Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])C1
Yield: 95 %

Procedure:
The method of Example 1 was followed using 4-chloro-3-nitropyridine (1.0 eq), tert-butyl pyrrolidin-3-ylcarbamate (2.0 eq), and DIEA (2.0 eq) in EtOH yielding tert-butyl 1-(3-nitropyridin-4-yl)pyrrolidin-3-ylcarbamate (95%) LCMS (m/z): 309.1 (MH+); LC Rt=1.922 min.
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=CC(C#N)=CC=3)CC2)=CC=1OCC.[CH3:27][O:28][C:29](=[O:51])[C:30]1[CH:35]=[C:34]([Cl:36])[N:33]=[C:32]([NH:37][CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[CH:31]=1.Cl>O1CCOCC1.C(O)C>[CH3:27][O:28][C:29](=[O:51])[C:30]1[CH:31]=[C:32]([NH:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[N:33]=[C:34]([Cl:36])[CH:35]=1
Reactant: COC(=O)c1cc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)nc(NC2CCNCC2)c1

Procedure:
The title compound was prepared in analogy to the synthesis of (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediate B16/step 2) from 2-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-6-chloro-isonicotinic acid methyl ester by cleavage of the BOC group with 4 M HCl in dioxane and ethanol at rt. MS (ISP): 270.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][OH:14].[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:14][CH2:13][CH2:12][O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of 4-bromobenzyl bromide (3.00 g) and 2-methoxyethanol (1.04 ml) in tetrahydrofuran (30 ml) was added sodium hydride (60%) (0.58 g) in a stream of nitrogen. The mixture was stirred at this temperature for 15 minutes and at room temperature for further 4 hours. To the mixture was added water (1 ml) under ice-cooling. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 1-bromo-4-(2-methoxyethoxymethyl)benzene (3.10 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH2:45][O:46]C>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][O:46][CH3:45])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COCCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-methoxyethane and isolated as light-yellow gum (2.5 mg, 18%). MS(m/e): 341.3 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl:21][Si](C)(C)C>C(#N)C>[Cl:21][CH2:12][C:11](=[O:13])[C:3](=[N:2][OH:1])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(=NO)C(=O)CCl
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
In 15 ml of acetonitrile was dissolved 1.07 g of tert-butyl 2-hydroxyimino-3-oxobutyrate, followed by addition of 2.8 ml of triethylamine. Then, 2.5 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 1.5 hours, after which it was concentrated under reduced pressure. The residue was suspended in 15 ml of tetrahydrofuran and the suspension was filtered in a nitrogen gas stream to remove insolubles. This filtrate containing tert-butyl 2-trimethylsilyloxyimino-3-trimethylsilyloxy-3-butenoate was cooled to -30° C. and 0.46 ml of sulfuryl chloride was added dropwise. After the temperature of the system was increased to 20° C., the reaction mixture was concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and elution was carried out with 100 ml of hexane-ether (1:1, v/v). The eluate was concentrated under reduced pressure to give 1.08 g of tert-butyl 4-chloro-2-hydroxyimino-3-oxobutyrate. Yield 85.2%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+]([O-])=O.Cl.Cl.[NH2:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18]>C1COCC1.C(O)C.O>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:17](=[O:18])[CH2:16][CH2:15][NH:14][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:24][CH:23]=1
Reactant: NCCC(=O)c1ccc(N)cc1
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)CCNc2cc(N)ncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
