Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1(O)[CH2:15][CH2:14][CH2:13][CH:12](C(C)(C)C)[CH2:11][CH2:10][CH:9]1O[SiH](C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=[O:26]>N1C=CC=CC=1>[CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:26])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C[SiH](C)OC1CCC(C(C)(C)C)CCCC1(O)Cc1ccccc1
Solvent: c1ccncc1
Product: OC1CCCC(Cc2ccccc2)CCC1
Temperature: 0 °C

Procedure:
1.7 g of the above product (b) was dissolved in 40 ml of pyridine. To the solution was added 0.43 ml of thionyl chloride while cooling with an ice bath. After stirring at 0° C. for twenty minutes, the reaction solution was poured into ice water, and extracted with ether. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to afford 1.6 g of the titled compound as pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2cnn(C)c2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2cnn(C)c2)nc1-c1ccc(C)cc1
Yield: 15.5 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(1-methyl-1H-pyrazol-4-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.114 g; 0.301 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.017 g (15%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:18])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(O)cc2O1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1ccccc1

Procedure:
A mixture of 2,2-dimethyl-7-hydroxy-4-phenylchroman (3.72 g), sodium hydride (0.53 g, 60% dispersion in oil) and 2-dimethylaminoethyl chloride (1.58 g) in toluene (59 ml) was stirred and boiled under reflux for 6 hours. Water was added to the cooled mixture and the organic layer was separated and extracted with 5 N hydrochloric acid (3×30 ml). The combined acid extract was basified, extracted with ether and the ether extract dried (magnesium sulphate). Removal of the solvent gave 2,2-dimethyl-7-dimethylaminoethoxy-4-phenylchroman which was isolated as its hydrochloride salt, m.p. 165°-167° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[N:10][CH:11]([CH3:15])[CH2:12][O:13][CH3:14])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1C=CC=CC=1>[Cl:23][CH2:24][C:25]([N:10]([CH:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:4]1[CH:5]([CH3:9])[CH2:6][CH2:7][CH2:8][C:3]=1[CH2:1][CH3:2])=[O:26]
Reactant: CCC1CCCC(C)C1=NC(C)COC
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC1=C(N(C(=O)CCl)C(C)COC)C(C)CCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
174 g (0,83 mole) of 2-ethyl-6-methyl-N-(1-methyl-2-methoxy-ethyl)-cyclohexylideneamine and 101g (1 mole) of triethylamine were added dropwise one after the other with stirring and at a temperature of 5°C to a solution of 94 g (0,83 mole) of chloroacetyl chloride in 3000 ml of benzene. The reaction mixture was then refluxed for 5 hours, cooled to room temperature, washed with water, dried with sodium sulfate, filtered and concentrated under water-jet vacuum. Distillation of the residue under high vacuum gave 150,5 g of a 2-chloro-N-(1 -methyl-2-methoxy-ethyl)N-(2-ethyl-6-methyl-cyclohexenyl)acetamide as a mixture of its isomers b.p. 140°-148°/0.1 Torr.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3=[N+:12]([O-])[O:13][N:14]=[C:10]3[CH:9]=2)=[CH:5][CH:4]=1.P(OCC)(OCC)OCC>C(O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3=[N:12][O:13][N:14]=[C:10]3[CH:9]=2)=[CH:18][CH:19]=1
Reactant: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3)ccc21
Agent: CCOP(OCC)OCC
Solvent: CCO
Product: FC(F)(F)c1ccc(Oc2ccc3nonc3c2)cc1

Procedure:
Following the procedure of Example 2, 5-(4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole N-oxide (0.7 g) and triethyl phosphite (5 ml) in 75 ml of ethanol are heated under reflux for 2 hours. The reaction is cooled and stripped, and the residue is purified to give 5-(4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole, m.p. 77°-78°.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1.Cl.Cl[CH2:19][CH2:20][CH2:21][NH2:22]>CN(C)C=O>[O:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:7][CH2:8]1
Reactant: NCCCCl
Reactant: Oc1cccc(CN2CCOCC2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCOc1cccc(CN2CCOCC2)c1
Temperature: 20 °C
Yield: 64 %

