Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: Cc1cccc(Br)c1
Product: Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1

Procedure:
The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1-bromo-3-methylbenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][CH2:34][C:35]3=[O:40])O1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][CH2:34][C:35]3=[O:40])=[C:3]([O:13][CH2:14][O:15][CH3:16])[C:4]=1[O:11][CH3:12])[CH3:10]
Reactant: CCOc1ccc(Br)c(OCOC)c1OC
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCOC)c1OC
Temperature: 85 °C
Yield: 56.7 %

Procedure:
A stirring solution of 1-bromo-4-ethoxy-3-methoxy-2-(methoxymethoxy)benzene (300 mg, 1.030 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h, to this cesium carbonate (1 g, 3.092 mmol), Pd(PPh3)4 (59 mg, 0.051 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (265 mg, 1.030 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded 4-(4-Ethoxy-3-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one as a solid (200 mg, 56%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C@@H:5]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10]2.Cl[CH2:17][CH2:18]Cl>>[O:12]=[C:11]([C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:14]([OH:13])=[O:15])[CH:17]=[CH2:18]
Reactant: ClCCCl
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)[C@@H]1CCCC[C@H]1C(=O)O

Procedure:
A mixture of aluminum chloride (66.7 g., 0.5 mole), trans-1,2-cyclohexanedicarboxylic anhydride (38.5 g., 0.25 mole) and 1,2-dichloroethane (1 liter) in a 2 liter 3-neck flask equipped with a gas inlet tube, a mechanical stirrer and a drying tube is stirred rapidly and ethylene is bubbled in for 4.5 hours. This mixture is poured into 900 ml. of 5% hydrochloric acid and ice. The layers are separated and the organic layer is washed with water and taken to dryness in vacuo. The aqueous layer is extracted with ether (300 ml.). This extract is washed with water and combined with material from the original organic layer and taken to dryness. The residue is heated with 300 ml. of 10% potassium carbonate on a steam bath for fifteen minutes. After cooling, the mixture is extracted three times with ether. The aqueous layer is acidified and the product trans-2-[1-oxo-2-propenyl]cyclohexanecarboxylic acid (31.6 g.) is extracted into ether, dried and concentrated in vacuo. The crude crystalline trans-2-(1-oxo-2-propenyl)cyclohexanecarboxylic acid is recrystallized from ether-hexane, m.p. 101°-102°.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])(C)C)=[N:7][C:8]=1[CH3:9])#[N:2].[CH2:19]1COC[CH2:20]1>CO.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH2:16][CH2:19][CH3:20])=[N:7][C:8]=1[CH3:9]
Reactant: C1CCOC1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1C#N
Agent: [Ni]
Solvent: CO
Product: CCCCOC(=O)Nc1cc(C)c(CN)c(C)n1
Reaction time: 144 h

Procedure:
To a mixture of tert-butyl 5-cyano-4,6-dimethylpyridin-2-ylcarbamate (10.8 g, 43.7 mmol) in THF (100 ml) were added about 15 cm3 of a Raney-Ni suspension in MeOH under Ar. The flask was sealed, and the suspension was vigorously stirred at it for 6 d under an atmosphere of hydrogen. The reaction mixture was filtered over a plug of cellite and eluted with DCM (200 ml), DCM-MeOH (9:1, 200 ml) and NH3 in MeOH (7N, 100 ml). Removal of all volatiles in vacuo afforded the crude product which was recrystallized from MeOH-DCM to afford the title compound. LCMS RtM=1.13 min, [M+H]+=252.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)=[C:14]([F:20])[C:15]([F:19])=[C:16]([CH3:18])[CH:17]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)=[C:14]([F:20])[C:15]([F:19])=[C:16]([CH3:18])[CH:17]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCCCc1ccc(-c2c(C=Cc3ccc(CCC)cc3)cc(C)c(F)c2F)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2c(CCc3ccc(CCC)cc3)cc(C)c(F)c2F)cc1
Yield: 60.3 %

