Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.Cl[C:20]([O:22][CH3:23])=[O:21]>O1CCCC1>[CH3:23][O:22][C:20]([C:11]1[N:10]([CH3:13])[N:9]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:12]=1)=[O:21]
Reactant: COC(=O)Cl
Reactant: Cc1ccc(C)n1-c1ccn(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(-n2c(C)ccc2C)nn1C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
A solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (Intermediate 7, 0.56 g, 3.21 mmol) (Intermediate 7) in tetrahydrofuran (26.8 mL) cooled to −78° C. was treated dropwise with a 2.5M solution of n-butyllithium in hexanes (1.44 mL, 3.60 mmol). The reaction was stirred at −78° C. for 1.5 h. After this time, the reaction was treated dropwise with methyl chloroformate (0.28 mL, 3.63 mmol). After this time, the cooling bath was removed. The reaction continued to stir for 1 h, at which time the reaction was concentrated in vacuo. The residue was then partitioned between water (100 mL) and diethyl ether (3×75 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 5-10% ethyl acetate/hexanes) afforded 5-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (0.33 g, 44%) as an off-white solid; ES+-HRMS m/e calcd for C12H15N3O2 [M+H+] 234.1237, found 234.1237.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O1CCCCC1[N:29]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[N:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>C(Cl)Cl.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.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:21]([C:31]2[NH:30][N:29]=[CH:33][CH:32]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 56.1, 4.0 g, 8.95 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.73 g, 13.42 mmol), Pd(PPh3)4 (0.517 g, 0.447 mmol), K3PO4 (5.70 g, 26.8 mmol) and toluene (45 mL) was stirred at 80° C. for 5 h under an argon atmosphere. The RM was filtered through Hyflo®, washed with EtOAc (100 mL) and the combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1) to give the protected intermediate, of which 1.5 g (3.02 mmol) was dissolved in DCM (20 mL), treated with TFA (2.32 mL, 30.2 mmol) and stirred for at RT for 76 h. The solvent was evaporated off under reduced pressure and the residue was treated with sat. aq. Na2CO3 (80 mL) and extracted with EtOAc. The combined extracts were washed with brine (50 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 40 g, n-hexane/EtOAc from 9:1 to 1:1) to give the title compound as beige crystals. UPLC-MS (Condition 2) tR=1.02 min, m/z=382.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 6.91 (s, 1H) 7.38 (d, J=8.99 Hz, 2H) 7.80-8.00 (m, 3H) 8.73 (d, J=2.35 Hz, 1H) 8.88 (d, J=2.74 Hz, 1H) 10.73 (s, 1H) 13.29-13.42 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[CH:5][CH:4]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC2CCCCO2)cc1
Yield: 99.9 %

