Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-])=[O:15].C(O)(=O)C>CO.O>[OH:15][N:14]=[C:17]1[CH:22]=[CH:21][C:20](=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:12]#[N:13])[CH:19]=[CH:18]1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
80 g of KOH are dissolved in 400 ml of methanol and heated up to 55° C. To the solution are added 50 ml (0.37 mol) of p-methoxyphenylacetonitrile, followed by 35 ml (0.34 mol) of nitrobenzene. The reaction mixture is stirred at 55° C. for 4 hrs. After cooling, 500 ml of water are added with stirring. The resulting solution is acidified by addition of 110 ml of acetic acid in 100 ml of water, leading to a precipitate. The mixture is then filtered, and the solid is washed with a mixture of methanol and water. The crude product is dried in air and recrystallized from 500 ml of ethyl acetate. 45.6 g (53%) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(4-methoxyphenyl)-acetonitrile are obtained in the form of orange crystals having a melting point of 161-163° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C.C(Cl)Cl>[CH2:22]([O:21][C:19]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17])=[O:20])[CH3:23]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1c(C)n(C)ccc1=O
Reaction time: 0.25 h

Procedure:
With stirring, 11.2 ml of triethylamine are added at room temperature to a suspension of 5.56 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 100 ml of acetonitrile and 100 ml of methylene chloride, followed by the addition of 7.64 ml of ethyl chloroformate. Within 15 minutes a complete solution forms and, after a further 45 minutes, the volatile constituents are removed by evaporation under reduced pressure. The residue is dried under a high vacuum and the unreacted starting material is crystallised from ethyl acetate. 3-Ethoxycarbonyloxy-1,2-dimethyl-4(1H)-pyridinone is obtained from the mother liquor in the form of a yellow foam with a melting point of 113°-115° C.; thin-layer chromatogram: Rf=0.05 (7:3 mixture of methylene chloride and acetone), 0.10 (9:1 mixture of methylene chloride and isopropanol, 0.20 (9:1 mixture of methylene chloride and methanol), and 0.35 (4:1 mixture of methylene chloride and methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[CH3:18][Zn]Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([CH3:18])[N:8]=[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc(N(CC)CC)c1
Reactant: C[Zn]Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C)nc(N(CC)CC)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-6-diethylamino-isonicotinic acid ethyl ester (10.1 g, 31.6 mmol) in dioxane (120 mL), Pd(dppf) (262 mg, 0.322 mmol) is added. MeZnCl (8.40 g, 72.4 mmol) is added dropwise to the mixture before it is stirred at 75° C. for 18 h. The mixture is carefully diluted with water, then extracted with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-diethylamino-6-methyl-isonicotinic acid ethyl ester (6.39 g, containing some methyl ester) as a pale yellow oil; LC-MS: tR=0.70 min, [M+H]+=237.11.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][NH:12][CH3:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].O>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:21](=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CNCc1c(C)[nH]c2ccccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12

Procedure:
To a solution of 2-methyl-3-(methylaminomethyl)indole (1.5 g, 8.6 mmole) and triethylamine (1.7 g, 17.3 mmole) in CH2Cl2 at 5° C. under a nitrogen atmosphere was added acryloyl chloride (0.86 g, 9.48 mmole). After 1 hr the reaction solution was poured into H2O (100 mL) and the layers were separated. The organic fraction was washed with H2O (100 mL) followed by brine and then dried over Na2SO4. Concentration under vacuum gave the title compound as an orange oil which solidified under high vacuum: MS (ES) m/e 457 (2M+H)+. This material was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13](OC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[C:25]1([N:31]2[C:35]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:34](=[O:41])[NH:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(C)=[O:44]>>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][C:12](=[O:44])[CH2:13][N:38]3[CH2:37][CH2:36][C:35]4([N:31]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:32][NH:33][C:34]4=[O:41])[CH2:40][CH2:39]3)[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: CS(C)=O
