Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[N:14][CH:15]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccnc(N)n1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: CC(C)(C)c1ccnc(NC(=O)c2ccc(Cl)nc2)n1

Procedure:
N-(4-tert-Butyl-pyrimidin-2-yl)-6-chloro-nicotinamide was prepared from 4-tert-butyl-pyrimidin-2-ylamine (prepared as described in J. Org. Chem. 1977, 221) and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after silica gel purification with 20-40% EtOAc in hexanes gradient followed by suspension in hexanes and filtration. HRMS m/z calcd for C14H15N4OCl [M+H]+: 291.1007. Found: 291.1007.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[O:1][CH2:12]1
Reactant: BrCBr
Reactant: N#Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCO2
Temperature: 120 °C
Yield: 94.8 %

Procedure:
To a solution of 3,4 Dihydroxy benzonitrile (5.0 g, 37.0 mmol) in 20 ml of DMF was added dibromomethane (19.25 g, 110.0 mmol) and potassium carbonate (25.50 g, 184.90 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), reaction mixture was cooled to room temperature. Water (50 ml) was added to the reaction mixture and extracted the compound with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to give the title compound as yellow solid (5.16 g, 94.8%).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([S:42]([CH3:41])(=[O:44])=[O:43])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2c(C)cc3cn(S(C)(=O)=O)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (0.800 g, 1.71 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.476 mL, 3.42 mmol), followed by methanesulphonyl chloride (0.265 mL, 3.42 mmol). The dark colored homogeneous reaction mixture was stirred for 1 h at 20° C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) yielding a brown solid that was recrystallized from ethyl acetate to afford the title compound as colourless crystals with a melting range of 135-175° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]ccc23)cc1
Temperature: 110 °C

Procedure:
To a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (3.1 g, 20 mmol) dissolved in DMF (60 ml) are added 4-nitrophenol (4.9 g, 35 mmol) and potassium carbonate (5.3 g, 38 mmol). The resulting solution is heated to 110° C. overnight. After the completion of reaction as indicated by disappearance of starting material, the reaction mixture is cooled to ambient temperature and poured into cold water. The resulting solids are collected by filtration and washed with water (3×100 ml). The crude product is purified by flash column chromatography using hexanes:ethyl acetate (1/1 v/v) as eluent to afford the title compound as a solid: 1H NMR 400 MHz (DMSO-d6) δ 12.34 (bs, 1H), 8.35 (m, 3H), 7.57 (m, 3H), 6.61 (m, 1H); HRMS (MALDI-FTMS) calculated for C12H9N4O3 [MH]+ 257.0669,found 257.0670.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21])=[N+:2]=[N-:3].[C:22]([O:26][CH3:27])(=[O:25])[C:23]#[CH:24]>C1C=CC=CC=1>[F:21][C:5]1[CH:6]=[C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:24]=[C:23]([C:22]([O:26][CH3:27])=[O:25])[N:3]=[N:2]1
Reactant: C#CC(=O)OC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Solvent: c1ccccc1
Product: COC(=O)c1cn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)nn1
Yield: 68.6 %

Procedure:
A solution 1.0 g (3.4 mmol) of the azide of Example 17 in 50 mL benzene was treated with 573 mg (6.8 mmol) of methyl propiolate followed by warming at reflux for 24 h. The mixture was cooled and the product isolated by filtration of the reaction mixture. These procedures afforded 880 mg of the title compound as a white solid. High Resolution Mass Spectrum (EI): calcd for C16H16FN5O5 : 377.1135. found: 377.1131.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])=[CH:14][CH:15]=1)=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1>C(Cl)Cl.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=4[F:26])=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 1 h at reflux. Title compound: ESI-MS: 517.1 [M+H]+; tR=3.37 min (System 1); TLC: Rf=0.11 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([CH:11]=O)=[CH:9][NH:8][N:7]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:10]3[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:7][NH:8][CH:9]=3)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: O=Cc1c[nH]nc1-c1cccs1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]nc3-c3cccs3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(2-thienyl)-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+:16].[K+].[C:18]([OH:22])(=[O:21])[CH:19]=O>CO>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[CH:19][C:18]([O-:22])=[O:21])#[N:11].[K+:16]
Reactant: O=CC(=O)O
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
18.6g (0.1 mol) of (3,4-dichlorophenyl)acetonitrile and 35 g (0.25 mol) of potassium carbonate were initially charged in 200 ml of methanol and admixed with 22.2 g (0.15 mol) of 50% strength agueous glyoxylic acid, and the mixture was stirred at room temperature for 5 h. The residue was filtered off, washed with methylene chloride, stirred with 1 l of water at room temperature overnight and filtered off, and the precipitated product was washed with water and dried. Yield 26.2 g, m.p. 235-238° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:32][C:33]1[N:37]([CH2:38][C:39](O)=[O:40])[N:36]=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:37]3[C:33]([CH3:32])=[CH:34][C:35]([C:42]([F:45])([F:44])[F:43])=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)Nc1cncc(C(=O)c2cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c3c(F)cncc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (22 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (166 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (70%, 37 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])[CH3:11].[OH-].[K+]>CO>[CH2:10]([O:12][C:13]([N:15]1[CH2:16][CH:17]=[C:18]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Yield: 57.5 %