Procedure:
In a manner similar to Preparation 5 stir 4-methoxyphenol (0.161 mol), 3,4-dihydro-2H-pyran (0.193 mol), CH2Cl2 (50 mL), p-TsOH (0.161 mol) at 0° C. for 10 minutes, then add triethylamine (1.77 mol). Evaporate, add diethyl ether (Et2O), and extractively work up to give 33.5 g (100%) of 2-(4-methoxyphenoxy)tetrahydro-2H-pyran as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.06-6.95 (m, 2H), 6.89-6.77 (m, 2H), 5.31 (t, J=3.3 Hz, 1H), 4.00-3.89 (m, 1H), 3.78 (s, 3H), 3.64-3.56 (m, 1H), 2.07-1.93 (m, 1H), 1.88-1.83 (m, 2H), 1.65 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 154.49, 151.09, 117.78, 114.49, 97.31, 62.11, 55.67, 30.50, 25.27, 18.95.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)[CH:14]([CH3:16])[CH3:15].[NH3:24]>C1(C)C=CC=CC=1>[NH2:24][C:13]([CH:14]([CH3:16])[CH3:15])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: N
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(N)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.8 g of p-toluenesulphonic acid×4 H2O are added to 500 g (3.16 mol) of ethyl isobutyrylacetate in 1,500 ml of toluene p.a., the mixture is saturated with ammonia gas while stirring at room temperature and allowed to stand overnight. It is then heated under reflux in a water separator and ammonia gas is continuously introduced until the calculated amount of water has separated (47 ml of water after reflux for 8 hours). The mixture is allowed to cool overnight, and the precipitate which has deposited is filtered off with suction and washed with toluene. The combined toluene phases are washed several times with water, dried using sodium sulphate, concentrated in vacuo and distilled in a high vacuum.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6].[C:13](C1NC=CN=1)(C1NC=CN=1)=[O:14].[Br:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:39]=1[C:33]1([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:32][C:31]2=[O:40]>C(Cl)Cl>[Br:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:39]=1[C:33]1([CH2:34][CH2:35][N:36]([C:13]([O:6][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=3[C:2]([F:11])([F:12])[F:1])=[O:14])[CH2:37][CH2:38]1)[CH2:32][C:31]2=[O:40]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C1CC2(CCNCC2)c2c(Br)cccc21
Reactant: OCc1ccccc1C(F)(F)F
Solvent: ClCCl
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To o-(trifluoromethyl)benzyl alcohol (35 mg, 0.20 mmol) in CH2Cl2 (4 mL) was added was a solution of carbonyl diimidazole (29 mg, 0.18 mmol) in CH2Cl2 (4 mL). The mixture was stirred at rt for 2 h. A 1-mL aliquot of the resulting solution (0.05 mmol) was added to a solution 7-bromospiro[indene-1,4′-piperidin]-3(2H)-one (14.5 mg, 0.05 mmol) in CH2Cl2 (1 mL). The mixture was stirred at rt for 16 h, concentrated, redissolved in MeCN (1 mL) and heated at 60° C. for 2 h. Prep HPLC afforded the title compound. LC-MS Method 1 tR=2.06, min, m/z=484, 482.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:28][NH:29][CH2:30][C@H:31]([C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:30][C@@H:31]([OH:32])[C:33]4[N:34]=[CH:35][CH:36]=[CH:37][N:38]=4)[CH3:28])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Reactant: CNC[C@@H](O)c1ncccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)C[C@@H](O)c2ncccn2)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A mixture of N-(4-fluorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (216 mg, 0.570 mmol), (1R)-2-(methylamino)-1-pyrimidin-2-ylethanol dihydrochloride (Preparation 104, 155 mg, 0.686 mmol) and diisopropylethylamine (600 μL, 3.44 mmol) in dry DMF (10.0 mL) was stirred at 60° C. for 20 hours. The solution was then diluted with water (75 mL). The resulting precipitate was collected by filtration and the collected solid was dried at 60° C. in vacuo, providing 209 mg of a tan solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:36])[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH2:31]([O:30][C:29](=[O:36])[NH:22][C:19]1[S:20][CH:21]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:18]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Cc1ncoc1C(=NOCc1csc(N)n1)c1ccccc1
Reactant: CCCCCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCOC(=O)Nc1nc(CON=C(c2ccccc2)c2ocnc2C)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (95 mg, 0.3 mmol) in dichloromethane (2 mL) were added pyridine (36 mg, 0.45 mmol) and after 15 min stirring pentyl carbonochloridoate (91 mg, 0.6 mmol). After stirring at room temperature for 4 h the mixture was passed through a cartridge filled with basic alumina and 1 g silica. After rinsing with dichloromethane the final compound was eluted with heptane/ethylacetate (1/1) to afford after purification on silica pentyl {4-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy) methyl]-1,3-thiazol-2-yl}carbamate (60 mg, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:33]3[O:32][C:36]4=[CH:37][CH:38]=[CH:39][C:40]4=[CH:35][CH:34]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3-c3ccc4cccc-4o3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 2-benzofuryl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=1)=[O:22].N1C=CC=CC=1>S(Cl)(Cl)=O.ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:2]=2[F:1])=[O:6])=[C:15]([C:21](=[O:22])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.3 %