Product: O=C(CN1CCC2(CC1)C(=O)NCN2c1ccccc1)Cn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.212 g (0.9165 mmol) of 1-phenyl-1,3,8-triazaspiro[4.5]decane-4-one were placed into a 10 ml round bottom flask equipped with a magnetic stirring bar. 2 ml of dimethylsulfoxide (dried over barium oxide) was added and the solution was stirred in a closed flask at room temperature for 20 hours. The reaction was allowed to proceed overnight to ensure completion. The solvent was removed with vacuum using gentle heat (approximately 45 deg.). 10 ml ethyl acetate was added to the stirring residue (oil) and a copious white precipitate formed immediately. The solution was stirred for 30 minutes to ensure homogeneity. Upon filtration, washing with ethyl acetate, and drying, 345 mg of a free flowing white solid, 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-(1-phenyl-4-oxo-1,3,8-triazaspiro[4.5]dec-8-yl)propanone (AIT-0098) was obtained. Yield: 90%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17].[N:18]([O-:20])=[O:19].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(OCCCCl)c(OC)c1
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 14.0 of the above-obtained solution mainly containing methyl 4-(3-chloropropoxy)-3-methoxybenzoate, 0.20 g (2.60 mmol) of sodium nitrite, and 17.5 mL of acetic acid. The resulting mixture was heated to 40-50° C. under stirring. To the reaction mixture was dropwise added slowly 22.4 g (215.2 mmol) of nitric acid (60 wt. %), and the mixture was kept at the same temperature for 2 hours. After the reaction was complete, 42 mL of water was added to the reaction mixture. Then, the organic portion was separated and washed with warm water. Analysis of the organic portion by high performance liquid chromatography (absolute quantitative analysis) indicated that 15.7 g (reaction yield: 96.2%) of methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate was produced.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22])[CH3:29]
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, brown solid, MS: m/e=376.3 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and ethyl bromoacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ncccn1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ncccn1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
A mixture of 4-bromobenzene sulfonyl chloride (3.0 g, 11.74 mmol) and 2-aminopyrimidine (1.17 g, 12.3 mmol, 1.05 eq) in anhydrous pyridine (23 mL) was stirred at 50° C. for 17 hours. The reaction was quenched with 2N aqueous hydrochloric acid (100 mL) and the resultant reaction mixture was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (1×100 mL) and brine (1×100 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure. Recrystallization from ethyl acetate-dichloromethane gave the desired product as a white solid (2.95 g, 80%). LC-MS (ES MH+=314/316); TLC (Rf=0.42, 75% ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[C:4]([CH3:27])[CH:3]=1>C1COCC1.CO.[Pt](=O)=O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-fluoro-2-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (303 mg) in THF (dry) (30 mL) and MeOH (30 ml) and the mixture was stirred at 50° C. under hydrogen for 4 hr. The starting material was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and recovered. Platinum(IV) oxide (30 mg) was added to a solution of the purified starting material in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from MeCN/IPE to give the title compound (115 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]([F:25])([F:24])[F:23]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:19])=[O:20])=[CH:14][C:13]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.O[CH2:35][CH2:36][C@@H:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:38]([O:40][CH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]>C(Cl)Cl>[Br:1][CH2:35][CH2:36][C@@H:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:38]([O:40][CH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](CCBr)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
