Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C:32]1[S:33][CH:34]=[N:35][N:36]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C:32]1[S:33][CH:34]=[N:35][N:36]=1)=[O:29]
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Reactant: Nc1nncs1
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)Nc2nncs2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-amino-1,3,4-thiadiazole
Reaction SMILES: [Na].[OH-:2].[K+].Br[CH2:5][CH2:6][C:7](=[O:19])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.[CH3:20][OH:21]>CC1C(=O)CCC1=O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][C:7](=[O:19])[CH2:6][CH2:5][C:6]2([CH3:5])[C:7](=[O:2])[CH2:8][CH2:9][C:20]2=[O:21])[CH:16]=[CH:15][CH:14]=1
Reactant: [OH-]
Reactant: CO
Reactant: COc1cccc(CCCC(=O)CCBr)c1
Agent: CC1C(=O)CCC1=O
Agent: [K+]
Agent: [Na]
Product: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1

Procedure:
Add sodium (0.05 g) to a 0.12% methanolic potassium hydroxide solution (15 cc). To this solution add 1-bromo-6-(m-methoxyphenyl)hexan-3-one (0.9 g) in methanol (5 cc) and 2-methylcyclopentane-1,3-dione (0.4 g), and reflux the mixture for 6 hours. After working up as in the preparation of the title compound in a previous example, obtain the crude Michael adduct 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[CH:9].[CH3:10][O:11][C:12]([C:14]1[C:19](Br)=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu]I.CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[C:19]([C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13]
Reactant: C#Cc1ccccc1Cl
Reactant: COC(=O)c1nc(SC)ncc1Br
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(SC)ncc1C#Cc1ccccc1Cl
Temperature: 100 °C
Yield: 74.3 %

Procedure:
A mixture of 1-chloro-2-ethynylbenzene (0.63 g, 4.6 mmol), 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (1.0 g, 3.8 mmol), triethylamine (2.5 ml), triphenylphosphine (0.125 g, 0.48 mmol), copper (I) iodide (0.025 g, 0.13 mmol), bistriphenyphosphinepalladium (II) dichloride (0.10 g, 0.14 mmol) and dimethylformamide (1 ml) was stirred in a heavy-walled Smith process vial and irradiated with microwaves to maintain 100° C. for 20 min. The mixture was diluted with dichloromethane (20 ml) and washed with 5% hydrochloric acid (20 ml), water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and water (20 ml) then dried (MgSO4) and evaporated in vacuo. The residual oil was purified by flash column chromatography over silica using a 1:4 mixture of hexane and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 5-(2-chlorophenylethynyl)-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (0.9 g) as a yellow oil. 250 MHz 1H-NMR (CDCl3) δ (ppm): 2.5 (s, 3H) (—SCH3), 3.9 (s, 3H) (—CO2CH3), 7.1-7.5 (m, 4H) (ArH), 8.65 (s, 1H) (ArH); m/z (M+H)+. 319, HPLC purity 91%, HPLC retention time 4.08 min.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:31]([CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:13]3[CH:14]=[C:15]([C:18]([N:20]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1)[CH3:3]>C(Cl)(Cl)Cl.ClCCl.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:31]([CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:13]3[CH:14]=[C:15]([C:18]([N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:8][CH:9]=1)(=[O:1])[CH3:3]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3ccc(C(C)O)cc3)c(CCCN3CCCCC3)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(-c2nn3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3c2CCCN2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 0.05 h

Procedure:
To a solution of 2-(4-(1-hydroxyethyl)phenyl)-N,N-diisopentyl-3-(3-(piperidin-1-yl)propyl)pyrazolo[1,5-a]pyridine-5-carboxamide (35 mg, 0.053 mmol) in chloroform (1 mL) was added activated manganese dioxide (92 mg, 1.06 mmol,) and the mixture was heated to 50° C. for 24 h. The reaction mixture was then diluted with dichloromethane and filtered through a 0.45 um filter, concentrated and then purified by preparative HPLC on a reverse-phase Zorbax SB-C18 column 21.2×100 mm eluted with MeOH-water-0.1% TFA. Isocratic 30% for 3 minutes then Gradient: 30% to 100% MeOH over 14 minutes. LCMS m/z 545.4 (M+H)+, ret. time=2.45 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(#N)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[N:5]=[C:4]([C:15]([NH:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)O)nc1-c1ccsc1
Reactant: NCc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1c(N)cc(C(=O)NCc2cccnc2)nc1-c1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 584.4 %