Procedure:
A solution of 2-fluoro4-cyanobenzoic acid (1 g, 6.06 mmol) in thionyl chloride (5 ml) was refluxed for 2 hr. After concentration, the residue was dissolved in dichloromethane (5 ml). And a solution of the compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (1.2 g, 4.25 mmol) in dichloromethane (10 ml) and pyridine (1.47 ml, 18.18 mmol) were added. The mixture was stirred at r.t. overnight. The precipitate was filtered and washed with a little amount of dichloromethane to give N-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(2-fluoro-4-cyanophenyl)carboxamide (2.03 g, 78%). MS found for C20H11Cl2FN4O2 M+=429, (M+2)+=431.
Reaction SMILES: [I:1]I.[OH-].[Na+].[C:5]([S:9]([CH2:12][C@@H:13]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([NH:16][C@@H:17]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:18]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24])=[O:19])=[O:15])(=[O:11])=[O:10])([CH3:8])([CH3:7])[CH3:6]>CO.O>[C:5]([S:9]([CH2:12][C@@H:13]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([NH:16][C@@H:17]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][C:41]=1[I:1])[C:18]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:26][CH2:27]1)[OH:24])=[O:19])=[O:15])(=[O:11])=[O:10])([CH3:8])([CH3:6])[CH3:7]
Reactant: II
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1nc[nH]c1I)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 0.08 h

Procedure:
10.4 ml (2.08 mmol) of a 0.2N methanolic iodine solution and 2.4 ml (0.48 mmol) of 0.2N sodium hydroxide solution are simultaneously added dropwise at 0° while stirring to a mixture of 630 mg (1 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide and 20 ml (4 mmol) of 0.2N sodium hydroxide solution in 20 ml of methanol. The colourless reaction mixture is stirred at 0° for 5 minutes and thereafter at room temperature for 2.5 hours. Subsequently, the mixture is diluted with 25 ml of water and extracted twice with 80 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue (750 mg) is chromatographed using a 15:1 mixture of methylene chloride and methanol as the eluent. There are obtained 504 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-5-iodoimidazole-4-propionamide, MS: 757 (M+H)+, and 38 mg of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-2,5-iodoimidazole-4-propionamide, MS: 883 (M+H)+, each as a colourless solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[S:8].[Br:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>CC(C)=O>[BrH:9].[C:19]1([CH:10]2[S:8][C:2]3=[N:3][CH2:4][CH2:5][CH2:6][CH2:7][N:1]3[C:11]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: S=C1NCCCCN1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Solvent: CC(C)=O
Product: Br
Product: OC1(c2ccccc2)C(c2ccccc2)SC2=NCCCCN21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 2.6 g. portion of hexahydro-2H-1,3-diazepin-2-thione is dissolved in 150 ml. of acetone and clarified. A 5.5 g. portion of 2-bromo-2-phenylacetophenone is added and the solution is refluxed for one hour and then stirred at room temperature for 16 hours. The solid is collected, washed with acetone and dried in vacuo at 60° C., giving 6.5 g. of the desired product, m.p. 195°-197° C. (dec.).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]=1[CH3:14])=O.[N+]([O-])(O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.CC#N>C(O)(C(F)(F)F)=O>[CH3:13][N:9]1[C:8]([CH3:14])=[C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:32][CH:31]=3)[N:35]=2)[S:11][C:10]1=[O:12]
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Reactant: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: Cc1c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)sc(=O)n1C

Procedure:
This compound was prepared by condensation between 5-(3-dimethylamino-acryloyl)-3,4-dimethyl-3H-thiazol-2-one and N-[4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine nitrate. Pale solid. Anal. RP-HPLC: tR=10.9 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>97%). 1H-NMR (CDCl3) δ: 2.42 (m, 4H, CH2), 2.53 (s, 3H, CH3), 3.04 (m, 4H, CH2), 3.28 (s, 3H, CH3), 6.84 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 6.86 (d, 2H, J=9.0 Hz, Ph-H), 7.54 (d, 2H, J=9.0 Hz, Ph-H), 8.35 (d, 1H, J=5.5 Hz, pyrimidinyl-H), and 9.33 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH3:11][NH:12][CH:13](O)[CH3:14].[OH-:16].[Na+]>C1C=CC=CC=1>[OH:16][CH2:14][CH2:13][N:12]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:11]
Reactant: CNC(C)O
Reactant: COc1cccc(CCl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cccc(CN(C)CCO)c1

