][N:18]([C:19]1[CH:20]=[N:21][C:22]([O:25][C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)[C:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH:9]=1)=[O:34]
Reactant: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1Oc1ccc(N(C)C(=O)c2c[nH]c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
The tert-butyl-3-(methyl(6-(2-methylpyridine-3-yloxy)pyridine-3-yl)carbamoyl)-1H-indole-1-carboxylate (40 mg, 0.087 mmol) was added to a mixed solution of dichloromethane (1 ml) and TFA (1 ml), and the mixture was stirred at room temperature for 1 hour. Subsequently, the product was filtered, washed, and dried to yield a target compound as a white solid (28 mg, 90%)
Reaction SMILES: CO.[CH:3]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:44])=[CH:11][C:12](=[O:43])[N:13]3[CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([N:24]([CH2:32][C:33]4[CH:42]=[CH:41][C:36]5[O:37][CH2:38][CH2:39][O:40][C:35]=5[CH:34]=4)C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[ClH:45].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:45].[CH:3]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:44])=[CH:11][C:12](=[O:43])[N:13]3[CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:32][C:33]4[CH:42]=[CH:41][C:36]5[O:37][CH2:38][CH2:39][O:40][C:35]=5[CH:34]=4)[CH2:20][CH2:19]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C3CC3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(C3CC3)ccc12
Reaction time: 1.5 h

Procedure:
To 1 mL of methanol solution containing 95 mg of tert-butyl (1-(2-(7-cyclopropyl-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 1.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 45 mg of 7-cyclopropyl-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O: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]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:26][C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(OCCCn2ccnn2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(COc3ccc(OCCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(3-[1,2,3]triazol-1-yl-propoxy)-phenol in 4.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 8 ml water the resulting precipitate was collected , washed with water (2×10 ml), methanol/water 1:1 (2×10 ml), ethyl acetate/n-heptane 1:2, a small amount of diethyl ether and dried to yield 233 mg (88%) of a slightly yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:3]1[CH:4]=[C:5]2[C:10](=[N:11][C:2]=1[CH3:1])[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: Cc1ccc2c(n1)NCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1nc2c(cc1Br)CCCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a vial is added 7-methyl-1,2,3,4-tetrahydro-[1,8]naphthyridine (390 mg, 2.63 mmol) and N-bromosuccinimide (468 mg, 2.63 mmol) in 20 mL of CH2Cl2. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated. The residue is purified by flash column chromatography to give 575 mg of 6-bromo-7-methyl-1,2,3,4-tetrahydro-[1,8]naphthyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=2)[CH:15]=[O:16])=[CH:6][CH:5]=1)[CH3:2].[SH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:14]([CH:15]=[O:16])[CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Reactant: CCOC(=O)CCCS
Product: CCOC(=O)CCCSc1ccc(-c2ccc(OCC)cc2)cc1C=O
Yield: 73 %

Procedure:
Ethyl 4-(4-(4-ethoxyphenyl)-2-formylphenylthio)butyrate was synthesized from 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After concentration of an extracted solution, crystallization from hexane/isopropyl ether yielded ethyl 4-(4-(4-ethoxyphenyl)-2-formylphenylthio)butyrate (Yield 73%) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10](F)[C:7]=1[CH:8]=O.O.[NH2:21][NH2:22]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:7]=1[CH:8]=[N:21][NH:22]2
Reactant: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Temperature: 25 °C