Procedure:
A suspension 5.51 g (0.05 mol) of 7-azaindol, 9.6 g (0.056 mol) of 4-oxo-piperidine-1-carboxylic acid ethyl ester and 5 g (0.075 mol) of potassium hydroxide in 120 ml of methanol was heated at 75° C. for 16 hours. The crude mixture was cooled at room temperature and the precipitate formed was filtered off. 7.8 g (57% of yield) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1.Cl[C:32]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:33].Cl>C1COCC1>[OH:30]/[C:28](/[C:25]1[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=1)=[CH:29]\[C:32](=[O:33])[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CSc1ccc(C(C)=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC(=O)CCCC(=O)/C=C(\O)c1ccc(SC)cc1
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (1.5 M; 28 mL, 42 mmol) was added to a solution of 1-(4-methylthiophenyl)ethan-1-one (5.16 g, 31 mmol) in THF (120 mL) and stirred for 30 minutes at −72° C. A solution of methyl 4-(chloroformyl)butyrate (1.78 g, 10.8 mmol) was added to the above solution and stirred for 30 minutes and then warmed slowly from the −72° C. to −45° C. To the reaction mixture was added 3N HCl (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and evaporated. Trituration of the residue with diethyl ether/hexane gave a mixture of the title compound and starting material (˜30% yield) as a solid (2.42 g). The crude material was used in the next step without purification. A small quantity of pure sample was obtained at the beginning of the trituation. Mp. 92-93° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1.[Na+].[I-:18]>CC(=O)CC.CCCCCCC>[I:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)C1(CCCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)C1(CCCCCI)CC1
Yield: 97.7 %

Procedure:
To a solution of tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g, 128 mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166 mmol). The reaction mixture was stirred under reflux for 24 h, diluted with heptane (220 mL) and filtered through a layer of silica 2 cm) in a glassfilter. The residue was eluted with a mixture of heptane and EtOAc (3:1, 5×100 mL). The combined filtrate and elutes were evaporated in vacuo to give tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (42.3 g, 99%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=3.18 (t, J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=174.0, 79.9, 34.1, 33.6, 30.8, 28.2 (3×), 26.8, 24.3, 15.4 (2×), 7.4. HRMS calcd for C13H2IO2 (M+): 338.0743. found: 338.0743.
Reaction SMILES: [H-].[Na+].CCO.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7]1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)C>[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([C:8]2[C:9]3[C:14](=[N:13][CH:12]=[CH:11][CH:10]=3)[NH:6][CH:7]=2)([OH:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC1(c2c[nH]c3ncccc23)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.6 %

Procedure:
A 60% dispersion of NaH in mineral oil (9.5 g, 179 mmol) was slowly added to 150 ml EtOH (0° C.). This solution was added to 7-azaindole (5.3 g, 44.9 mmol) and 11.25 g (44.9 mmol) 1-benzyl-piperidin-3-one (as HCl salt). The resulting mixture was stirred for 72 hours at room temperature. Ethylacetate was added to the mixture and the organic layer was washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/ethylacetate gradient (1:1 to pure ethylacetate)) to give compound 3 as an oil (10.3 g, 74.7%). 1H-NMR (400 MHz, CDCl3): δ 10.0 (bs, 1H), 8.27 (dd, J=5 Hz, 2 Hz, 1H), 8.14 (dd, J=8 Hz, 2 Hz, 1H), 7.35-7.24 (m, 6H), 7.03 (dd, J=5 Hz, 8 Hz, 1H), 3.96-3.88 (bs, 1H), 3.60 (dd, J gem=13 Hz, 2H), 3.07-3.01 (m, 1H), 2.95-2.89 (m, 1H), 2.39 (d, J=10 Hz, 1H), 2.16-1.96 (m,2H), 1.92-1.78 (m, 2H), 1.72-1.65 (m, 1H). (TLC EtOAc Rf 0.09).
Reaction SMILES: SCCC[Si](OC)(OC)OC.OCCOCCOCCOCC[N:24]([CH2:26][CH2:27][CH2:28][Si:29]([O:40][CH2:41]CCC)([O:35][CH2:36]CCC)[O:30][CH2:31]CCC)C>>[NH2:24][CH2:26][CH2:27][CH2:28][Si:29]([O:40][CH3:41])([O:30][CH3:31])[O:35][CH3:36]
Reactant: CCCCO[Si](CCCN(C)CCOCCOCCOCCO)(OCCCC)OCCCC
Agent: CO[Si](CCCS)(OC)OC
Product: CO[Si](CCCN)(OC)OC