6-Chloro-5-nitro-pyrimidin-4-ylamine (379 mg, 2.1 mmol) in THF (2 mL) was added to an ice cold solution of Example 9B (510 mg, 2.1 mmol) in THF (20 mL) and ethanol (20 mL). The mixture was stirred at 0 C for 20 min, at room temperature for 1 hr and heated at 75 C for 2 h. The mixture was allowed to cool to room temperature, diluted with water (50 mL), concentrated, and filtered. The filter cake was washed with water and dried to give 0.55 g (83% yield) of the title compound. MS(ESI(+)) m/e 303.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=O)[CH3:2].[NH2:15][OH:16].Cl.[OH-].[Na+]>CCO>[NH2:14][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:15][OH:16])[CH3:2])=[CH:9][C:8]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: CC(=O)c1ccc(N)c(S(N)(=O)=O)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)c1ccc(N)c(S(N)(=O)=O)c1
Reaction time: 2 h
Yield: 81 %

Procedure:
To a suspension of 5-acetyl-2-aminobenzenesulfonamide (see compound 13) (0.45 g, 2.1 mmol) in 96% EtOH (40 ml) was added H2NOH.HCl (0.28 g, 4 mmol) and 2M NaOH (2 ml). The mixture was boiled for 2 h and the solvent was evaporated. The residue was triturated with water (25 ml) and the product was filtered off and dried, yielding 0.39 g (81%) of 2-amino-5-(1-hydroxyiminoethyl)benzenesulfonamide as yellow powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 230–233° C.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C:40](O)=[O:41])[CH:39]=1)[NH:36][CH:35]=[C:34]2[CH2:43][CH:44]1[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45]1.N.CO>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C:40]([NH2:2])=[O:41])[CH:39]=1)[NH:36][CH:35]=[C:34]2[CH2:43][CH:44]1[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
TBTU (5.68 g, 17.68 mmol) and triethylamine (1.79 g, 17.68 mmol) were added to a solution of 5-bromo-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxylic acid (3.28 g, 8.84 mmol) in dichloromethane (100 mL). After the mixture was stirred for 0.5 h at 20° C., NH3/MeOH was added into the solution, and stirring continued for 2 h. The mixture was washed with water and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum:ethyl acetate=10:1 to 5:1 to 2:1), giving 1.1 g (33.6%) of the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.C(OCC)(=O)C.[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].[CH3:26][O:27][CH:28]([O:44][CH3:45])[CH2:29][NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:45][O:44][CH:28]([O:27][CH3:26])[CH2:29][N:30]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:33][CH2:32]1)[C:1]([NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[F:18])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccccc1F
Reactant: COC(CNC1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(CN(C(=O)Nc1ccccc1F)C1CCN(C(=O)OC(C)(C)C)CC1)OC
Reaction time: 1 h
Yield: 53 %

Procedure:
20% Phosgene in toluene (4.0 ml, 7.6 mmol) was diluted with ethyl acetate (20 ml, 205 mmol). 2-Fluoroaniline (0.600 ml, 6.2 mmol) was added to the mixture in one portion causing a white precipitate. Mixture was heated to reflux and held with stirring for 1 hour. Mixture was concentrated by roto-vap. Residue was dissolved in a small amount of dichloromethane. Resulting solution was added to a mixture of tert-butyl 4-(2,2-dimethoxyethylamino)piperidine-1-carboxylate (1.99 g, 6.9 mmol), dichloromethane (30 mL) and aqueous sodium bicarbonate (15 mL) while stirring vigorously. Reaction stirred at room temperature for 2 hours. Layers were separated and the aqueous phase was discarded. Material was washed twice with 1N hydrochloric acid and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as yellow oil in 53% yield. MS (M−H)−=424.1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
1 mmol 2,6-dichloro-3-nitropyridine, 1.05 mmol of 2,4-dichlorobenzeneboronic acid, and 3 mmol of Na2CO3, were dissolved in 1.5 ml THF and 0.5 ml water and purged with nitrogen. 0.05 mmol of [1,1′-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) was added to reaction and stirred at room temperature under nitrogen for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 10% ethylacetate 90% hexanes to obtain 2-(2,4-dichlorophenyl)-6-chloro-3-nitropyridine.