Procedure:
0.33 g of Pd/C was added to 6.50 g of the compound (24) having been dissolved in 100 mL of toluene and 100 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 3.94 g of 2-(4-propylphenyl)ethyl-2,3-difluoro-4-(4-pentylphenyl)toluene (Compound 1-2-3-3) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:4][CH3:5].[C:17]([N:36]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=2)=[N:39][N:38]=[N:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:3]([C:6]1[N:15]([CH2:51][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40]3[N:36]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:37]=[N:38][N:39]=3)=[CH:54][CH:53]=2)[C:14](=[O:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2ccccc2c(=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of sodium hydride (60% dispersion in mineral oil, 0.3 g) in DMF (50 ml) was added 2-propyl-4(3H)-quinazolinone (1.0 g) and the mixture was stirred at room temperature for 15 minutes. After addition of 4-[2'-(N-trityltetrazol-5-yl)phenyl]benzyl bromide (5.0 g), the reaction mixture was stirred at room temperature for 19 hours and concentrated to dryness. The residue was extracted with ethyl acetate-water and the organic layer was washed with water, dried and concentrated to dryness. The resulting syrup was purified by column chromatography on silica gel to give a colorless amorphous (2.34 g, 66%).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:27]=[CH:26][N:17]([C@@H:18]3[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]3)[C:16](=[O:28])[N:15]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41]([CH3:52])[CH2:42][O:43][C:44](N1C=C[N+](C)=C1)=[O:45])([O-:34])=[O:33]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:27]=[CH:26][N:17]([C@@H:18]3[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([O:21][C:44]([O:43][CH2:42][CH:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N+:32]([O-:34])=[O:33])[CH3:52])=[O:45])[CH2:19]3)[C:16](=[O:28])[N:15]=2)=[O:12])=[CH:29][CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OCC(=O)Nc2ccn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)n2)cc1
Reactant: CC(COC(=O)n1cc[n+](C)c1)c1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(COC(=O)O[C@H]1C[C@H](n2ccc(NC(=O)COc3ccc(C(C)(C)C)cc3)nc2=O)O[C@@H]1CO)c1ccccc1[N+](=O)[O-]
Yield: 73 %

Procedure:
As described for 11 with N4-((4-tertbutylphenoxy)acetyl)-2′-deoxycytidine (4) (5 g, 6.93 mmol) in 50 ml dichloromethane and 2 (2.71 g, 8.32 mmol) in 50 ml dichloromethane. Purification by precipitation using toluene yielded 3.16 g (73%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]1([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:12])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(ccn2-c2ccccc2)c1
Yield: 28.1 %

Procedure:
The suspension of methyl indole-5-carboxylate (4) (0.70 g, 4.82 mmol), 4-iodobenzene (0.65 mL, 5.79 mmol), K2CO3 (0.93 g, 6.75 mmol), CuO (0.04 g, 0.48 mmol) in DMF (2 mL) was refluxed for 2 days. The reaction mixture was quenched with water, followed by extraction with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:4) to afford 6 (0.30 g). 1H NMR (500 MHz, CD3OD): δ 6.83 (d, J=3.2 Hz, 1H), 7.431-7.44 (m, 1H), 7.42 (d, J=3.1 Hz, 1H), 7.49-7.51 (m, 2H), 7.54-7.60 (m, 3H), 7.77 (dd, J=8.7, 1.1 Hz, 1H), 10.06 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:17]([N:36]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=2)=[N:39][N:38]=[N:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>>[CH2:1]([C:5]1[N:6]([CH2:51][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40]3[N:36]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:37]=[N:38][N:39]=3)=[CH:54][CH:53]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(=O)C(C)C)c(C#N)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 74(a), but using 1.42 g of 2-butyl-4-isobutyrylimidazole-5-carbonitrile (prepared as described in Preparation 27) 4.49 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.76 g of potassium t-butoxide. 3.04 g of the title compound was obtained as crystals, melting at 115°-116° C.
Reaction SMILES: [C:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][C:8]2[N:9]=C(C)[O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:32]>C(O)C>[ClH:32].[NH2:9][C:8]1[CH:13]=[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[OH:11]
Reactant: CCCCCCCCCCCCCCCCOc1cc2nc(C)oc2cc1C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(N)c(O)cc1C(C)(C)C
Yield: 92 %

