Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=[O:2].[Br:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1>O1CCOCC1.O>[Br:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:15]=[O:2])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(OCCBr)cc1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(OCCBr)cc1
Yield: 97.4 %

Procedure:
A suspension of selenium dioxide (0.821 g, 7.4 mmol) in 1,4-dioxane (40 mL) and water (3 mL) was heated at 55° C. until selenium dioxide was dissolved. To the solution was added 1-[4-(2-bromoethoxy)phenyl]ethanone (1.80 g, 7.4 mmol), and the reaction was heated to reflux for 4 hours. The reaction was filtered, concentrated, and purified by column chromatography (SiO2, 50% ethyl acetate/hexane) to provide the title compound (1.853 g, 97% yield): ES-MS (m/z) 257 [M+H]+.
Reaction SMILES: [CH3:1]I.[Mg].[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[O:10])=[CH:7][CH:6]=1.Cl>O1CCCC1>[O:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=[C:11]1[C:9]([C:8]1[CH:20]=[CH:21][C:5]([Cl:4])=[CH:6][CH:7]=1)([OH:10])[CH3:1]
Reactant: CI
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccccc2o1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Cl)cc1)c1cc2ccccc2o1
Temperature: 0 °C

Procedure:
14.2 g of methyl iodide in 50 ml of tetrahydrofuran are dripped slowly onto 2.43 g of magnesium chips in about 30 ml of tetrahydrofuran. When all the magnesium has dissolved, 25.6 g of 2(p-chloro-benzoyl)benzofuran dissolved in 350 ml of tetrahydrofuran are added slowly. After the addition, the mixture is kept under reflux for 2 hours. It is cooled, poured into 500 g of crushed ice and 10 ml of concentrated HCl, then extracted with ethyl ether. The organic phase is washed with water, dried with anhydrous sodium sulphate, and evaporated to dryness, to leave a residue which crystallises from petroleum ether: M.P. 64°-66° C.
Reaction SMILES: O=S(Cl)Cl.[C:5]1([C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])[OH:6].[CH3:13][O:14][CH:15](OC(OC)C)[CH3:16].C1(C(=CC=CC=1)O)O.[OH-].[Na+]>>[CH3:13][O:14][CH:15]([O:6][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[OH:8])[CH3:16]
Reactant: COC(C)OC(C)OC
Reactant: Oc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COC(C)Oc1ccccc1O

Procedure:
0.5 parts of SOCl2 is added to 113 parts by weight of pyrocatechol-bis-[(1-methoxy)-ethyl]-ether and 55 parts by weight of pyrocatechol at 40° C. and the whole is stirred at this temperature for half an hour. It is then allowed to cool and 2 parts by volume of 25% by weight aqueous caustic soda solution is added. The product is separated and dried over sodium sulfate and the solvent is evaporated. There remains 168 parts of the abovementioned compound having a boiling point of 85° to 90° C. at 0.5 mm.
Reaction SMILES: [CH:1]12C[CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10]C(=O)[CH:2]21)=[O:9].NC1C=CC(C(O)=O)=CC=1>C(O)(=O)C>[C:8]([OH:10])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1
Temperature: 110 °C
Yield: 95 %

Procedure:
32.83 g (0.2 mol) of 5-norbornene-2,3-dicarboxylic acid anhydride and 400 Ml of glacial acetic acid were put into a 1000 Ml flask, heated to 110° C. to dissolve, and then 41.1 g (0.3 mol) of excess 4-aminobenzoic acid was added thereto to form a mixed solution. Subsequently, the mixed solution was stirred and reacted for 2 hours, and was then precipitated at room temperature. Subsequently, the precipitate was washed with glacial acetic acid and water, and was then dried in a vacuum oven at 60° C. to prepare 4-nedimide benzoic acid in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=1>[O-]CC.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
3.0 g (8.6 mmol) of N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]acetamide (intermediate 5) were dissolved in 100 ml of 20% sodium ethoxide solution and heated to reflux for 4 hours. A further 2.0 g (29.4 mmol) of solid sodium ethoxide were added and the mixture was heated to reflux for another 3 hours. For workup, the solvent was removed in vacuo, and the residue was taken up in 200 ml of H2O and extracted twice with dichloromethane. The combined organic phases were dried with MgSO4 and concentrated. For further purification, chromatography was effected on silica gel (1:1 ethyl acetate/heptane) to obtain the aniline as a yellowish oil in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH:10]=O)[C:3]=1[OH:12].C[C:14]1[CH2:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1>>[OH:12][C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[C:5]([CH2:8][OH:9])[C:4]=1[CH:10]=[C:18]1[C:17](=[O:19])[N:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[CH:14]1
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Product: Cc1ncc(CO)c(C=C2C=NN(c3ccccc3)C2=O)c1O