Procedure:
To a 80% suspension of 0.28 mol of sodium hydride in dimethylformamide, 0.06 mol of 3-morpholinomethylphenol is added portionwise, under stirring at a temperature of about 20° C., then the mixture is stirred 15 minutes at room temperature and a solution of 0.08 mol of 3-chloropropylamine hydrochloride in 20 ml of dimethylformamide is added thereto at 5°-10° C. The reaction mixture is stirred 24 hours at room temperature, then, after addition of 400 ml of ice-water, it is extracted 4 times with 100 ml of ethyl acetate. The organic solution is washed twice with 30 ml of 10% sodium hydroxide, then 3 times with 20 ml of water. The mixture is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Thus, 3-(3-morpholinomethylphenoxy)propylamine is obtained, in the form of a yellow oil. Yield: 64%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+].Cl>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)CCCCCCCOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCCCCCOCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 8-benzyloxyoctanoate was dissolved in 15 ml of THF. 15 ml (30 mmol) of phenylmagnesium bromide (2 M THF solution) was added dropwise to the obtained solution in ice bath. After stirring at room temperature for 4 hours, a saturated aqueous ammonium chloride solution and then 1 N hydrochloric acid were added to the reaction mixture to terminate the reaction. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under educed pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:19]3[NH:18][C:17]4[CH:22]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:23][CH2:24][C:16]=4[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Li+].Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:19]3[NH:18][C:17]4[CH:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24][C:16]=4[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4cnccn4)cc3)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4cnccn4)cc3)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.2 %

Procedure:
To a stirred solution of ethyl 2-(7-(4-(pyrazin-2-yl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (15 mg, 0.035 mmol) in dioxane (1 mL) was added 1 M lithium hydroxide solution (0.175 mL, 0.175 mmol). The reaction mixture was stirred at room temperature for 5 h and acidified with HCl solution. The mixture was purified by HPLC to give the title compound (8 mg) as a pinkish solid. LCMS m/z=400.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.04-2.12 (m, 1H), 2.35 (dd, J=16.0 and 9.0 Hz, 1H), 2.62-2.75 (m, 4H), 3.44-3.50 (m, 1H), 5.17 (s, 2H), 6.74 (dd, J=8.7 and 2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 8.15 (d, J=8.3 Hz, 2H), 8.61 (d, J=2.5 Hz, 1H), 8.72 (dd, J=2.3 and 1.6 Hz, 1H), 9.26 (d, J=1.5 Hz, 1H), 10.47 (s, 1H), 12.20 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].[CH:27](Br)([CH3:29])[CH3:28].COC1C=CC(CCCCCCCCC)=CC=1C(C1C=CC=CC=1)=O>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:27]([O:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:29])[CH3:28]
Reactant: CC(C)Br
Reactant: CCCCCCCCCc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: CCCCCCCCCc1ccc(OC)c(C(=O)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCc1ccc(OC(C)C)c(C(=O)c2ccccc2)c1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
2-Isopropoxy-5-nonyl benzophenone was prepared as follows. To 25 g of 2-hydroxy-5-nonyl benzophenone in 100 mL CH2Cl2 was added 20 g NaOH in 100 mL water, followed by the addition of 48 g isopropyl bromide and 2.5 g tetra-n-butyl-ammonium bromide. The entire mixture was stirred vigorously at 40° C. for 3 days. The reaction mixture was worked up as described for the preparation of 2-methoxy-5-nonyl benzophenone (Example II) to give 16 g of yellow oil (57% yield), identified as the desired product.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]>N1C=CC=CC=1>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: c1ccncc1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Yield: 94.2 %