Procedure:
7.3 g of the benzoxazole compound obtained in Step (d) above was refluxed for 3 hours together with 30 ml of ethanol and 20 ml of concentrated hydrochloric acid. After the completion of the reaction, the reaction mixture was allowed to stand and cool. The crystals thus precipitated were collected by filtration, washed with water and then washed with acetone. Thus, 6.9 g (92% yield) of 2-amino-5-tert-butyl-4-hexadecyloxyphenol hydrochloride was obtained.
Reaction SMILES: CS([O:5][C:6]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:16])(=O)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([NH:21][S:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:16])[C:6]=1[OH:5])(=[O:14])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)Oc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CC(C)(C)N
Product: CC(C)(C)NS(=O)(=O)c1cccc(Cl)c1O

Procedure:
2-Chloro-6-chlorosulfonylphenyl methanesulfonate was treated with t-butylamine and then base to give N-t-butyl 3-chloro-2-hydroxybenzenesulfonamide. Without purification, this material was nitrated using nitric acid in acetic acid to give N-t-butyl 3-chloro-2-hydroxy-5-nitrobenzenesulfonamide. Using sodium dithionite, this compound was reduced to give the aminophenol. The hydrochloride salt of this has also been prepared.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.N([O-])=O.[Na+].C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].[FH:27]>N1C=CC=CC=1>[F:27][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: F
Reactant: COC(=O)c1nc(N)cnc1OC
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(F)cnc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 140 mL of 70% solution of hydrogen fluoride in pyridine was dissolved 17.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate at an ice-cooled temperature. Then, 7.8 g of sodium nitrite was added at −50° C. in three portions. After the foaming had ceased, the temperature was slowly elevated, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of 300 mL of ice and 200 mL of chloroform, the deposited insoluble matter was filtered off, and then the organic layer was separated. The remaining aqueous layer was extracted with ten portions of chloroform, provided that the total quantity of liquid came to 500 mL. The organic layers thus obtained were united, pH was adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=4:1] to obtain 14.3 g of methyl 6-fluoro-3-methoxy-2-pyrazinecarboxylate as a solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[CH:3]=2)=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2ccncc2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccncc2)c1

Procedure:
Using the same method as in Example 1-(ii), 4-(3-aminophenyl)pyridine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 82%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[CH2:23][N:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36](F)([F:38])[F:37])[CH:30]=2)[N:26]=[C:25]1[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)C1C=CC=CC=1>C1COCC1>[F:38][CH:36]([F:37])[C:31]1[CH:30]=[C:29]([C:27]2[N:26]=[C:25]([CH:40]3[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]3)[N:24]([CH2:23][C@H:18]3[CH2:19][CH2:20][CH2:21][CH2:22][N:17]3[CH3:15])[CH:28]=2)[CH:34]=[CH:33][C:32]=1[F:35]
Reactant: O=C(OCc1ccccc1)N1CCCC[C@@H]1Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC[C@@H]1Cn1cc(-c2ccc(F)c(C(F)F)c2)nc1C1CCNCC1