Procedure:
m-Methoxybenzyl chloride (25 g.) was added slowly to a hot stirred solution of methylaminoethanol (31 g.) in benzene (63 ml.). After heating on a steam-bath for 1 hour, the resulting mixture was cooled and treated with 5N-sodium hydroxide (50 ml.). The aqueous layer was separated and extracted with ether (100 ml.). The combined organic layers were washed with water, dried over anhydrous potassium carbonate, filtered and evaporated. The residue was distilled in vacuo to give N-2-hydroxyethyl-N-m-methoxybenzyl-N-methylamine as a colourless oil, b.p. 116°-118°/0.2 mm.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1.[Na+].[Cl-]>CN(C=O)C.[H][H]>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][N:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccccc1
Reactant: [H][H]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
Phenol (306 mg) was dissolved in dry DMF (5 mL) and subsequently, sodium hydride (60% in mineral oil, 130 mg) was added which resulted in strong hydrogen gas evolution. The mixture was then allowed to stir at RT for 30 minutes. Subsequently, 5-bromo-2-nitro-pyridine (600 mg) was added und the resulting mixture was stirred at 60° C. for 12 hours. The reaction mixture was poured into ice water and the aqueous phase was saturated with NaCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give 2-nitro-5-phenoxy-pyridine as a light yellow foam (267 mg). MS (EI): 216.1 (M+).
Reaction SMILES: [C:1](=O)([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[O:2]C1C=CC=CC=1.[NH2:21][NH2:22]>CO>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:2])[NH:21][NH2:22]
Reactant: NN
Reactant: CC1(C)CC(OC(=O)Oc2ccccc2)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(OC(=O)NN)CC(C)(C)N1
Reaction time: 3 h

Procedure:
Into a 300 ml 3-neck flask were added 16.9 grams (0.061 mole) of phenyl 2,2,6,6-tetramethyl-4-piperidinyl carbonate and 100 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 3.4 grams (0.067 mole) of 64% aqueous hydrazine. The hydrazine was added slowly to the stirring methanol solution at room temperature. There was a slight exotherm. The reaction mixture was stirred for 3 hours and then allowed to stand overnight (i.e. for 20 hours) at room temperature. The next day, the methanol was stripped off on a rotating evaporator and the liquid residue dissolved in 150 ml of MtBE and washed with 50 ml of 10% NaOH which was saturated with salt. The MtBE solution was dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue, a very viscous liquid, was slurried in 20 ml of hexane until a solid formed. The solid was filtered off and air dried. The product weighed 6.4 grams (49% crude yield), had a melting point of 93°-94° C. and gas chromatography indicated it was about 95% pure. The infrared scan contained a strong carbonyl peak at 1710 cm-1 and a moderate carbonyl peak at 1625 cm-1. An additional 5.26 grams of crude product was recovered by extracting the aqueous wash with methylene chloride and stripping off the solvent.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([CH2:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][N:26]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[C:35]=2[Cl:44])[C:27]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[CH:3]=1.[OH-].[Na+]>CO>[ClH:44].[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][N:26]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[C:35]=2[Cl:44])[C:27]([CH2:29][CH2:30][CH:31]([CH3:32])[CH3:33])=[O:28])[CH:3]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1Cc1c(CN(C(=O)CCC(C)C)c2ccc(OC)c(OC)c2Cl)nc2ccccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N(Cc2nc3ccccn3c2Cc2cc(Br)ccc2OCC(=O)O)C(=O)CCC(C)C)c(Cl)c1OC
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.3 %

Procedure:
A solution of 240 mg (0.35 mmol) ethyl 2-{4-bromo-2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}(imidazolo[1,2-a]pyridin-3-yl))methyl]phenoxy}acetate in 4 mL methanol is treated with 55 mg (1.3 mmol) sodium hydroxide. The solution is stirred at room temperature for 3 hr and the solvent removed in vacuo. The residue is redissolved in 5 mL dichloromethane and acidified with 1M hydrochloric acid in ether. The solvent is removed in vacuo and 5 mL dichloromethane is added. The solution is filtered through Celite and the filtrate treated with excess IM hydrochloric acid in ether. The solvent is removed in vacuo and the residue triturated with ether to give 133 mg (58%) 2-{4-bromo-2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}(imidazolo[1,2-a]pyridin-3-yl))methyl]phenoxy}acetic acid mono hydrochloride. Mass Spec m/z (M++1) 658.