Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].N1C=CC=CC=1.Cl[C:24](OCC)=[O:25]>O1CCOCC1>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[CH:11][C:12]=2[N:13]=[C:24]1[OH:25])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CCNc1nc(Cl)ccc1N
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCN(CC)CCn1c(O)nc2ccc(Cl)nc21
Reaction time: 1 h

Procedure:
The solution of 80 grams of 2-(2-diethylaminoethylamino)-3-amino-6-chloropyridine in 900 ml of dioxane was treated with stirring with 32 ml of pyridine and 36.6 ml of ethyl chloroformate and stirred for one hour. The product precipitating thereby was washed with water and dried (2-(2-diethylaminoethylamino)-3-carbethoxy-amino-6-chloropyridine, M.P. 205°-206° C.) and subsequently melted with occasional stirring and held for 3 hours at 190°-210° C. After cooling the solidified melt was recrystallized from methanol under the addition of activated carbon and isopropanolic H Cl. M.P. of the hydrochloride 252°-254° C.; Yield 52.8 grams.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=1>>[C:40]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=[CH:42][C:43]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(-c4ccccc4)cc3)CN2C1=O
Yield: 26.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-biphenylcarbonyl chloride (113 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 35 mg (27%) of 18-(4-biphenylcarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.9% pure (HPLC), MS m/z 749 (M−H)−, HRMS: calcd. 751.3013 and found 751.3008 (M+H)+, mp 160-162° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1cccc(F)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([CH:19]=[CH2:20])=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].Cl[C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>ClCCl>[Cl:8][C:9]1[C:18]([CH:19]2[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20]2)=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C=Cc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)OC)c2Cl)C1
Reaction time: 12 h

Procedure:
6.4 ml (46 mmol) of triethylamine were added slowly dropwise at room temperature to a solution of 8.5 g (31 mmol) of methyl 2-chloro-3-ethenyl-4-methylsulfonylbenzoate and 7.2 g (46 mmol) of ethyl 2-chloro-2-hydroxyiminoacetate in 200 ml of dichloromethane. After the mixture had been stirred for in each case 2 hours, 3 further portions of in each case 4.8 g (31 mmol) of ethyl 2-chloro-2-hydroxyiminoacetate and then 4.3 ml (31 mmol) of triethylamine were added. Stirring was continued for 12 hours at room temperature, and the reaction mixture was then stirred into 600 ml of water. After extraction with dichloromethane, drying and removal of the solvent, the residue was chromatographed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11].C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]
Reactant: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)C(CC1CCCC1=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (prepared as in Example 25, 408.5 mg, 1.28 mmol), N-methylmorpholine N-oxide (679 mg, 5.79 mmol), and powdered molecular sieves (1.29 g) in methylene chloride (2.6 mL) at 25° C. was treated with tetrapropylammonium perrhuthenate (45 mg, 0.12 mmol). The resulting mixture was stirred at 25° C. for 2 h. At this time, the reaction was filtered through a pad of celite (ethyl acetate as eluent). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid methyl ester (278.2 mg, 68.5%) as a clear oil: EI-HRMS m/e calcd for C15H16C12O3 (M+) 314.0476. found 314.0476.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([C:20](OC)=[O:21])[CH2:17][CH:16]2[CH2:18][CH:9]1[CH:10]1[CH:15]2[CH:14]2[CH2:19][CH:11]1[CH:12]=[CH:13]2.[OH-].[K+].Cl>O1CCCC1>[CH3:7][C:8]1([CH2:20][OH:21])[CH2:17][CH:16]2[CH2:18][CH:9]1[CH:10]1[CH:15]2[CH:14]2[CH2:19][CH:11]1[CH:12]=[CH:13]2
Reactant: COC(=O)C1(C)CC2CC1C1C3C=CC(C3)C21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(CO)CC2CC1C1C3C=CC(C3)C21
Temperature: 0 °C
Yield: 82.4 %

Procedure:
37.6 g of lithium aluminum hydride and 800 ml of tetrahydrofuran were added to a flask and maintained at 0° C. in a nitrogen atmosphere. Then, 200 g of 8-methyl-8-methoxycarbonyltetracyclo[4.4.0.12,5.17,10]dodec-3-ene dissolved in 200 ml of tetrahydrofuran was added from a dripping funnel over one hour, followed by a reaction for 2.5 hours at 70° C. The reaction solution was allowed to cool to room temperature and a 10% aqueous solution of potassium hydroxide was added gradually, followed by further addition of 10% aqueous solution of hydrochloric acid. The reaction solution was then extracted with toluene and the reaction product was salted out from saturated brine. The salt-out product was washed several times with water and dried over anhydrous magnesium sulfate. Toluene was evaporated to obtain 145 g of a white solid of 8-methyl-8-hydroxymethyltetracyclo[4.4.0.12,5.17,10]dodec-3-ene shown by the following formula (19).
Reaction SMILES: C(OC(N1CCC([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)CC1)=O)(C)(C)C.Br[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1>C(OCC)C>[N:18]1([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:17]1
Reactant: BrCc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Solvent: CCOCC
Product: c1csc(Cn2cc(N3CCCCC3)c3cccnc32)c1

