Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:13]2=[O:30])=[CH:8][CH:7]=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:19][CH:18]=3)[C:13]2=[O:30])=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCOc1ccc(N2CCN(c3ccc(Oc4ccccc4)cc3)C2=O)cc1
Reaction time: 8 h

Procedure:
Palladium(II) hydroxide (20 mg) was added to a solution of 1-(4-(2-dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in ethanol (5 mL) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was shaken for 8 hours. The catalyst was filtered off and the filtrate was concentrated. The product with the molecular weight of 417.51 (C25H27N3O3); MS (ESI): 418 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C@@H:30]([CH2:32][OH:33])[CH3:31]>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:29][C@H:30]([CH3:31])[CH2:32][OH:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(C)(=O)=O
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(SCc2ccccc2)n1
Temperature: 80 °C

Procedure:
To a solution of the product of step i) (21.2 g) in NMP (40 ml) was added (R)-alaninol (10 g) and the whole heated at 80° C. for 4 h. The reaction mixture was then partitioned between EtOAc and H2O. The organic phase was collected, dried (MgSO4) and the solvent removed to leave a pale yellow oil. This was purified by silica gel chromatography (60:40 iso-hexane EtOAc) to afford the subtitle compound as a colourless oil. Yield: 13.9 g.
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)CC>[Cu].C(OCC)(=O)C>[Cl:11][C:10]1[CH:2]=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: [Cu]
Solvent: CCC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with 2,3-dichlorobenzoic acid (4.55 g, 23.8 mmol) and copper powder (3.02 g, 47.6 mmol). Propionic acid (30 mL) was added, and the resulting mixture was heated to 130°-135° C. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (1 hour). Ethyl acetate (30 mL) was added as the reaction mixture was cooled to room temperature. The resulting mixture was filtered, and the solids were washed with ethyl acetate. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting yellow organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum to afford 3.55 g of 3-chlorobenzoic acid as a pale yellow solid, mp 153°-153.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[SH:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:31][CH3:32])[N:4]=[C:3]([CH2:2][S:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1)[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: Cn1ccnc1S
Reactant: CCCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A mixture of propyl 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.3 g), 2-mercapto-1-methylimidazole (821 mg), potassium carbonate (1.08 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (7:3, v/v), propyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2- [(1-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylate (1.77 g, 51%) was obtained and recrystallized from acetone/isopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[CH:12]=1.[Li]CCCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[C:12]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2ccccc2F)nn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccc2F)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (1.44 g, 8.1 mmol) in THF (41 mL) was added n-BuLi (1.6 M in hexane, 6.10 mL, 9.8 mmol) dropwise at −75° C. under Argon. The resulted orange solution was stirred at −75° C. for 1 h, then DMF (0.82 mL, 10.6 mmol) was added dropwise at −75° C. and the reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.45 g, 87%) as an off white solid. MS: m/e=206.0 [M]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][CH2:8]Cl)=[CH:2]1.[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]=2[N:20]=1>C(Cl)(Cl)Cl>[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][N:16]([CH2:8][CH:7]=[CH:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH2:17][CH2:18][C:19]=2[N:20]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccoc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccoc1)CC2
Yield: 30 %

Procedure:
Prepared from 3-(3-furyl)allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 30% of theory, Melting point: 130°-136° C.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:13])=[C:7]([O:14][CH3:15])[CH:6]=1)=O.CCOC(C)=O.C([O-])(O)=O.[Na+].[CH:28]([NH2:30])=[O:29]>>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([C:3]2[N:30]=[CH:28][O:29][C:2]=2[CH3:16])=[CH:6][C:7]=1[O:14][CH3:15]
Reactant: COc1cc(C(=O)C(C)Br)cc(OC)c1Br
Reactant: NC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncoc2C)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one (1.07 g, 3.04 mmol) in formamide (10 mL) in an oven-dried flask under argon was heated at 110° C. for 16 hrs. After cooling to room temp, EtOAc and saturated aqueous NaHCO3 were carefully added and the mixture was stirred for 15 minutes. It was then extracted with EtOAc twice and the combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. Purification by chromatography (30% EtOAc-hexanes) gave 4-(4-bromo-3,5-dimethoxyphenyl)-5-methyloxazole as a yellow solid (0.496 g, 55% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].N1C=CN=C1.[CH3:16][Si:17]([CH3:23])([C:19]([CH3:22])([CH3:21])[CH3:20])Cl>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][Si:17]([CH3:23])([CH3:16])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Yield: 88 %

