Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([B:11]([OH:13])[OH:12])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:15]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=1.CS(O)(=O)=O>O1CCOCC1>[OH:12][B:11]([OH:13])[C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:1][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(B(O)O)cc(C(=O)O)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Nc2nccc(C(F)(F)F)n2)cc(B(O)O)c1
Temperature: 110 °C

Procedure:
3-Amino-5-(dihydroxyboranyl)benzoic acid (205 mg, 1.13 mmol) was added to a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (203 mg, 1.11 mmol) in dioxane (3.00 mL). Methanesulfonic acid (70.0 μL, 1.08 mmol) was added to the reaction mixture and heated to reflux at 110° C. overnight. The reaction mixture was cooled to room temperature and the crude mixture was directly purified by reverse HPLC to afford 3-(dihydroxyboranyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}benzoic acid. MS APCI C12H10BF3N3O4 [M+H]328. found 328.
Reaction SMILES: C([O:9][CH2:10][C:11]#[C:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1.[CH3:21][NH:22][NH2:23].[OH-].[Li+]>C(O)C.O>[CH3:21][N:22]1[C:11]([CH2:10][OH:9])=[CH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:23]1
Reactant: O=C(C#CCOC(=O)c1ccccc1)c1ccccc1
Reactant: CNN
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccccc2)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of 4-oxo-4-phenylbut-2-yn-1-yl benzoate (1a) (750 mg, 2.84 mmol) and methylhydrazine (0.30 mL, 5.68 mmol) in ethanol (25 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was taken in a mixture of ethanol (3 mL) and tetrahydrofuran (9 mL). Lithium hydroxide (204 mg, 8.51 mmol), previously dissolved in water (3 mL) was added and the mixture was stirred at room temperature for 2 hours. Ethanol and tetrahydrofuran were removed under reduced pressure and the resulting aqueous layer was extracted with ethyl acetate (2×5 mL). The organic layer was successively washed with a saturated solution of sodium hydrogenocarbonate (5 mL) and brine (5 mL) before being dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 50/50) to provide (1-methyl-3-phenyl-1H-pyrazol-5-yl)methanol (1b) (341 mg, 1.81 mmol, 64%).
Reaction SMILES: O=C1CCC(=O)N1OC(=O)C1C=CC(CN(CCC(OC(C)(C)C)=O)[C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=CC=1.C(#N)C.[OH2:55]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:41])=[O:55])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Reactant: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCC(=O)O

Procedure:
4-{[(2-tert-Butoxycarbonylethyl)-(16-tert-butoxycarbonylhexadecanoyl)-amino]methyl}benzoic acid 2,5-dioxopyrrolidin-1-yl ester was reacted with A1,B1-diBoc desB30 insulin as described in general procedure B. The work up was similar using a gradient 28-48% acetonitrile/water containing 0.1% TFA.
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)Cl.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:1][C@@H:3]2[CH2:4][O:5]2)=[CH:14][CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Temperature: 45 °C
Reaction time: 96 h
Yield: 66.6 %