Reaction SMILES: CC(N=N[C:8]([C:11]#N)([CH3:10])C)(C#N)C.C([O:18][C:19]1(C)[CH:26]2[CH2:27][CH:22]3CC(CC1C3)C2)(=O)C(C)=C.O=[C:31]1[CH:35]([O:36]C(=O)C(C)=C)[CH2:34]CO1.C(OC(O)C1C2C(=CC=CC=2)C=CC=1)(=O)C=C>C(#N)C.O1CCCC1>[O:18]1[CH2:19][CH2:26][CH2:27][CH2:22]1.[CH:35]([O:36][CH:8]([CH3:10])[CH3:11])([CH3:31])[CH3:34]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)OC1CCOC1=O
Agent: C=CC(=O)OC(O)c1cccc2ccccc12
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.039 mol of Vazo® 52 low-temperature polymerization initiator (E. I. du Pont de Nemours and Company) was added to a solution of 70.30 g (0.3 mol) 2-methyl-2-adamantyl methacrylate, 51.05 g (0.3 mol) 2-methyl-acrylic acid 2-oxo-tetrahydro-furan-3-yl ester, 34.23 g (0.15 mol) hydroxynaphthylmethyl acrylate and 22.40 g (0.039 mol) of the PAG formed in Example 1 in a 178 g acetonitrile:tetrahydrofuran 2:1 mixture. The monomers and initiator solution were degassed for 10 minutes. Under inert atmosphere, 5 mL of the monomer and initiator solution were introduced into a reactor preheated to 80° C. (oil bath). The remainder of the monomer and initiator mixture was fed into the reactor at 80° C. over a two hour period. Upon completion of the addition, the reaction mixture was refluxed for two additional hours. The mixture was cooled to room temperature and the polymerization solution was precipitated into a large amount of diisopropyl ether, filtered and dried under vacuum. The resulting crude polymer was dissolved in 25-30 wt % tetrahydrofuran (THF) and precipitated into diisopropyl ether. The material was next filtered with a 0.2 micron filter, and the filtrand was slowly added to diisopropyl ether to provide a THF: diisopropyl ether 1:10 v/v solution. The precipitated polymer was isolated by filtration and dried overnight at 40° C. under vacuum.
Reaction SMILES: [O:1]=[C:2]1[NH:18][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[N:9]=[C:4]2[N:3]1[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.Br[C:28]1[N:33]=C2N(CCC3CCOCC3)C(=O)NC2=N[CH:29]=1.C(C1C=CC(B(O)O)=CC=1)#[N:47].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:29][C:28]1[NH:33][N:47]=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([C:8]3[N:9]=[C:4]4[N:3]([CH2:19][CH2:20][CH:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:2](=[O:1])[NH:18][C:5]4=[N:6][CH:7]=3)=[CH:17][CH:16]=2)[N:15]=1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CCC1CCOCC1
Reactant: N#Cc1ccc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(-c3cnc4[nH]c(=O)n(CCC5CCOCC5)c4n3)cc2)n[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
4-(2-Oxo-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile. 6-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 108.B) (2.5 g, 7.60 mmol), 4-cyanophenylboronic acid (1.69 g, 11.5 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferocene]palladium (II) dichloromethane (0.62 g, 0.70 mmol) were combined in dioxane (10 mL). Sodium carbonate (0.91 g, 15.2 mmol) in water (10 mL) was added and the reaction stirred at 100° C. overnight. The cooled reaction solution was filtered through Celite and the filter cake was washed with ethyl acetate. Filtrate and ethyl acetate wash were combined and solvent removed under reduced pressure. The resulting material was purified using reverse-phase preparatory HPLC (20-80% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X-C ion exchange column to remove TFA. The column was washed successively with water, methanol, and then 5% ammonium hydroxide in methanol. The product was released with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator. The residue was triturated with ethyl ether in hexane to give a fine powder and dried under vacuum at 50° C. to give the desired product (1.2 g, 46%) as a white solid. MS (ESI) m/z 350.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]3[C:30](O)=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:33][N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.NO>CN(C=O)C>[OH:33][NH:34][C:30]([C@H:25]1[C@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:29][CH2:28][O:27][CH2:26]1)=[O:31]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCOCC3C(=O)O)cc2)c2ccccc2n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=N