Procedure:
Provided that, the substituent introduced to methylene at 4-position are not always present stably depending on the variation. For example, when to introduce pyridoxal residue to methylen at 4-position, 3-methyl-1-phenyl-2-pyrazolin-5-one is reacted with pyridoxal, then actually obtain not 4-(3-hydroxy-5-hydroxymethyl-2-methylpyridin-4-yl-methylene)-1-phenyl-2-pyrazolin-5-one, but 1-(5-hydroxy-3-methyl-1-phenyl-1H-4-yl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=3)=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:9][N:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:42](O)(C(F)(F)F)=[O:43]>C(#N)C.O>[Cl:32][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][C:7]3[CH:8]=[CH:9][N:10]=[C:5]([C:3](=[O:4])[NH:2][CH2:1][CH2:42][OH:43])[CH:6]=3)=[CH:13][CH:14]=2)=[O:20])=[CH:27][C:26]=1[C:28]([F:31])([F:29])[F:30]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Sorafenib derivative S-6: S-5 (180 mg; 0.30 mmol) was dissolved in acetonitrile (3 ml), and a solution of N,N,N′,N′-tetramethyl-O—(N-succimidyl)uronium tetrafluoroborate (TSTU) (99 mg; 0.32 mmol) in acetonitrile (3 ml) was added, and N,N-diisopropylethylamine (67 μl; 0.37 mmol) was added. HPLC shows complete reaction after 10 min. 0.1% TFA in water (2 ml) is added, and the mixture is purified preparatively HLPC. S-6 is obtained as “off-white” solid substance (163 mg; 0.24 mmol; 78%). MS: M+H=692.1368; calculated for C30H25ClF3N5O9: 692.1371.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH:2]1[C:3]2=[C:8]3[C:10]([C:9]4[CH:14]=[CH:15][CH:2]=[C:3]5[C:8]=4[C:7]2=[CH:6][C:5]2[CH:4]=[CH:5][CH:6]=[CH:7][C:4]5=2)=[CH:11][C:12]2[CH:13]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]3=[CH:14][CH:15]=1
Reactant: Brc1cc2ccccc2c2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1ccc2c(c1)cc1c3cccc4c5ccccc5cc(c5cccc2c51)c43
Temperature: 25 °C
Yield: 3.5 %

Procedure:
To a stirred solution of 9-bromophenanthrene (50 g) in benzene (250 mL) was added solid aluminum chloride (50 g) gradually in portions. After the addition was complete, the mixture was heated at reflux for one hour, then cooled to ambient temperature. A slow addition of 2N HCl (250 mL) was then made (caution: exothermic). The resultant mixture was heated to reflux for an hour. Once cooled the mixture was filtered. The crude solid was washed with several portions of water and air-dried. The black solid (13.5 g) was placed in a soxhlet extractor and extracted with hot THF. The concentrated extracts were sublimed under a nitrogen flow at 300° C. and 640 mTorr to provide 1.2 g of dibenzo[b,k]perylene. The sample was pure by HPLC analysis (Keystone PAH, 5 micron, 100×3 mm).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)#[C:2][CH2:3][CH2:4][CH3:5].[CH3:22][O:23][C:24]1[CH:45]=[CH:44][C:27]([C:28](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([O:17][CH2:16][C@H:15]2[O:18][C@@H:11]([N:10]3[CH:19]=[C:6]([C:1]#[C:2][CH2:3][CH2:4][CH3:5])[C:7](=[O:21])[NH:8][C:9]3=[O:20])[CH2:12][C@@H:13]2[OH:14])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27]2[CH:44]=[CH:45][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:34][CH:33]=1
Reactant: CCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: CCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.5 %

Procedure:
To 20.4 g (69.3 mmol) of 5-(1-pentynyl)-2'-deoxyuridine in 300 mL of dry pyridine was added 22.8 g of 4,4'-dimethoxytrityl chloride. The reaction was stirred for 17 h at room temperature and then concentrated. The residue was taken up in CH2Cl2 and washed twice with 0.5% aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Purification of the crude product by column chromatography afforded 21.9 g (52.9% yield) of product.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.Cl[C:20]1C2C(=CC=CC=2)C(C=O)=C2C=1C=CC=C2.C(I)C>>[CH2:1]([S:2][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:17]=[O:18])=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH3:20]
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: CSc1c2ccccc2c(C=O)c2ccccc12
Solvent: CCI
Product: CCSc1c2ccccc2c(C=O)c2ccccc12

Procedure:
Using the procedure described in 3A, 10-chloro-9-anthracenecarbaldehyde (Aldrich) and ethyl iodide (Fisher) gave an oil which solidified to give 10-ethylthio-9-anthracenecarbaldehyde mp 74°-75.5° (C, H, S).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([O:32]C)=[O:31])=[CH:22][N:21]=3)[C@H:16]([CH3:34])[CH2:15]2)=[C:10]([CH3:35])[C:9]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CCOC(C)=O>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:32])=[O:31])=[CH:22][N:21]=3)[C@H:16]([CH3:34])[CH2:15]2)=[C:10]([CH3:35])[C:9]=1[CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)[C@H](C)C2)c1C
Temperature: 75 °C
Yield: 96.6 %