Procedure:
##STR19## HSCH2CH2CH2Si(OCH3)3 ; HO(C2H4O)3C2H4N(CH3)(CH2)3Si(OC4H9)3 ;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([NH2:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]2[N:23]=[C:24]([C:26](N)=[O:27])[S:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([NH:16][C:26]([C:24]3[S:25][C:21]4[CH:20]=[C:19]([O:18][CH3:17])[CH:30]=[CH:29][C:22]=4[N:23]=3)=[O:27])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(N)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2nc(C(N)=O)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(C(=O)Nc3nnn(Cc4ccc(Cl)c(Cl)c4)c3C)sc2c1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-amine (Intermediate 19) (0.1 g, 0.39 mmol), 6-(methyloxy)-1,3-benzothiazole-2-carboxamide (81 mg, 1 eq), HATU (0.192 g, 1.3 eq) and DIPEA (0.12 mL, 1.3 eq) in DMF (5 mL) was stirred at 45° C. for 48 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography eluting with DCM/MeOH (99/1) to give after recrystallisation from acetonitrile the title compound as pink pale crystals (110 mg, 65%). HRMS calculated for C19H15Cl2N5O2S (M+H)+448.0402, found: 448.0406, Rt: 3.08 min. MP: 176° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4].Cl[C:21]1[C:22]2[N:29]=[N:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:23]=2[N:24]=[CH:25][N:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[C:23]2[N:24]=[CH:25][N:26]=[C:21]([O:18][C@@H:13]([CH2:14][O:15][CH2:16][CH3:17])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][N:9]=3)=[O:19])[C:22]=2[N:29]=[N:28]1
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1
Reactant: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1nnn2-c1ccccc1Cl)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
Sodium hydride (82 mg, 2.05 mmol) was added to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (177 mg, 0.75 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (Intermediate AP2) (200 mg, 0.75 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 60% EtOAc in isohexane to afford the product (136 mg, 38.9%). 1H NMR (400 MHz, CDCl3) δ1.24 (t, 3H), 3.61-3.74 (m, 2H), 4.13-4.21 (m, 2H), 6.13 (t, 1H), 7.51-7.62 (m, 3H), 7.67-7.71 (m, 1H), 7.93-7.98 (m, 1H), 8.36-8.40 (m, 1H), 8.57-8.59 (m, 1H), 8.71 (s, 1H), 9.19 (s, 1H); m/z (ESI+) (M+H)+=463.23; HPLC tR=2.43 min
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([CH2:44][CH2:45][OH:46])[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][N:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([CH2:44][CH2:45][OH:46])[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
A mixture of Intermediate 120c (35 mg, 0.10 mmol), Intermediate 110b (54 mg, 0.15 mmol) and DIPEA (53 μL, 0.30 mmol) in dioxane (1 mL) was stirred at 50° C. overnight. After cooling, the reaction mixture was loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The resultant residue was purified by FCC on silica, using a gradient of 1-8% MeOH in DCM followed by MDAP (Method 7) purification, to afford the title compound (4 mg, 7%) as a glassy white solid. LCMS (Method 5): Rt 3.02 min, m/z 586 [MH+]. NMR (400 MHz, d4-MeOD): 1.20-1.30 (2H, m), 1.25 (9H, s), 1.40-1.52 (1H, m), 1.63-1.83 (3H, m), 1.85-1.92 (2H, m), 2.01 (3H, s), 2.06-2.20 (3H, m), 2.24 (1H, td, J=11.7, 3.1 Hz), 2.31-2.38 (1H, m), 3.04-3.09 (1H, m), 3.76-3.81 (1H, m), 3.81 (2H, t, J=5.4 Hz), 4.08 (2H, t, J=5.4 Hz), 4.98 (1H, dd, J=8.1, 6.5 Hz), 5.36 (1H, t, J=3.8 Hz), 6.12 (1H, s), 7.24 (1H, t, J=7.4 Hz), 7.28-7.37 (3H, m), 7.44 (1H, d, J=7.8 Hz), 7.66 (1H, dd, J=9.9, 0.6 Hz), 8.46 (1H, d, J=1.9 Hz).
Reaction SMILES: CO.[N+:3]([C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:9]=[C:8]([C:17]([NH:19][C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:22]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:21]=2)=[O:18])[CH:7]=1)([O-])=O>C1COCC1.[Pd]>[NH2:3][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:9]=[C:8]([C:17]([NH:19][C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:22]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:21]=2)=[O:18])[CH:7]=1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc([N+](=O)[O-])n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(NC(=O)c3cc(N)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Reaction time: 16 h
Yield: 99.3 %

Procedure:
Methanol (5 mL) and Pd/C were added to a solution of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxamide (183 mg, 0.38 mmol) in THF. The flask was then evacuated and filled with hydrogen. The reaction mixture was stirred for 16 hrs. The catalyst was filtered on celite and the solution was concentrated and dried to give 5-amino-1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxamide (170 mg, quantitative).