To a slurry of N-bromo succinimide (1.86 g, 10.4 mmol) in DCM (16.2 ml) was added a solution of triphenyl phosphine (2.56 g, 9.74 mmol) in DCM (7.2 ml). The solution was stirred for a further 5 minutes after addition. Pyridine (338 μl, 4.18 mmol) was added, followed by a solution of cyclopentyl(2R)-4-hydroxy-2-[(tert-butoxycarbonyl)amino]butanoate (1.0 g, 3.48 mmol) in DCM (8.8 ml). The solution was stirred for 18 hrs, concentrated in vacuo and the residual solvent azeotroped with toluene (3×16 ml). The residue was triturated with diethyl ether (10 ml) and ethyl acetate:heptane (1:9, 2×10 ml). The combined ether and heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9-2:8) to provide 1.02 g (84% yield) of title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]#[N:14].[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH:22]=O.[OH-].[Na+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13]([NH2:14])=[N:15][C:16]2[C:17]([CH:22]=1)=[CH:18][N:19]=[CH:20][CH:21]=2
Reactant: N#CCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccncc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc2ccncc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 23.4 %

Procedure:
A solution of 2,6-dichloro-3-nitrophenyl-acetonitrile (1.02 g, 4.42 mmol), 4-amino-pyridine-3-carbaldehyde (0.4 g, 3.28 mmol) and NaOH (52 mg, 1.31 mmol) in EtOH (2.0 mL) is heated to 105° C. for 24 hours. The reaction mixture is diluted with EtOAc (50 ml) and washed with saturated K2CO3 and brine. The organic layer is dried, filtered and concentrated to give crude product. Flash silica gel column purification eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (100/6) affords the titled intermediate as a solid (257 mg, 23.4%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[I:34])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[I:34])[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)c1ccccc1I
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccccc3I)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.083 g, 0.299 mmol) was reacted with N-(2-azidoethyl)-2-iodobenzamide (0.095 g, 0.299 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2-iodobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.74 (d, 2H), δ 7.57 (t, 1H), δ 7.36 (s, 1H), δ 7.22 (s, 2H0, δ 6.97 (m, 1H0, δ 6.39 (s, 1H), δ 5.97 (s, 2H), δ 4.48 (t, 2H0, δ 3.85 (m, 2H0, δ 2.44 (t, 2H), δ 2.18 (t, 2H), δ 1.45 (m, 13H, δ 1.18 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.3, 150.4, 149.5, 148.2, 141.8, 139.9, 138.7, 131.3, 128.4, 128.3, 122.3, 106.5, 92.8, 84.9, 49.2, 40.5, 29.2, 28.9, 28.3, 28.2, 28.0, 25.5 ppm; HRMS (ESI) calcd for C24H32N7O3(M+) 593.1611, found 593.1603, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-iodobenzamide hydrochloride (0.125 g, 79% yield). 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), δ 7.88*d, 1H), δ 7.45 (t, 1H), δ 7.34 (d, 1H), δ 7.15 (t, 1H), δ 6.47 (s, 1H), δ 4.78 (s, 2H), δ 3.99 (s, 2H), δ 2.83 (s, 2H), δ 2.44 (t, 2H), δ 1.76 (s, 2H), δ 1.64 (s, 2H), δ 1.29 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 171.6, 159.2, 147.3, 142.1, 139.8, 131.2, 128.2, 127.7, 124.4, 92.1, 52.2, 40.8, 39.4, 31.2, 28.3, 28.1, 27.7, 24.1, 20.9, 15.9, 10.7 ppm; HRMS (ESI) calcd for C19H24IN7O (M+) 493.1087, found 493.1085.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1.O1CCCC1>[C].[Pd].CO>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1
Reactant: COC(=O)/C=C/c1ccc(OC2Cc3ccccc3C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
A mixture of methyl (E)-3-[4-[(2,3-dihydro-1H-inden-2-yl)oxy]phenyl]-2-propenoate (0.76 g, 2.6 mmol), tetrahydrofuran (10 mL), methanol (5 mL) and 10% palladium carbon (50% water-containing product, 0.10 g) was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-methanol to give the title compound (0.85 g, yield 89%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH2:21])=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([Br:22])=[CH:24][CH:25]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a stirred solution of 6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylamine (3.0 g, 10.6 mmol) in 30 ml of dry pyridine, at 0° C., under argon atmosphere, was added portionwise 4-bromo-benzoyl chloride (2.32 g, 10.6 mmol). The reaction mixture was allowed to warm to r.t. under stirring overnight then evaporated to dryness. The residue was treated with 50 ml of