Procedure:
To a solution of methyl 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylate (500 mg, 1.0 mmol, 1.0 eq) in THF (5 mL) is added an aqueous solution of LiOH (1 M, 2.0 mL, 2.0 mmol, 2.0 eq) and the resulting solution is heated to 75° C. for 4 h. The reaction mixture is diluted with EtOAc (50 mL) and washed with water (3×15 mL). The combined aqueous washes were adjusted to pH 6 with aqueous HCl (1 M), then extracted with dichloromethane (3×50 mL). The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to yield the desired product as a white solid (470 mg, 96%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:16]=[C:14]1[NH:13][C:12]2[CH:17]=[C:8]([CH:5]3[CH2:6][CH2:7][CH:2]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[O:15]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccc3oc(=O)[nH]c3c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4oc(=O)[nH]c4c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 5-(4-oxo-cyclohexyl)-3H-benzooxazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14](=[O:22])NC2C=CC=CN=2)=[C:12]([CH3:23])[NH:11][C:10]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:34]([CH3:35])=[N:33]C(C)=N3)=[CH:26][CH:25]=2)=[C:9]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].[OH-:42].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([OH:22])=[O:42])=[C:12]([CH3:23])[NH:11][C:10]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:8]4[CH:13]=[CH:12][N:11]=[CH:10][C:9]=4[N:33]=[C:34]3[CH3:35])=[CH:26][CH:25]=2)=[C:9]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: [OH-]
Reactant: CCOC(=O)C1=C(c2ccc(-n3nc(C)nc3C)cc2)NC(C)=C(C(=O)Nc2ccccn2)C1c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(C)=C(C(=O)O)C1c1ccccc1Cl
Yield: 81 %

Procedure:
A mixture of the (-)-cyanoethyl ester from (b), above, (271 mg, 0.566 mmol) and aqueous sodium hydroxide (2.54 ml, 0.55M, 1.40 mmol) in dioxane (7.5 ml) was stirred at room temperature under nitrogen for 1 hour. Hydrochloric acid (1.40 ml, 1M, 1.40 mmol) was added dropwise, and the mixture was concentrated under reduced pressure. The resulting yellow solid was suspended in water, filtered off, and dried in vacuo, to give the title compound, (200 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>C1(C)C=CC=CC=1>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([CH:17]3[CH:16]1[C:15](=[O:18])[CH:14]=[CH:13][C:12]3=[O:19])[C:4]([Cl:9])=[C:5]2[Cl:8]
Reactant: O=C1C=CC(=O)C=C1
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Yield: 64 %

Procedure:
A mixture of 54.6 g. (0.2 mole) of hexachlorocyclopentadiene, 21.6 g. (0.2 mole) of p-benzoquinone, and 10 ml. of toluene were placed in a 125 ml. round bottom flask and heated for three hours so that the toluene refluxed gently. At the end of this period the reaction mixture suddenly solidified completely, indicating completion of the reaction. The crude product was bright yellow. The damp material was transferred to a Buchner funnel, rinsed with absolute ethanol, dried on the funnel, and crystallized from ethanol. 49 g. of bright yellow dense crystals were obtained, m.p. 189°-193° C. (reported 188° C.). The yield was 64%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:32])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[NH2:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H](N)Cc1ccc(-c2ccno2)cc1

Procedure:
Crude N-diphenylmethylene-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (280 mg) was treated with p-toluenesulfonic acid monohydrate (100 mg) in acetonitrile (35 ml) and water (3,5 ml) at ambient temperature for 3.5 hours. After concentration the residue is extracted with ether and 1N sodium hydroxide, washed with brine, dried concentrated to give crude 3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester, which is used for the next step without further purification.
Reaction SMILES: BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[NH:35][C@H:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33][S:32]2)=[CH:27][C:26]=1[O:40][C:41](=[O:43])[CH3:42])(=[O:23])[CH3:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=2)=[CH:27][C:26]=1[O:40][C:41](=[O:43])[CH3:42])(=[O:23])[CH3:22]
Reactant: COC(=O)[C@@H]1CSC(c2ccc(OC(C)=O)c(OC(C)=O)c2)N1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1csc(-c2ccc(OC(C)=O)c(OC(C)=O)c2)n1
Yield: 29.8 %