Procedure:
To a mixture of (R)-epichlorohydrin (12.4 g, 134 mmol) and 4-tert-butylphenol (10.0 g, 66.8 mmol) in acetone (50 ml) was added potassium carbonate (9.24 g, 66.8 mmol). The mixture was stirred at 45° C. for 96 hours. The reaction mixture was then concentrated to remove acetone. The residue was partitioned between ethyl acetate and water and extracted twice with ethyl acetate. The organic phases were combined and washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography (silica, methylene chloride/heptane) to give 9.18 g (67%) of (S)-2-(4-tert-butyl-phenoxymethyl)oxirane.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>C(Cl)Cl>[Cl:2][C:3]1[N:4]=[C:5]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH2:15][CH2:14]3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
To 2-Chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine HCl salt from General Procedure B-3 (50 mg) in dry DCM (3 ml) and triethylamine (3.5 equiv., 60 ul) was added ethanesulfonyl chloride (1.1 equiv., 10 ul) at 0° C. and the reaction mixture was allowed to warm up to room temperature overnight. Extraction with DCM/brine gave 2-chloro-6-(4-ethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a crude product (67 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and ether trituration gave 291. NMR (CDCl3): 1.40 (3H, t, J=7.4), 2.65-2.69 (4H, m), 3.00 (2H, q, J=7.4), 3.37-3.41 (4H, m), 3.86 (2H, s), 3.89-3.91 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+505.15 (100%)
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][C:25](=O)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][CH:25]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, pyrrolidine, glacial acetic acid and sodium triacetoxyborohydride. 1H NMR (400 MHz, DMSO-d6): δ 8.80 (t, J=5.82 Hz, 1H), 8.01-7.95 (m, 2H), 7.76-7.74 (m, 1H), 7.61-7.56 (m, 1H), 3.55-3.44 (m, 1H), 3.43-3.41 (m, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.74-2.66 (m, 1H), 2.64-2.50 (m, 1H), 2.27-2.24 (m, 1H), 2.10-1.99 (m, 5H), 1.89-1.76 (m, 6H), 1.75-1.68 (m, 2H), 1.33-1.29 (m, 5H), 1.27-1.24 (m, 2H). m/z: 476.2 [M+H]+
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[OH:4].Cl.N1C=CC=CC=1>>[NH:8]1[CH:9]=[C:5]([C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH:30]=2)([OH:4])[CH:2]([CH3:1])[CH3:41])[N:6]=[CH:7]1
Reactant: CC(C)C(O)(c1cccc(-c2ccccn2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccccn2)c1)c1c[nH]cn1
Yield: 68.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-methyl-1-[3-(2-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (527 mg), pyridine hydrochloride (205 mg), the title compound (197 mg) was obtained as colorless plate crystals.
Reaction SMILES: F[B-](F)(F)F.NC1O[C:9]([CH:20]([CH3:22])[CH3:21])=[N+:10]2[N:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=12.[C:23]1([C:29]#[C:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN1CCN(C)C1=O>[CH:20]([C:9]1[N:10]2[N:19]=[CH:18][C:17]3[C:12]([C:11]2=[C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:22])[CH3:21]
Reactant: CC(C)c1oc(N)c2c3ccccc3cn[n+]12
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Temperature: 40 °C
Yield: 40.1 %

Procedure:
A mixture of 1-amino-3-isopropyloxazolo[4,3-a]phthalazinium tetrafluoroborate (1.58 g) and ethyl phenylpropiolate (1.74 g) in 1,3-dimethyl-imidazolin-2-one (30 ml) was maintained at 40° C. for 19 hours and then the resulting brown solution was poured into water (200 ml), and the mixture was extracted with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (1:1 v/v; 3×200 ml). The extracts were combined, dried over magnesium sulphate, and evaporated, and the resulting residue was subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (19:1 v/v), to give ethyl 3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazine-2-carboxylate (0.72 g) in the form of a yellow solid, m.p. 141°-142° C. [Elemental analysis: C, 77.1; H, 6.24; N, 7.8%; calculated C, 77.1; H, 6.19; N, 7.8%; NMR (in CDCl3) : 0.93 (3H, t, J=7 Hz), 1.57 (6H, d, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.35 (1H, septet, J=7 Hz), 7.23-7.50 (8H, m), 7.60-7.66 (1H, m), 8.35 (1H, s); Mass spectrum (electron impact) m/z=358].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure F, 1-{6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}ethanone (30 mg, 0.077 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (42 mg, 0.154 mmol) to afford the desired product (24 mg, 68%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.13 (s, 1H), 8.48 (s, 1H), 8.29 (dd, J=8.8, 1.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.56 (dd, J=11.4, 2.3 Hz, 1H), 4.65-4.61 (m, 1H), 3.50-3.46 (m, 1H), 2.91 (s, 6H), 2.75 (s, 3H), 2.58-2.54 (m, 2H), 2.34-2.28 (m, 2H), 1.91-1.81 (m, 4H); ESI MS m/z 456 [C25H27ClFN3O2+H]+; HPLC 97.1% (AUC), tR=9.52 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C@@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C@@H:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](NCc1ccc(OC)cc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](c1ccccc1)N(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of (S)-methyl 2-((4-methoxybenzyl)amino)-2-phenylacetate (1.6 g, 5.61 mmol) in anhydrous dichloroethane (20 mL) was added 4-methoxy benzaldehyde (0.76 g, 5.61 mmol) and few drops of HOAc. After 30 min, the reaction mixture was cooled to 0° C., sodium triacetoxy borohydride (2.38 g, 11.22 mmol) was added and the contents were allowed to stir at ambient temperature. After 2 h, the reaction was quenched with ice cold H2O (10 mL), and the organic contents were extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was purified by flash column chromatography to afford (S)-methyl 2-(bis(4-methoxybenzyl)amino)-2-phenylacetate as pale yellow liquid (1.5 g, 66%). MS: [M+H]+ m/z 406.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[O:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[CH:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2o1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3o2)cc1Cl
Temperature: 0 °C
Yield: 60.9 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (121 mg, 0.91 mmol) and pyridine (0.15 mL, 1.8 mmol) and was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (166 mg, 61%) as a light pink foam: EI-HRMS m/e calcd for C22H23ClN2O4S (M+) 446.1067, found 446.1077.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][C:3]=1[CH:7]=[CH:8][C:9]([Cl:11])=[O:10].[OH-].[Na+].[H][H]>[Pd]>[CH3:1][C:2]1[N:6]=[CH:5][NH:4][C:3]=1[CH2:7][CH2:8][C:9]([Cl:11])=[O:10]
Reactant: Cc1nc[nH]c1C=CC(=O)Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc[nH]c1CCC(=O)Cl
Temperature: 80 °C
Reaction time: 72 h
Yield: 22.3 %