MeOH and 25 ml of 2N NaOH and stirred at r.t. for 1 h. The mixture was concentrated to ca. 10 ml by rotary evaporation, diluted with 200 ml of water, stirred for 15 min at r.t. and the suspended solid filtered and washed with water. After drying under vacuum, the crude solid was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Biotage SNAP 100 g) using DCM as eluant A and DCM/MeOH 9:1 as eluant B. Elution with a gradient from A/B 100:0 to 70:30 over 25 CV gave a pink solid that was triturated with EtOAc (50 ml), filtered, washed with EtOAc and dried affording 3.01 g (yield: 61%) of the title compound as a whitish solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@:13]3([CH3:35])[CH2:17][CH2:16][CH2:15][N:14]3C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.N1CCCCC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C@:13]3([CH3:35])[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@]1(c2ncc(-c3ccc(Br)cc3)[nH]2)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C[C@@]1(c2ncc(-c3ccc(Br)cc3)[nH]2)CCCN1
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To (S)-(9H-fluoren-9-yl)methyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (intermediate LS32; 329 mg; 0.62 mmol) in 3 mL DMF was added 1.5 mL piperidine. The reaction mixture was concentrated via a nitrogen stream overnight. The resultant residue was washed with hexane and passed through an MCX cartridge (Oasis; 6 g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 193 mg of (S)-5-(4-bromophenyl)-2-(2-methylpyrrolidin-2-yl)-1H-imidazole which was dissolved in 6 mL dichloromethane and combined with di-t-butyldicarbonate (413 mg; 1.89 mmol), DMAP (15 mg; 0.13 mmol) and TEA (0.17 mL; 1.30 mmol). After 48 h, the reaction mixture was concentrated and purified via chromatography on a Biotage system providing (S)-tert-butyl 5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-imidazole-1-carboxylate (intermediate LS33; 150 mg; 48%) as an off white solid. LC (Cond'n 5): RT=3.75 min; MS: Anal. Calcd. for [M+H]+ C24H32BrN3O4: 506.2. found 506.4
Reaction SMILES: [OH-].[NH4+:2].N.[CH2:4]([O:8][CH2:9][CH:10]=[CH2:11])[CH:5]1[O:7][CH2:6]1>>[CH2:9]([O:8][CH2:4][CH:5]([OH:7])[CH2:6][NH2:2])[CH:10]=[CH2:11]
Reactant: [NH4+]
Reactant: C=CCOCC1CO1
Agent: N
Agent: [OH-]
Product: C=CCOCC(O)CN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ammonium hydroxide (28%–30% (about 14.82 mol) of ammonia in water, 202 mL, 3 mol) was charged to a one liter, one-neck, round-bottom flask that was cooled in an ice bath. To the above solution allyl glycidyl ether (57.07 g, 0.5 mol) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature and stirred for two days after completion of the allyl glycidyl ether addition. 3-Allyloxy-2-hydroxy-propylamine was separated by distillation at 76° C.–82° C. under 0–1 mbar as a clear liquid (˜33 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:18]2([OH:23])[CH2:22][O:21][CH2:20][CH2:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:24]I>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:18]2([O:23][CH3:24])[CH2:22][O:21][CH2:20][CH2:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 1.3 g) was added to a solution of 4-(3-benzyloxy-5-fluorophenyl)-4-hydroxytetrahydrofuran (9.1 g) in tetrahydrofuran (30 ml). The mixture was stirred at room temperature for about 1 hour then cooled to about 0° C. with an ice-bath. Methyl iodide (4 ml) was added and the mixture stirred at room temperature for about 20 hours. The mixture was quenched with aqueous 10% hydrochloric acid (1 ml) and the tetrahydrofuran was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and evaporated to give 5.9 g of the title compound as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1>C(O)(=O)C.[C].[Pd]>[O:1]=[C:2]1[CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1
Reactant: COC(=O)c1ccc(C=C2CCOC2=O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC2CCOC2=O)cc1
Reaction time: 4 h

Procedure:
20.00 g (0.09 mol) of methyl 4-([2-oxodihydro-3(2H)-furanylidene]methyl)benzoate from Ex. V are suspended in 240 ml of glacial acetic acid, 2.00 g of 10% palladium-carbon are added and the mixture is hydrogenated at atmospheric pressure for 4 hours. The reaction mixture is filtered through kieselguhr and the solvent is distilled off under reduced pressure.