Procedure:
In a CCl4 (5 mL) solvent, NBS (N-bromosuccinimide) (10.6 mg, 0.06 mmol) and AIBN (2,2′-azobis(2-methylpropionitrile)) (3.0 mg) were added to a solution of Compound 105 (11.2 mg, 0.03 mmol), and the reaction mixture was refluxed for 5 hours. After volatile materials evaporate, the residual was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (4:1) to obtain a solid Compound 103 (3.0 mg, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[N:19]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 98.1 %

Procedure:
A mixture of the title compound of Example 2 (45.1 g, 205 mmol) and NaN3 (39.9 g, 614 mmol, 3.0 eq) in DMF (200 mL) was heated and stirred at 70° C. for 48 h when TLC (solvent system C) indicated the reaction to be complete. The reaction mixture was cooled to rt and poured into cold water (200 mL). The aqueous mixture was extracted with Et2O (500 mL) and the organic extract was back-washed with water (2×100 mL), dried (Na2SO4) and the solvent was evaporated in vacuo to afford the title compound (45.5 g, 98%) as a colorless oil: 1H-NMR (CDCl3) ∂ 3.66-3.80 (m, 1H), 3.57 (m, 1H), 3.45 (m, Japp =4.0 Hz, 1H), 3.12 (m, 2H), 1.90-2.05 (m, 2H), 1.69-1.83 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: COc1ccc(N)cc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methoxy-3-trifluoromethyl aniline (500 mg, 2.62 mmol) in 20 mL of tetrahydrofuran was added potassium carbonate (470 mg, 3.4 mmol), followed by phenyl chloroformate (532 mg, 3.4 mmol). This solution was stirred overnight at room temperature, then concentrated and purified by silica gel chromatography using a gradient of ethyl acetate/hexanes 0-20% to afford phenyl 4-methoxy-3-(trifluoromethyl)phenylcarbamate as a white solid. 1H NMR (300 MHz, CDCl3) 7.75-7.65 (m, 2H), 7.60-7.40 (m, 2H), 7.27-7.19 (m, 3H), 7.00-6.93 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of 4-fluorophenol (96.8 g), methyl 6-chloropyridine-3-carboxylate (30 g) and cesium carbonate (285.3 g) in DMSO (875 mL) was stirred and heated to 130° C. over a period of 1.75 h then cooled overnight. The reaction mixture was reheated to ˜150° C. over a period of 1.5 h, kept at this temperature for ˜1 h, then cooled to ˜40° C. and poured into water (4 L). The aqueous solution was extracted with ether (1.0 L) then adjusted to pH7-8 by addition of 2M HCl. The solution was extracted with further ether (2×1.0 L), then adjusted to pH 2 by addition of 2M HCl causing precipitation of a solid. The precipitate was collected by filtration, washed with water and dried overnight at 40° C. in vacuo to give the title compound as a beige/pink solid (36.7 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:33][C@H:32]([CH2:34][O:35][C:36]6[CH:40]=[CH:39][O:38][N:37]=6)[O:31][C:30]5=[O:41])=[CH:25][C:24]=4[F:42])[CH2:19][CH2:18]3)=[O:16])[N:10]=[CH:9]2)C=CC=CC=1.Cl.C(N(CC)CC)C>C(O)C.CO>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][O:35][C:36]5[CH:40]=[CH:39][O:38][N:37]=5)[O:31][C:30]4=[O:41])=[CH:25][C:24]=3[F:42])[CH2:19][CH2:18]2)=[O:16])[N:10]=[CH:9]1
Reactant: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CO
Product: O=C(CCc1c[nH]cn1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
3-(4-(4-(3-(1-Triphenylmethyl-4-imidazolyl)propanoyl)-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (460 mg, 0.63 mmol), was dissolved in a mixture of ethanol (20 ml) and MeOH (10 ml), cooled to 0° and treated with a solution of hydrogen chloride in ethanol (3.8 M, 5 ml). After stirring 48 hours at ambient temperature, the pH was adjusted to 8 with triethylamine, and the mixture evaporated to dryness. The residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 0 to 20% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (60 mg). MS (ESP): 485 (MH+) for C23H25FN6O5;
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[CH2:3][CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.NN>C(O)C>[CH3:1][N:2]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[CH2:3][CH2:4][NH2:5]
Reactant: CN(CCN1C(=O)c2ccccc2C1=O)Cc1ccc2ccccc2n1
Agent: NN
Solvent: CCO
Product: CN(CCN)Cc1ccc2ccccc2n1
Temperature: 65 °C

Procedure:
To 2-[2-(methyl-quinolin-2-ylmethyl-amino)-ethyl]-isoindole-1,3-dione (1 eq) in ethanol was added hydrazine (2 eq). A reflux condenser was attached and the solution was heated 65° C. for 19 hours. The solution was then filtered, concentrated, and co-evaporated from toluene to yield N1-methyl-N1-quinolin-2-ylmethyl-ethane-1,2-diamine in quantitative yield as a dark oil. MH+(216)