Procedure:
To a mixture of Example 266A (12 mg, 0.05 mmol), C-pyridin-3-yl-methylamine (6 μL, 0.1 mmol) in N,N-dimethylformamide (400 μL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (17 mg, 0.053 mmol), followed by N,N-diisopropylethylamine (17 μL). The reaction mixture was stirred at ambient temperature for 3 hr. It was diluted with 1 mL acetonitrile and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to provide the titled compound as white solid (98 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 9.35 (t, J=6.4 Hz, 1H), 8.56-8.38 (m, 3H), 7.93-7.90 (m, 1H), 7.74-7.66 (m, 2H), 7.40-7.32 (m, 3H), 7.36 (s, 1H), 4.52 (d, J=6.4 Hz, 2H). MS (m/e) 336 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][N:4]3[C:3]([CH3:8])=[C:2]([I:1])[C:6]([CH3:7])=[N:5]3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1n[nH]c(C)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C)c1I

Procedure:
Protocol T was followed using 4-Iodo-3,5-dimethyl-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3); 6.95–7.1 (m, 2H), 6.84–6.92 (dd, 2H), 5.00 (s, 2H), 3.62–3.82 (m, 4H), 3.02–3.12 (m, 4H), 2.22–2.32 (d, 6H). 13C NMR (400 MHz, CDCl3): 165, 158.2, 156.2, 150.2, 146.8, 141.8, 118.8, 115.4, 115.2, 52.8, 51.6, 50.2, 45.2, 42, 14.8, 12.6.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]1[CH2:19][CH:18]2[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]2)[CH2:14]1.[NH2-].[Na+].O>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:11][CH2:12][N:13]2[CH2:19][CH:18]3[CH2:20][CH2:21][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(CCN1CC2CCC(CC2)C1)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 20 parts of α-phenylacetonitrile in 300 parts by volume of toluene is added 94 parts of 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane dissolved in 500 parts by volume of toluene. The mixture is heated with stirring to about 80° C. and then 17 parts of sodium amide is added slowly over a period of 30 minutes. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether, the ether extract dried over calcium sulfate and distilled to afford 2-phenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile.
Reaction SMILES: [OH:1][CH2:2][C:3](O)=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:22]([O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27])[CH3:23].N1C=CN=C1>C(#N)C.C1(C)C=CC=CC=1>[CH2:22]([O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH:27][C:2](=[O:1])[CH2:3][OH:4])[CH3:23]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](C)NC(=O)CO
Temperature: 25 °C
Yield: 61 %