Procedure:
Methyl pheophorbide-a (5) (1.3 g, 2.09 mmol) was dissolved in 100 mL of pyridine and stirred at reflux for 8 hours under nitrogen in the dark. Pyridine was removed by evaporation and the residue was recrystallized from dichloromethane/methanol to give 1.08 g (92%) of methyl pyropheophorbide-a (39). UV/vis Omax (H)(CH2Cl2): 410 (112500), 509 (11400), 537 (9800), 611 (8500), 669 (47000) nm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](Cl)=[O:29]>CN(C)C(=O)C>[CH3:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[CH:27]=[C:26]([CH3:31])[CH3:25]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: CC(=O)N(C)C
Product: CC(C)=CC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 56.5 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), N,N-dimethylacetamide (2.0 mL) and 3,3-dimethylacryloyl chloride (83 μL, 0.74 mmol), and in the same manner as in Example 120, the title compound (142 mg, 57%) was obtained as a white powder.
Reaction SMILES: Cl.[C:2]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][C:14]=3[CH:15]=2)[S:9][CH:10]=1)([CH3:5])([CH3:4])[CH3:3].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:24]1.C(N(CC)CC)C.CN(C)CC(N)C>ClCCl>[C:2]([C:6]1[N:7]=[C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]([N:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:33])=[CH:24]4)=[O:21])=[CH:16][C:14]=3[CH:15]=2)[S:9][CH:10]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)Cl)ccc3o2)n1
Agent: CC(N)CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of 2-(4-tert-butylthiazol-2-yl)benzofuran-5-carbonyl chloride hydrochloride (140 mg), benzyl indole-3-carboxylate (73.3 mg), triethylamine (0.089 ml) and N,N-dimethylaminopyridine (4 mg) in dichloromethane (4 ml) was stirred under reflux for 7 hours. After being cooled to room temperature, the mixture was treated with N,N-dimethylpropylenediamine (0.018 ml) and diluted with dichloromethane. The dichloromethane solution was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give benzyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}indole-3-carboxylate (121 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.ClCC(=O)C[C:23]([O:25][CH3:26])=O.FC1C=CC(N=C=O)=CC=1.COCCO>O1CCOCC1.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH2:17][CH2:23][O:25][CH3:26])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Agent: O=C=Nc1ccc(F)cc1
Agent: [Zn]
Solvent: C1COCCO1
Solvent: COCCO
Product: COCCOC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.063 g, 0.25 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, 2-methoxyethanol (0.2 mL, 2.5 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0048 g, 0.0050 mmol) in anhydrous dioxane (1.0 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 120° C. for 1 h. Cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel(chloroform/ethyl acetate) to afford 2-methoxyethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.024 g, y. 33%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].C(O)=O>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCCN(C)C
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CCN(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using N1,N1,N2-trimethylethane-1,2-diamine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (61 mg, 0.135 mmol, 72.3%) as an off-white solid. MS: 405 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H) 2.53-2.70 (m, 4H) 3.02 (s, 3H) 3.11-3.80 (m, 6H) 7.53 (d, J=8.3 Hz, 1H) 7.58 (s, 1H) 7.89-7.99 (m, 2H) 8.10 (br. s., 1H) 8.50 (m, 2H).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[N:14]([Si](C)(C)C)=[N+:15]=[N-:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[N:14]([C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]1)=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.7 %

Procedure:
A 500 mL round-bottomed flask was charged with tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (15.42 g, 83.25 mmol), (1S,2S)-(−)-[1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)]chromium (III) chloride (1.18 g, 1.67 mmol) and azidotrimethylsilane (12.8 mL, 91.58 mmol) and the resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for 48 hours. The dark red-brown mixture was diluted with chloroform (250 mL) and washed sequentially with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in methanol (830 mL) and treated with potassium carbonate (11.51 g, 83.25 mmol) and the mixture was stirred at ambient temperature for 5 hours. The methanolic solution was filtered through a pad of Celite washed with methanol and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous back extracted with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (Biotage 40M; 20% ethyl acetate/hexanes) to give (3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (18 g, 95%). Enantiomeric excess was determined by Chiral HPLC (AD-H, Chiralcel, 10% EtOH: 90% hexanes at 0.80 mL/min, 94.5% e.e.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].N[C:20]1C=CC(O)=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:20])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1ccc(O)cc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Product: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-3-methylphenol for 4-aminophenol. 1H-NMR (acetone-d6) δ 8.39 (d, J=5.7 Hz, 1H), 8.29 (br s, 1H), 7.51 (dd, J=2.7, 0.6 Hz, 1H), 6.98 (dd, J=5.7, 2.4 Hz, 1H), 6.82 (br s, 1H), 6.77 to 6.76 (m, 2H), 4.56 (br s, 2H), 2.92 (d, J=5.1 Hz, 3H), 2.16 (d, J=1.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=O.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: COc1c(C(=O)CCC(=O)O)ccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1c(CCCC(=O)O)ccc2c1CCCC2
Reaction time: 6 h

Procedure:
42 g (0.15 mol) of 3-(1-methoxy-2-naphthoyl)propionic acid [cf. W. I. Awad, F. G. Badder, A. E. Marei, J. Chem. Soc. 1954, p. 4538] are hydrogenated for 6 h at 60° C. and 30 bar of hydrogen in 800 ml of ethanol in the presence of 12 g of palladium/animal carbon (10% strength) as a catalyst. The catalyst is filtered off, the solution is evaporated and the residue is flash chromatographed on silica gel using methylene chloride/methanol 10:1 as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11](=[O:23])[CH:10]=1.Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:11](=[O:23])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cc(Cl)ccc2Br)cc1=O
Reactant: BrCc1cccnc1
Agent: Br
Product: CC(C)(C)OC(=O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
206 mg (purity 94%, 0.49 mmol) of tert-butyl [4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]acetate and 184 mg (0.73 mmol) of 3-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 274 mg (purity 88%, quant.)
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.O[C:17]1[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1.ClC1C=C(O)C=NC=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:3]([CH2:2][O:1][C:17]2[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=2)([CH3:15])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)c1ncccc1O
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OCC1(C)CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate and ethyl 3-hydroxypicolinate instead of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.