Procedure:
One operates as in preparation 13 starting with 3.97 g of 8-bromooctanol, 19 cm3 of dimethylformamide, 1.55 g of imidazole and 3.32 g of dimethyl tertbutyl chlorosilane. After chromatography on silica (eluant: cyclohexane-toluene 8-2), one obtains 5.4 g of the expected product.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].Cl[CH:6]([O:8][C:9]([O:11][CH:12]([CH3:20])[CH2:13][NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:10])[CH3:7]>C1COCC1>[C:1]([O:4][CH:6]([O:8][C:9]([O:11][CH:12]([CH3:20])[CH2:13][NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:10])[CH3:7])(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)NCC(C)OC(=O)OC(C)Cl
Reactant: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCC(C)OC(=O)OC(C)OC(C)=O
Reaction time: 96 h
Yield: 24.8 %

Procedure:
A THF solution (100 ml) of TBA acetate (6.93 g, 23 mmol) prepared by freeze-drying an aqueous solution of equimolar TBA-OH and acetic acid, was added to a stirred solution of N-[2-(1-chloroethoxycarbonyloxy)propyl]methacrylamide (4.736 g, 19 mmol) from Example It(i) above in THF (100 ml) at room temperature. Following stirring for 4 days the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with water (5×20 ml ). The organic phase was dried (MgSO4 ) and the solvent removed under reduced pressure. Flash chromatography (silicagel, hexane/ethyl acetate (3:4)) gave 1.29 g (25%) of the title product.
Reaction SMILES: [H-].[Na+].C(O/[N:7]=[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])\[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=1[OH:18])(=O)C.N#N.O>CN(C=O)C>[Cl:17][C:11]1[C:10]2[O:18][N:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[C:9]=2[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(/C(=N\OC(C)=O)c2cccc(F)c2F)c(O)c1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3cccc(F)c3F)noc2c1Cl
Temperature: 45 °C

Procedure:
To a mixture of 1.4 g of NaH in 200 ml of DMF, a solution of 19 g of E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime in 200 ml of DMF is added dropwise in an atmosphere of N2. The mixture is stirred for one half hour and then warmed at 45° C. for one half hour. Water is added and a product precipitates and is filtered and dried giving 7-chloro-3-(2,3-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 184°-189° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1COCC1.Cl.[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])[CH3:20].C(=O)([O-])O.[Na+]>O>[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1)=[O:25])[CH3:20]
Reactant: CCSc1ccccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cnc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of 3-amino-5-trifluoromethylpyridin-2-ol (0.75 g) and THF (5 ml), 2-ethylsulfanylbenzoic acid hydrochloride (0.93 g) was added under ice-cooling, heated to room temperature, and stirred for 2 hours. After the mixture was allowed to stand overnight, the mixture was heated to 50° C., and stirred with heating for 6 hours. To the mixture, sodium hydrogen carbonate (0.35 g) was added, and stirred with heating for further 2.5 hours. After the mixture was allowed to stand, water was poured thereinto, and the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 1.37 g of 2-ethylsulfanyl-N-(2-hydroxy-5-trifluoromethylpyridin-3-yl)-benzamide (Compound (1B)-506).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3([O:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][O:14]3)[CH2:11]2)[CH2:7]1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH:8]2[CH:12]([CH2:11][C:10]3([O:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][O:14]3)[CH2:9]2)[CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C=C1CC2CC3(CC2C1)OCC(C)(C)CO3
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CC2CC3(CC2C1)OCC(C)(C)CO3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product of Step 2 (400 mg, 1.359 mmol) and 10% Pd—C—50% wet (85 mg, 0.799 mmol) in EtOAc (8.0 mL) was stirred 16 hrs at room temperature under a hydrogen atmosphere. The catalyst was then filtered off and the volatiles were removed under reduced pressure to give ethyl[5,5-dimethylhexahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′-yl]acetate as a colorless oil. MS ESI: [M+Na]+ m/z 297.7.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4]([Br:17])[N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC.N#N>CN(C=O)C.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>[Br:17][C:4]1[N:3]=[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(Br)nc(-c3ccccn3)c2s1
Temperature: 80 °C