Procedure:
One equivalent each of hydroxyacetic acid (10.0 g), dicyclohexylcarbodiimide, (L)-alanine ethyl ester hydrochloride and imidazole was stirred in 500 mL acetonitrile. The reaction mixture, initially at 0° C. was allowed to warm to room temperature overnight and then heated at 65° C. for 2 hours. After the addition of an equal volume of toluene, the reaction mixture was filtered and the solvent removed by rotovaping from the filtrate to give crude product. An aliquot of the crude product was chromatographed on silica gel to give N-(hydroxyacetyl)alanine ethyl ester (61% yield). 1H NMR (300 MHz, DMSO-d6 /TMS): δ1.19 (t , 3H, J=7.1 Hz), δ1.31 (d, 3H, J=7.2 Hz), δ3.83 (s, 2H), δ4.09 (d×q, 2H, J=1.2 and 7.1 Hz, irradiation in the methyl region eliminates the smaller coupling constant), δ4.32 (d×q, 1H, J=7.3 and 7.3), and δ 8.31 (br d, 1H, J=7.2 Hz). 13C NMR (75 MHz, CDCl3 /TMS): 13.59, 17.54, 47.31, 61.02, 61.48, and 172.17. [α]25D =-4.1°±0.4° (c=1.99, CHCl3). HRMS: calcd for C7H14NO4 (M+H)+, 176.0923; found, 176.0921.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH2:7][S:8]C(=O)C)=[O:6])[CH2:3][CH2:2]1.CO.C[O-].[Na+].Cl[C:18]1[N:25]=[C:24]([S:26][CH3:27])[C:23]([Cl:28])=[C:22]([CH3:29])[C:19]=1[C:20]#[N:21]>CCOC(C)=O.CCCCCC>[CH:1]1([NH:4][C:5]([C:7]2[S:8][C:18]3=[N:25][C:24]([S:26][CH3:27])=[C:23]([Cl:28])[C:22]([CH3:29])=[C:19]3[C:20]=2[NH2:21])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(=O)SCC(=O)NC1CC1
Reactant: CSc1nc(Cl)c(C#N)c(C)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
To a mixture of thioacetic acid S-cyclopropylcarbamoylmethyl ester (8.58 g, 49.5 mmol) and MeOH (100 ml) is added sodium methoxide solution (25% wt. in MeOH)(15.4 ml, 67.5 mmol). The resulting solution is stirred at room temperature for 20 minutes, then treated with 2,5-dichloro-4-methyl-6-methylsulfanyl-nicotinonitrile (10.5 g, 45.0 mmol). The mixture is refluxed at 100° C. for 2 hours, cooled to room temperature, and quenched by adding water (100 ml). The mixture is partitioned between water and EtOAc (300 ml each), and the layers are shaken and separated. The aqueous layer is extracted with EtOAc (2×150 ml). The combined organic layers are washed with brine (200 ml), dried (anhydrous magnesium sulfate), filtered, and concentrated to give an orange solid. Flash chromatography (1:1 hexane:EtOAc) affords the title compound as a yellow solid (8.4 g, 57%). Mass (m/z): 328.1 (M++1).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CS(C1C=CC=C(N)C=1)(=O)=O)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)CS(=O)(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-benzenesulfonyl)-acetic acid ethyl ester (prepared in one step from (3-amino-phenylsulfanyl)-acetic acid ethyl ester) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 13.08 (1H, br s), 10.26 (1H, s), 8.16 (1H, s), 7.77-7.45 (5H, m), 7.26-7.15 (2H, m), 4.80 (2H, m), 4.39 (2H, s), 4.38 (1H, d), 3.98 (1H, d), 2.86 (1H, m), 1.65-1.34 (6H, m), 1.25-1.13 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 53.55; H, 6.90; N, 8.48%; C30H36N4O7S.C7H17NO592.0H2O requires: C, 53.67; H, 6.94; N, 8.46%.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2cccc(C)c2)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)c1
Reaction time: 24 h
Yield: 62 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (31 mg, 0.074 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a colourless oil (18 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:6])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH:7]1[CH2:12][CH2:11][N:10]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:9][CH2:8]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 92 %

Procedure:
The above 2-methyl-2-piperidin-4-yl-propionic acid ethyl ester (606 mg, 3.82 mmol) was mixed with 2-chloro-5-nitropyridine (760 mg, 3.82 mmol) in 10 mL of tetrahydrofuran. To this solution was added diisopropylethylamine (1.33 mL). The mixture was heated in a microwave at 140° C. for 30 minutes. Solvents were evaporated and the residue was extracted with methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-methyl-2-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid ethyl ester as a solid (1.13 g, 92%). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([O:8]CC)=[O:7])C.[OH-].[K+]>C(O)C.O>[CH2:15]([CH:12]([CH2:13][CH3:14])[CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:17])=[O:3])[CH3:16]
Reactant: CCOC(=O)C(CC(CC)CC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(CC)CC(C(=O)O)C(=O)O
Temperature: 105 °C
Yield: 96.7 %