Procedure:
To a suspension of Lithium aluminium hydride (0.638 g, 0.0168 mol, 5.0 eq) in 20 mL THF at 0° C., add (R)-benzyl-2-((4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate in small portions (2.2 g, 0.0033 mol, 1.0 eq). Stir the reaction at RT for 4 hours. After completion, cool the reaction and quench with ice cold water followed by 10% NaOH solution and stir at RT and filter the resulting suspension through Celite®, wash the solid cake with EA. Dry the filtrate over anhydrous sodium sulfate and concentrate under reduced pressure to get 1.6 g of the title compound. (ES+): m/z 407 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.75 g, 8.88 mmol) in dichloroethane (80 mL) was added azetidine (0.6 g, 10.53 mmol) and the mixture was stirred at RT for 30 min. Sodium triacetoxyborohydride (3.9 g, 18.44 mmol) was added and the resulting solution was stirred at RT for 18 h. The reaction mixture was partitioned between water and DCM and the layers separated. The organic layer was extracted further with DCM and the combined aqueous layers were concentrated in vacuo. The resultant white semi-solid was suspended in DCM and a saturated aqueous solution of NaHCO3 was added. The layers were thoroughly mixed, the organic layer isolated and the aqueous layer further extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.0 g, 95%). BOC-deprotection of 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.67 mmol) using TFA:DCM (1:4) gave the title compound as a yellow oil (185 mg, 79%)
Reaction SMILES: [C:1]([C:4]1[C:5]([F:23])=[C:6]([Cl:22])[C:7]([N:14]2[CH2:19][C@H:18]([CH3:20])[O:17][C@H:16]([CH3:21])[CH2:15]2)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].Cl.[NH2:25][OH:26]>CO.N1C=CC=CC=1>[Cl:22][C:6]1[C:7]([N:14]2[CH2:19][C@H:18]([CH3:20])[O:17][C@H:16]([CH3:21])[CH2:15]2)=[C:8]([CH:13]=[C:4]([C:1](=[N:25][OH:26])[CH3:2])[C:5]=1[F:23])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(C)=NO)c(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 5-acetyl-3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluorobenzoate (Intermediate 107, 800 mg, 2.32 mmol) in methanol:Pyridine (1:1, 6 mL) was added hydroxylamine hydrochloride (223 mg, 3.48 mmol) and the mixture was stirred at room temperature for 12 hours. Solvents were removed under vacuum and the residue was subjected to silica gel column chromatography using a gradient of ethyl acetate in pet. ether to give title compound. Yield: 700 mg (87%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[N:13][CH:14]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cncc(CO)c2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cncc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-3-yl]-methanol (195 mg, 1.00 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.18 mL, 1.29 mmol) followed by DMAP (12 mg, 0.10 mmol) and Ms-Cl (0.10 mL, 1.26 mmol). After stirring at 0° C. for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.66 min; [M+H]+=274.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[C:22]1[C:26]([NH2:27])=[CH:25][NH:24][N:23]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][C:26]3[C:22]([C:16]4[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=4[CH3:14])=[N:23][NH:24][CH:25]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cc1ccc(C)c(-c2n[nH]cc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3ccc(Cl)nc23)c1
Reaction time: 14 h

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (400.4 mg, 1.853 mmol, 1.16 equiv) in dichloromethane (6 mL) was added 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine (300.0 mg, 1.602 mmol, 1.0 equiv) and triethylamine (0.70 mL, 5.0 mmol, 3.1 equiv) at room temperature. After 14 hours, the reaction mixture was partitioned between dichloromethane and half-saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic portions are dried over magnesium sulfate, filtered, and concentrated to yield 5-chloro-N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=367.1.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[N+:23]([O-])=O)=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[NH2:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccc(C#N)cc3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Zinc dust, 0.4 g (5.3 mmol) was added portionwise to a reaction flask containing a stirred mixture (10 min) of 1,5-bis-(4-cyano-phenoxy)-2-nitrobenzene 1.5 g (4.2 mmol) and 0.085 g (0.08 mmol) of ammonium chloride dissolved in 25 ml of methanol. The reaction mixture was allowed to stir for 1 h at RT. Reaction mixture was filtered through celite and the filtrate was concentrated to afford a brown viscous residue which was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford an oily residue, which was purified by column chromatography using chloroform-ethyl acetate (10:1) to afford 1.3 g of the required product. 1H NMR (DMSO-d6): δ 5.10 (2H, brs), 6.85 (3H, m), 7.06 (4H, m), 7.80 (4H, m).