Procedure:
50 mg of palladium-on-charcoal at 10% are added to 500 mg (2.65 mmol) of 3-(5-methyl-3H-imidazol-4-yl)acrylic acid chloride in 10 ml of a 0.5N solution of sodium hydroxide. The reaction mixture is placed under 6 bar of hydrogen pressure and stirred at 80° C. for 72 hours. After having filtered off the catalyst through celite, the residue is acidified to pH 2 with hydrochloric acid, concentrated to dryness and taken up in ethanol. The insoluble material is filtered off and the filtrate is concentrated to dryness. 102 mg of 3-(5-methyl-3H-imidazol-4-yl)propanoic acid chloride are obtained in the form of a white powder with a yield of 16%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].[CH2:12]([Sn](CC)(CC)CC)[CH3:13].[Cl-].[Li+]>CN(C=O)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH2:12]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6])[CH3:13]
Reactant: CC[Sn](CC)(CC)CC
Reactant: COc1ccc(C#N)cc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cc(C#N)ccc1OC
Temperature: 135 °C

Procedure:
To a solution of 3-bromo-4-methoxybenzonitrile (6-1, 0.3 g, 1.42 mmol) in DMF (14 mL) was added tetraethyltin (0.56 mL, 2.83 mmol), bis(tri-t-butylphosphine) palladium(0) (0.072 g, 0.141 mmol), and lithium chloride (0.18 g, 4.24 mmol) and the system was heated to 135° C. for 30 minutes in a microwave reactor. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 10% EtOAc in hexanes) to yield the desired product (6-2) as a clear oil. ESI+MS [M+H]+ C10H11NO: 162.1 found, 162.2 required.
Reaction SMILES: [OH:1][CH:2]([CH:12]1[C:16](=[O:17])[CH:15]=[CH:14][CH:13]1[CH:18]=[CH:19][CH:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[OH:34]O.[OH-].[Na+]>CO>[O:34]1[CH:14]2[CH:15]1[C:16](=[O:17])[CH:12]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:13]2[CH:18]=[CH:19][CH:20]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(C=CC1C=CC(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(C=CC1C2OC2C(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A solution of 3.30 g of 5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone in methanol (25 ml) was cooled to 0° C., and 48 ml of an aqueous 30% hydrogen peroxide and 0.48 ml of an aqueous 1N sodium hydroxide were dropwise added thereto. After stirring at 0° C. for 3 hours, the reaction mixture was extracted with an addition of ethyl acetate and saturated aqueous ammonium chloride, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 2.54 g (yield 74%) of 2,3-epoxy-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)cyclopentanone.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1I.C([Li])CCC>C1COCC1.CCCCCC>[I:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[CH:6]=1
Reactant: Cc1nc(I)c(I)n1-c1cnn(C)c(=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(I)cn1-c1cnn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A solution of 240 mg (0.543 mmol) 5-(4,5-diiodo-2-methyl-imidazol-1-yl)-2-methyl-2H-pyridazin-3-one in 17 ml of dry THF was cooled to −78° C. and 0.41 ml of a 1.6M solution of n-butyllithium (0.65 mmol) in hexane was added. The mixture was stirred for 5 min., quenched by addition of 0.5 ml of methanol and stirred for an additional 10 min at −78° C. Then 2 ml of saturated ammonium chloride solution was added and the mixture was allowed to warm up to room temperature. After standard workup with ethyl acetate/water, the crude material was purified by flash chromatography on silicagel using a 90:10 mixture of ethyl acetate/heptane as eluant to yield 53 mg (0.168 mmol, 31%) of the title compound as a light yellow solid, MS: m/e=316.9 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[C:3](=[O:7])[CH2:4][CH2:5][CH3:6]>C(O)C.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:2]([CH3:1])[C:3](=[O:7])[CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=1
Reactant: CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(=O)N(C)c1ccc(N)cc1
Yield: 103.4 %