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCOC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid (0.280 g, 0.658 mmol) and 1-hydroxybenzotriazole (HOBT, 0.177 g, 1.32 mmol) in DMF (10 mL) was added 1-(3-dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.253 g, 1.32 mmol) at 0° C. The reaction mixture stirred at 0° C. for 10 min, then warmed to 25° C. over 1 h. After recooling the reaction to 0° C. hydroxylamine (50% by wt in water, 0.6 mL, 6.6 mmol) was added. The reaction was allowed to warm to 25° C. over 19 h. The DMF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL) and this mixture was then washed with saturated aqueous sodium bicarbonate (3×30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude solid (0.170 g) which was purified by Biotage Flash 40S chromatography, eluting with 4% methanol in ethyl acetate, to afford (3S,4R)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide as an amorphous white solid (0.02 g, 6.6%) that was a 75.7:24.3 mixture of enantiomers, as determined by analytical chiral HPLC (Chiralpak IA column, 7:3 n-propanol/heptane, 1 mL/min, 254 nm). MS: 472 (M+H)+
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[C:29]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCCC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (728 mg, 2.76 mmol), benzoic acid (338 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.45 ml, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-benzoyloxyoctane as a colorless liquid substance (503 mg, yield: 93%/(S)-2-octanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([CH:17]3[CH2:21][CH2:20][C:19](=O)[CH2:18]3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C([BH3-])#N.[Na+]>CO.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([CH:17]3[CH2:21][CH2:20][CH:19]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:18]3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: NCCC(=O)O
Reactant: CC(C)Oc1ccc(-c2noc(C3CCC(=O)C3)n2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: CC(C)Oc1ccc(-c2noc(C3CCC(NCCC(=O)O)C3)n2)cc1Cl

Procedure:
To a slurry of 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentanone (0.178 g, 0.555 mmol) in MeOH (6.94 ml) and DCE (6.94 ml) was added acetic acid (0.254 ml, 4.44 mmol) followed by 3-aminopropanoic acid (0.494 g, 5.55 mmol). After about 1 h sodium cyanoborohydride (0.017 g, 0.277 mmol) was added to the reaction mixture. After about 15 h the reaction mixture was filtered, rinsing with MeOH. The filtrate was concentrated in vacuo and purified by RP HPLC to provide 3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentylamino)propanoic acid. LCMS (Table 1, Method c) Rt=1.64 min, m/z 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)Cl.C(O)(=O)C>[Br:23][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of the crude 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene of Example 2a (12.6 g, up to 30 mmole) in methylene chloride (100 ml) was diluted with 75 ml of acetic acid and cooled to about 5°. A 1M solution of bromine in acetic acid (33 ml, 1.1 equiv) was added and the reaction stirred at about 5°. After 1 hour, additional bromine solution (5 ml) was added. After 2 hours total reaction time, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated in vacuo. Recrystallization from ethanol gave the title compound (7.9 g), m.p. 122°-124°. Infrared and NMR spectral data were consistent with the assigned structure.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=[CH:32][N:31]=1)CCC>CN(C=O)C.[Cu]I.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>[CH3:17][S:16][C:13]1[S:12][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]3[C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:33]=[CH:32][N:31]=2)=[N:15][N:14]=1
Reactant: CSc1nnc(-c2ccc3c(c2)c(I)cn3C(=O)OC(C)(C)C)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(N2CCOCC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nnc(-c2ccc3c(c2)c(-c2nccc(N4CCOCC4)n2)cn3C(=O)OC(C)(C)C)s1
Temperature: 90 °C
Yield: 20 %

Procedure:
To a solution of tert-butyl 3-iodo-5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (1.2 g, 2.5 mmol) and 4-(2-(tributylstannyl)pyrimidin-4-yl)morpholine (1.38 g, 4.0 mmol) in DMF (10 mL) was added CuI (0.62 g, 3.2 mmol) and Pd(PPh3)4 (0.29 g, 0.25 mmol). The mixture was purged with Ar for 5 min then heated at 90° C. for 1 h. The mixture was poured into H2O and the aqueous layer was extracted with Et2O. The combined organic layers were dried, filtered and concentrated. The residue was purified with flash chromatography to give tert-butyl 5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-3-(4-morpholinopyrimidin-2-yl)-1H-indole-1-carboxylate (255 mg, 20%). MS (ESI, pos. ion) m/z: 511.1 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 9.12 (1H, d), 8.39 (2H, brs), 8.25 (1H, d), 7.9 (1H, dd), 6.79 (1H, d). 3.7-3.85 (8H, brs), 2.85 (3H, s), 1.65 (9H, s).