Procedure:
To a suspension of 2-(3-bromo-5-chlorophenoxy)-3-chloro-6-fluorobenzaldehyde (77.5 g, 213 mmol) in ethanol (120 mL) was added hydrazine hydrate (31 mL, 639 mmol). The resulting mixture was then heated at reflux for 4 days, after which the mixture was cooled to room temperature, diluted with water (100 mL) and the resulting solid was filtered. The solid was absorbed onto silica gel (300 g) and purified on a silica gel (1500 g) column (0-40% EtOAc/CH2Cl2) to give the title product as a white solid. LRMS (M+1)=358.8
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 90.6 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-methylpropan-1-one (500 mg, 1.85 mmol) was reacted with (R)-tert-butyl (1-(5-aminopyridin-2-yl)piperidin-3-yl)carbamate (815 mg, 2.78 mmol) to afford the desired product (880 mg, 88%) as a red solid: ESI MS m/z 525 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:48]=[CH:47][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:38]([CH3:46])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:49].O1CCOCC1>>[ClH:49].[CH2:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]3[N:17]=[C:15]([CH2:14][O:13][C:12]4[CH:47]=[CH:48][C:9]([CH2:8][CH:4]5[S:3][C:2](=[O:1])[NH:6][C:5]5=[O:7])=[CH:10][CH:11]=4)[N:38]([CH3:46])[C:19]=3[CH:20]=2)=[CH:26][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(Cc4ccccc4)cc3)cc21
Reaction time: 72 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-benzylphenoxy)phenyl}-N-methylcarbamate (0.91 g) and 4N hydrogen chloride/dioxane (10 ml) was allowed to stand at ambient temperature for 3 days. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (0.69 g).
Reaction SMILES: [CH:1]1([Si:6]([CH:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)([CH3:8])[CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:17][CH2:16][CH2:15][C:9]1([Si:6]([CH3:7])([CH3:8])[CH:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: C[Si](C)(C1C=CC=C1)C1C=CC=C1
Reactant: C[Si](C)(C)OCCBr
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC1([Si](C)(C)C2C=CC=C2)C=CC=C1
Reaction time: 12 h
Yield: 52 %

Procedure:
A solution of 11.5 g (61 mmol) of biscyclopentadienyidimethylsilane in THF was added to a suspension of 1.3 g (55 mmol) of HK in THF at −78° C. A purple solution was immediately formed. Then, the volatiles were removed and the residue was washed with hexane to give a pink solid. The solid was solved again in THF and a solution of 10.8 g (55 mmol) of 2-bromo-1-trimethylsiloxyethane in THF was added at room temperature. A pink suspension was immediately formed. The mixture was stirred for 12 h, and then the solvents were removed, the residue was treated with hexane and the supernatant solution was filtered. The removal of the hexane led to a reddish oil. This oil was distilled in order to obtain a yellow oil, which was characterized as a mixture of position isomers of (2-trimethylsiloxyethylcyclopentadienyl) dimethyl cyclopentadienyl silane (Tb: 135–140° C.; 1 mm Hg), (8.7 g, 28.6 mmol, yield: 52%). 1H-RMN(CDCl3): 6.82–6.40 (m, 7H); 3.82 (m, 2H); 3.10 (m, 2H); 2.73 (m, 2H); 0.20 (s, 15 H).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:25]=O.[BH4-].[Na+]>CO>[CH3:25][N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: C=O
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 50 ml of methanol, was added 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine and 15 ml of a 37% aqueous formaldehyde solution. After stirring at 70° C. for two hours, the mixture was cooled, and treated (portionwise) with 2.5 g of sodium borohydride over a period of five minutes. After stirring at ambient temperature for two hours, the reaction mixture was evaporated to a semi-solid. The semi-solid was stirred with 50 ml water, then extracted with ethyl acetate. The organic layer was washed with water, followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent yielded a residue which was purified by means of a high pressure liquid chromatography (silica gel, elution with 5% methanol/dichloromethane). The desired fractions were combined, then evaporated to afford 1-methyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine as an oil. The oil was dissolved in isopropanol, and acidified to pH 1with etheral-oxalic acid. The resultant precipitate was collected and dried to give 2.5 g (47%), of 1-methyl-4-(2,3,4,5,6-pentaflurophenoxy)-4-phenylpiperidine oxalate, m.p. 152°-154° C. (dec).