Procedure:
To a stirred solution of the product of step 1 (1.08 g, 4.88 mmol) in ethanol (20 mL) was added 10% palladium on activated carbon (0.100 g). The reaction vessel was evacuated and backfilled with nitrogen several times. After a final evacuation the reaction vessel was backfilled with hydrogen. After 3.5 hours the hydrogen atmosphere was removed and the mixture was filtered through Celite and concentrated to afford 0.97 g (100%) of product as an amber gum: 1H NMR (CDCl3) δ 6.93 (d, J=8.6 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 3.78 (br s, 2H), 3.20 (s, 3H), 2.04 (t, J=7.3 Hz, 2H 1.63-1.52 (m, 2H), 0.82 (t, J=7.4 Hz, 3H) ppm.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([O-])([O-])[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>O>[C:1]([C:9](=[CH:15][O:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Ethyl benzoylacetate (17.0 g, 88.4 mmol) and ethyl orthoformate (106 mL, 637 mmol) were dissolved in acetic anhydride (60.2 mL, 637 mmol) and stirred at 140° C. overnight. The reaction solution was returned to room temperature, then added with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (20.7 g, yield 94%) was obtained as an orange oil.
Reaction SMILES: C(OC1C(F)=CC=C2C=1C(CCN(C)C)=CN2)C1C=CC=CC=1.[CH2:24]([N:27]1[C:35]2[C:30](=[C:31]3[O:39][CH2:38][CH2:37][O:36][C:32]3=[CH:33][CH:34]=2)[C:29]([CH2:40][C:41]([NH2:43])=O)=[CH:28]1)[CH2:25][CH3:26]>>[CH2:24]([N:27]1[C:35]2[C:30](=[C:31]3[O:39][CH2:38][CH2:37][O:36][C:32]3=[CH:33][CH:34]=2)[C:29]([CH2:40][CH2:41][NH2:43])=[CH:28]1)[CH2:25][CH3:26]
Reactant: CCCn1cc(CC(N)=O)c2c3c(ccc21)OCCO3
Agent: CN(C)CCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Product: CCCn1cc(CCN)c2c3c(ccc21)OCCO3
Yield: 9 %

Procedure:
Following the procedure (step 6, scheme 1) used to prepare compound 1-7a, compound 40-6 gave compound 40-7 (5 mg, 9%) as yellow oil. 1H NMR (300 MHz, MeOD-d6): δ (ppm) 6.87 (s, 1H), 6.73 (d, J=8.8 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 4.26-4.24 (m, 2H), 4.16-1.15 (m, 2H), 3.91 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H), 1.71 (q, J=7.2 Hz, 2H), 0.80 (t, J=7.2 Hz, 3H). LCMS: calc 260.2 found 261.1 [MH]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: O=C(CCl)Nc1cccc(Cl)c1Cl
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,3-dichlorophenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure the residue purified by preparative HPLC to provide 9 mg (16%) of the desired product as a trifluoroacetic acid salt. 1H NMR (500 MHz, DMSO-d6) δ 2.62 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.68 (m, 2H), 7.88 (m, 2H), 8.12 (d, J=5 Hz, 1H), 10.12 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.