Procedure:
A solution of 2-(2-ethyl-butyl)-malonic acid diethyl ester (4.78 g, 19.5 mmol) in ethanol (43.5 mL) was treated with a solution of potassium hydroxide (3.3 g, 58.7 mmol) in water (10.9 mL). The reaction was then heated to 105° C. for 6 h. After this time, the reaction was concentrated in vacuo. The residue was diluted with water (50 mL) which was then acidified with a 2N aqueous hydrochloric acid solution and then extracted with a 90/10 methylene chloride/methanol solution (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-(2-ethyl-butyl)-malonic acid (3.55 g, 96%) as an off-white solid, which was used without further purification; EI+-HRMS m/e calcd for C9H16O4 [M+Na]+ 211.0941, found 211.0941. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79 (t, J=7.4 Hz, 6H) 1.09-1.39 (m, 5H) 1.65 (t, J=7.1 Hz, 2H) 3.22 (t, J=7.5 Hz, 1H) 12.65 (br. s., 2H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Product: CC(C)(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 50.9 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (5.0 g, 19.45 mmol) in tert-butylamine (20 ml, 0.19 mol) was stirred for 20 h at 125° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (25 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and then redissolved in 1 N sodium hydroxide (130 ml) followed by treatment with decolorising charcoal. After filtration, the clear solution was acidified to pH 2 and the precipitate was filtered off and recrystallised from methanol to give 2.91 g (52%) of the pure title compound; mp 368-372° C.; 1H-NMR (DMSO-d6): δ1.37 (s, 9H), 6.79 (br s, 1H), 7.11 (s, 1H), 10.55 (br s, 1H); MS: m/e 293/295 (M+); (C9H12N3Cl1O2S2) calc. C, 36.79; H, 4.12; N, 14.30; Cl, 12.07; S, 21.83; found C, 36.90; H, 4.11; N, 14.18; Cl, 12.05; S, 21.89.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=23)[CH:5]=[CH:4][CH:3]=1.[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C.O>CS(C)=O>[CH:19]1([CH2:25][NH:26][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=34)[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1ccn2ncc(-c3cccc(Cl)n3)c2c1
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccn2ncc(-c3cccc(NCC4CCCCC4)n3)c2c1
Temperature: 140 °C
Yield: 32.7 %

Procedure:
A mixture of 3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 6, 30 mg, 0.12 mmol), cyclohexylmethanamine (46 μL, 0.35 mmol) and triethylamine (50 μL, 0.36 mmol) in dimethylsulfoxide (0.5 mL) was heated at 140° C. for 20 hours. The mixture was then cooled, water was added and the resultant precipitate was filtered and dried in vacuo. Purification of the solid by flash chromatography (dichloromethane to 150:1 dichloromethane/methanol) gave the title compound (13 mg, 33%) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:33].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:33][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C. and treated with 5 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 6.50 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])[CH3:3].O.ON1[C:31]2C=CC=C[C:30]=2N=N1.C(O)C>C(Cl)Cl>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:22]([O:24][CH2:30][CH3:31])=[O:23])[CH2:10][CH2:11][C:12](=[O:13])[OH:14]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Boc-Glu (OBzl)-OH, 1.01 g (3.0 mmol), 620 mg (3.1 mmol) of N,N-dicyclohexylcarbodiimide (DCC) and 475 mg (3.1 mmol) of 1-hydroxybenzotriazole monohydrate (HOBt.H2O) were suspended in 12 ml of methylene chloride. The suspension was cooled to 0° C. and 175 μl of ethyl alcohol was added thereto. After reverting to room temperature, stirring was continued overnight. The mixture was extracted with ethyl acetate/water. After the organic layer was washed with aqueous saturated sodium chloride solution (brine), sodium sulfate was added thereto and dried. The organic layer was concentrated under reduced pressure. The resulting residue was dissolved in 12 ml of methanol, and 100 mg of 10% Pd/C was added to the solution. The mixture was stirred in a hydrogen atmosphere overnight and purified in accordance with the purification step A to give the crude product of the title compound.