Procedure:
This compound was prepared following the procedure described in example 7, parts E and F, starting with 0.3 g (1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester and 2.12 ml of a freshly prepared 0.61 M solution of 2-bromomethylthiophene in ethyl ether. After standard work-up, 0.29 g (100% of yield) of the expected product were isolated.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH2:38][OH:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C>CS(C)=O>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH:38]=[O:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N[C@H](CO)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N[C@H](C=O)CC1CCCCC1
Reaction time: 0.58 h

Procedure:
To a mixture of the dipeptide alcohol [18a] (2.0 g, 3.65 mmol), triethylamine (1.30 g, 12.85 mmol, 3.5 eq) and DMSO (6 ml) is added at room temperature SO3 ·pyridine (2.03 g, 12.75 mmol, 3.5 eq) in DMSO (6 ml) and the mixture is stirred for 35 minutes. The reaction mixture is poured on ice, and the resultant aqueous mixture is extracted with ethyl acetate (20 ml×3). The organic layer is subsequently washed with 10% aqueous citric acid, saturated aqueous sodium chloride (×2), 7% aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over MgSO4, and concentrated to dryness in vacuo. The resultant residue is purified with silica gel chromatography (SiO2 :100 g, CH2Cl2 :MeOH=95:5) to obtain Boc-His(Ts)-3-cyclohexylalaninal [14a] (1.67 g, 84%) in amorphous powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:10]2
Reactant: C=C[Mg]Br
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Br)c2cc[nH]c12
Temperature: -40 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 4-bromo-1-ethyl-2-nitro-benzene (8.7 g, 0.037 mol) in THF at −40° C. was added vinylmagnesium bromide (132 ml, 0.132 mol) dropwise, and the mixture was stirred at −40° C. for a further 2 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography to afford the title compound (1.35 g, 16%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:16]=[C:17]([CH2:18][OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 80 °C

Procedure:
2-Chloromethylquinoline hydrochloride (11.6 g, 54 mmol), 3-hydroxybenzyl alcohol (6.7 g, 54 mmol) and potassium carbonate (16 g, 116 mmol) are heated in DMF (45 mL) at 50° C. for 14 h. The temperature is increased to 80° C. and heated an additional 24 h. The reaction is cooled and added to water, filtered and the solid is washed with water to yield a semi-pure product. The residue is dissolved in ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The sample is then recrystallized from ethyl acetate and hexanes to provide the title compound. MS (ESI) 266 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:15](O)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.O.C(Cl)(Cl)(Cl)Cl>[CH:8]1([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Reactant: Nc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2-aminopyridine (25 mg, 0.26 mmol) in acetonitrile (500 μL) was treated with 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid (75 mg, 0.22 mmol), triphenylphosphine (63 mg, 0.24 mmol), triethylamine (91 μL, 0.66 mmol), and carbon tetrachloride (300 μL). The resulting reaction mixture was stirred at 25° C. for 15 h. The cloudy reaction mixture was diluted with water and then extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded impure 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyridin-2-yl-propionamide. Repurification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% methylene chloride) afforded pure 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyridin-2-yl-propionamide. (40 mg, 43%) as a white foam: mp 73-77° C.; EI-HRMS m/e calcd for C29H28N2O (M+) 420.2202, found 420.2003.
Reaction SMILES: O=C(COC1C=NC=CC=1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=O)=[CH:20][CH:19]=1>CC(C)=O>[O:28]=[C:26]([CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6]
Reactant: CCOC(=O)CCc1ccncc1
Reactant: COP(=O)(CC(=O)COc1cccnc1)OC
Solvent: CC(C)=O
Product: COP(=O)(CC(=O)CCc1ccncc1)OC

Procedure:
The process described in Example 1 for the preparation of dimethyl [2-oxo-3-(pyrid-3-yloxy)propyl]-phosphonate was repeated, using ethyl 3-(pyrid-4-yl)propionate in place of ethyl 3-pyridyloxyacetate, to give dimethyl [2-oxo-4-(pyrid-4-yl)butyl]phosphonate, RF = 0.63 (acetone). The n.m.r. spectrum in deuteriochloroform showed the following characteristic absorptions (δ values):
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[O:8][N:7]=1)=[O:5])C.CO.[OH-].[Li+]>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccco2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2ccco2)on1
Reaction time: 15 h
Yield: 90 %