Procedure:
A solution of 1-(4,6-dibromothiazolo[5,4-c]pyridin-2-yl)-3-ethylurea (Intermediate 8) (0.25 g, 0.65 mmol) and 2-(tributylstannyl)pyridine (0.21 mL, 0.65 mmol) in DMF (10 mL) was purged with N2 for 15 min followed by addition of tetrakis(triphenylphosphine)palladium (0) (0.075 g, 0.065 mmol). The reaction mixture was again degassed by purging N2 for 15 min then heated to 80° C. for 16 h. The solvent was distilled under reduced pressure, water (25 mL) added and extracted with EtOAc (3×100 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (100-200M, 2.50% MeOH-DCM) to afford the desired product that was finally triturated with ether (0.10 g, 40%). The regio chemistry was ascertained by NOE experiments.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]#[N:5].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>ClCCl>[C:4]([C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][O:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])#[N:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC(C#N)(CO)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(C#N)(COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution containing 4.24 g (19.5 mmol) of 2-hydroxymethyl-2-phenyl-heptanenitrile in 25 mL of dichloromethane are added 4.1 g (21.5 mmol) of p-toluenesulfonyl chloride and 6 mL of triethylamine. The reaction medium is stirred for 15 hours at room temperature and then treated with 1N hydrochloric acid solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated under pressure. A yellow oil is obtained and precipitated from a 9/1 heptane/diisopropyl ether mixture. The precipitate formed is filtered off and rinsed with diisopropyl ether. 5.26 g in the form of a beige-coloured powder are obtained in a yield of 72%.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH2:17][CH2:18][N:19]=2)=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:20]O>S(Cl)(Cl)=O>[CH3:20][O:6][C:5](=[O:7])[CH:4]([NH2:3])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][CH2:18][CH2:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: CO
Reactant: NC(Cc1ccc(C2=NCCN2)cc1)C(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(C2=NCCN2)cc1

Procedure:
(±)-2-Amino-3-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-propionic acid dihydrochloride (0.50 g, 1.6 mmol) was placed in thionyl chloride (1 mL) and methanol (25 mL). The mixture was heated to reflux for 30 minutes, at which time more thionyl chloride (3 mL) and methanol (75 mL) were added. After another 3 hours at reflux, the solution was concentrated, the residue was dissolved in a small amount of methanol and ethyl acetate was added to induce precipitation. The solid was collected and dried (0.40 g, mp 230° C. dec.).
Reaction SMILES: [F:1][C:2]1[C:3]([C@H:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:32]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10](=[O:21])[NH:9][C@H:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=2)=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
To a solution of (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-hydroxy-3-nitrobenzamide (83 mg, 0.191 mmol) and DCM (5 mL) were added acetic anhydride (0.2 mL, 2.120 mmol) and DIPEA (0.15 mL, 0.861 mmol). After stirring for 45 min, the reaction was quenched with water and after stirring for 3 days, the aqueous solution was filtered to give the title compound as a yellow solid. The resulting product was used in the next step without further purification. MS (ESI pos. ion) m/z: 478.1 (M+H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:15][CH2:14]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl ethylamine (6.5 ml) in dry THF (25 ml) cooled the contents to about −10° C. then N-butyl lithium (1.6 M, 23 ml) was added drop wise under nitrogen atmosphere and maintain the same temperature for about 45 minutes and cooled to about −75° C. for about 15 minutes then 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (step 1, 5 g) in THF (30 ml) was added and stirred for about 30 minutes then increase the reaction temperature to −35° C. and stirred for about 45 minutes and again cooled to −75° C. then benzyl bromide (3.5 g in 20 ml THF) was added drop wise and slowly allowed the reaction to room temperature and stirred the reaction for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with sat. NaHCO3 followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound as a light yellow colour liquid. 1H NMR (300 MHz, CDCl3): 1.16-1.18 (t, 3H); 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, 1H); 2.82 (s, 2H); 2.92-2.95 (m, 1H); 3.46-3.52 (m, 3H); 4.09-4.11 (m, 2H); 7.03-7.06 (m, 2H); 7.23-7.24 (m, 3H); ES Mass: 370 (100%) [M+Na].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1.[I:20]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:20][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1I
Temperature: 25 °C

Procedure:
Tert-butyl 3-(4-methoxyphenyl)-2,2-dimethylpropanoate (1.45 g, 5.48 mmol) was dissolved in ethanol (55 mL). Iodine (1.392 g, 5.48 mmol) and silver sulfate (1.710 g, 5.48 mmol) were added, and the reaction was stirred vigorously at room temperature, protected from light, for 1 hr. The reaction was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with sodium bisulfite (2×60 mL), water (70 mL), and brine (70 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes to afford tert-butyl 3-(3-iodo-4-methoxyphenyl)-2,2-dimethylpropanoate. 1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J=1.8 Hz, 1H), 7.08 (dd, J=8.4, 1.9 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 2.71 (s, 2H), 1.44 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:41][CH2:42][O:43][CH3:44]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:41][CH2:42][O:43][CH3:44]
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(O)c(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 3-(3-fluoro-4-hydroxyphenyl)-5-nitro-1-trityl-1H-indazole 3AW (3 g, 5.82 mmol) in DMF (40 mL) was added CsCO3 (2.85 g, 8.75 mmol) and bromoethylmethyl ether (711 μL, 7.57 mmol). The resulting mixture was stirred at rt for overnight then diluted with EtOAc (300 mL), which was washed with brine, dried (MgSO4) and concentrated. Chromatograph on silica gel (2:1, hexanes/EtOAc) gave 3-[3-fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 4AW (2.8 g).