Procedure:
4.14 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester was dissolved in 130 mL of THF 130 mL and 25 mL of methanol before the slow addition of 80 mL of aqueous 1N lithium hydroxide. Stirring for 15 hrs was followed by the removal of THF and methanol under reduced pressure. The residue was acidified with 1N HCl to produce a precipitate which was then filtered, washed with distilled water and dried to produce 3.22 g of 5-furan-2-yl-isoxazole-3-carboxylic acid as a white solid (Yield: 90%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][N:13]=1)[CH3:2].[NH:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.ClCCl.O.CC(O)=O>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]4)[CH:7]=[CH:6][CH:5]=3)=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D31) (52 mg) and methyl 3-azetidinecarboxylate (60.7 mg) in ethanol (10 mL) stirred at room temperature was added sodium acetate (32.9 mg) and AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. The residue was dissolved in dichloromethane (DCM) (10 mL), sodium triacetoxyborohydride (85 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford methyl 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylate (D32) (58.7 mg). MS (ES): C28H32N4O2S requires 488. found 489.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COc1cc(C(=O)O)ccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccc1C

Procedure:
From 3-methoxy-4-methylbenzoic acid, HATU and N-ethyldiisopropylamine in THP, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+23.0° (c=1.03, CHCl3), ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2F)c(-c2ccnc(Cl)n2)o1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2-furansulfonamide (72 mg, 0.151 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as a white solid (62 mg, 89%). 1H-NMR (DMSO-d6): δ ppm 10.57 (br s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.97 (m, 1H), 7.44-7.48 (m, 1H), 7.23-7.32 (m, 2H), 7.08 (m, 1H), 6.63 (m, 1H) 6.57 (d, J=5.2 Hz, 1H), 1.41 (s, 9H); MS: 458 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:14][CH:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]2)=[N:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:23][N:15]([CH:13]1[CH2:14][N:11]([C:5]2[C:6]3[N:7]([N:8]=[N:9][N:10]=3)[C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][N:4]=2)[CH2:12]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1cccs1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(Br)n3nnnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(-c3cccs3)n3nnnc23)C1
Temperature: 80 °C
Reaction time: 14 h
Yield: 69.5 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl (1-(5-bromotetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)(methyl)carbamate (50 g, 0.13 mol), thiophene-2-boronic acid (22 g, 0.17 mol), tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol), Cs2CO3 (50 g, 0.15 mol), 1,4-dioxane (1.5 L) and water (500 mL). After the air was purged by bubbling N2 into the solution, the resulting solution was stirred at 80° C. under N2 for 14 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 0-25% ethyl acetate in CH2Cl2, and then crystallized from methanol, to afford 35 g (70%) of the product as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[N:20][C:19]4=[O:30])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:33]([F:36])([F:35])[F:34])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[N:20][C:19]4=[O:30])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:33]([F:36])([F:35])[F:34])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one (32 mg, 0.062 mmol) in CH2Cl2 (1 mL) was added 0.4 mL of 1M BBr3 at −78° C. The mixture was stirred for 2 h at −78° C., then warmed up to room temperature. It was quenched with aqueous MeOH and NaHCO3 solution, extracted with EtOAc. The combined organic extracts were evaporated and the residue was purified by flash column chromatography on silica gel (0-100% gradient CH2Cl2/EtOAc, followed by 10% MeOH/EtOAc) to afford the title compound (30 mg, 96%).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][N:25]=[C:24]([CH3:29])[CH:23]=1.C(I)C>C1COCC1>[Cl:21][C:22]1[C:27]([F:28])=[CH:26][N:25]=[C:24]([CH2:29][CH2:1][CH3:2])[CH:23]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(Cl)c(F)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCCc1cc(Cl)c(F)cn1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Diisopropylamine (924 μL, 6.59 mmol) was dissolved in 9 mL of dry THF and the resultant solution was cooled to 0° C. in an ice bath. n-Butyllithium (3.07 mL of a 2.05M solution in THF, 6.29 mmol) was added via syringe to the amine solution and the resultant solution was stirred for 30 minutes at 0° C. The lithium diisopropylamide (LDA) solution was then cooled to -50° C. in an isopropyl alcohol/dry ice bath. To the cold LDA solution was added, dropwise from an addition funnel, over a 15 min period, a solution of 4-chloro-5-fluoro-2-picoline (435 μL, 3.0 mmol), the product of Example 64, in 9 mL of THF. The reaction solution turned dark orange-brown in color. The reaction solution was stirred at a temperature in the range -50° C. to -45° C. for 5 hours and then was cooled over a 15 min period to -78° C. Ethyl iodide (792 μL, 9.9 mmol) was added in one portion and the reaction solution was stirred at -78° C. for 20 min. The reaction was then quenched by pouring the reaction solution into 60 mL of 10% aqueous ammonium chloride solution. The aqueous mixture was extracted with 2×50 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was distilled to afford the title compound, b.p. 80°-82° C. (12 mm Hg); MS DCI-NH3M/Z: 174 (M+H)+ 40%; 1H NMR (CDCl3) d 0.96 (t, 3H, J=7.5 Hz), 1.73 (spt, 2H, J=7.5 Hz), 2.73 (t, 2H, J=7.5 Hz), 7.21 (d, 1H, J=6.0 Hz), 8.38 (s, 1H).