Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:10]=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccccc1C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (30 mL) was cooled to 0° C. and solid N-(2-tert-butylphenyl)acetamide (1.0 g, 5.2 mmol) was added in several portions. To the resulting solution was added KNO3 (578 mg, 5.7 mmol). The reaction mixture was allowed to warm to rt over 2 h and then stirred at rt overnight. The reaction mixture was poured over ice and a white precipitate formed. The precipitate was isolated by filtration (1.04 g, 84%). LCMS: (FA) ES+ 237.2 (M+1), ES− 235.1 (M−1).
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@@H:6]([CH3:34])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[C:21]([CH3:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:34][C@@H:6]([O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[C:21]([CH3:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)[CH2:5][NH:4][CH3:1]
Reactant: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 82.5 %

Procedure:
A mixture of 5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (2.25 g, 4.8 mmol) and chlorotris(triphenylphosphine)rhodium(I) (463 mg, 0.48 ml) in acetonitrile—water (17 ml:3 ml) was heated at reflux for 3 hours. After cooling, the solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give 5-[(1R)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (1.70 g, 83%); Mass spectrum: MH+ 430.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[O:6]1[CH2:11][CH2:10][CH:9](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7]1>CN(C=O)C.CCOCC>[O:6]1[CH2:11][CH2:10][CH:9]([S:3][C:1](=[O:4])[CH3:2])[CH2:8][CH2:7]1
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SC1CCOCC1
Temperature: 50 °C

Procedure:
A mixture of potassium thioacetate (10.21 g; 87.62 mmol) and toluene-4-sulfonic acid tetrahydro-pyran-4-yl ester (11.23 g; 43.81 mmol) in DMF (100 mL) was heated at 50° C. for 12 hours, cooled to room temperature, diluted with ether, washed with water, saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was taken forward without additional purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC=CC=1.C(Cl)(Cl)Cl.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>CCOCC>[N:1]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCCCCBr
Reactant: C1CCNCC1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N#CCCCCCCN1CCCCC1

Procedure:
In a flask equipped with a dropping funnel and a cooler was placed a mixture of 8.94 g of piperidine, 7.7 ml of benzene and 1.5 ml of chloroform. The mixture was refluxed by heating, and to the mixture was dropwise added 9.50 g of 7-bromoheptanenitrile. After the addition was complete, the mixture was further refluxed by heating for 4 hours and then cooled under ambient condition. To the mixture was added ether, and the resulting mixture was stirred for a while. The reaction mixture was filtered to remove insolubles. The insolubles were washed with ether. The filtrate and washings were combined and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 7-piperidinoheptanenitrile as a colorless oil, yield: 8.92 g (theoretical yield).
Reaction SMILES: CO[C:3](=O)[N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[CH:16]=[C:17]([F:27])[CH:18]=[C:19]4[C:25](=[O:26])[NH:24][CH2:23][CH2:22][C:21]=2[C:20]=34)=[CH:9][CH:8]=1)C.C(CN)O.[OH-].[Na+]>Br.C(O)(=O)C>[F:27][C:17]1[CH:18]=[C:19]2[C:25](=[O:26])[NH:24][CH2:23][CH2:22][C:21]3=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH2:6][NH:4][CH3:3])=[CH:12][CH:11]=4)[NH:14][C:15]([CH:16]=1)=[C:20]23
Reactant: COC(=O)N(C)Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: NCCO
Product: CNCc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Temperature: 25 °C
Reaction time: 46 h
Yield: 87.6 %

Procedure:
Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30%-32%, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500 ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25° C. and 35° C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2×50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2×25 ml) and dried to afford 10.76 g of product (88% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.577 (s, 3H), 3.053 (m, 2H), 3.406 (m, 2H), 4.159 (s, 2H), 7.36 (dd, 1H, J=2.4 Hz and J=9.3 Hz), 7.44 (dd, 1H, J=2.4 Hz and J=11.1 Hz), 7.63 (d, 2H, J=8.1 Hz), 7.70 (d, 2H, J=8.1 Hz), 8.265 (t, 1H, J=5.7 Hz), 11.77 (s, 1H). Exact mass calculated for C19H19FN3O: 324.1512. Found: 324.1497.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[CH:15]=[CH:16][N+:17]([O-:19])=[O:18])[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].P([O-])(O)(O)=O.[Na+]>C(OCC)C.C(O)C>[C:1]([O:4][C@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[CH2:15][CH2:16][N+:17]([O-:19])=[O:18])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=C[N+](=O)[O-])CC[C@]32O)C1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](CC[N+](=O)[O-])CC[C@]32O)C1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 13.86 g of 3β-acetoxy-21-nitro-5β-pregn-20-en-14β-ol (Eberlein W. et al., Chem. Ber., 1974, 107, 1275) in 440 ml of diethyl ether and 440 ml of ethanol, 2.86 g NaBH4 were added at room temperature. After 1 hr. the mixture was neutralized with aqueous sodium dihydrogenphosphate and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 13.40 g of 3β-acetoxy-21-nitro-5β-pregnane-14β-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br.Br[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(N(C(C)C)CC)(C)C>>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH3:25]
Reactant: Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reactant: CCN(CC)CCBr
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 150 °C

Procedure:
Cyclopropanecarboxylic acid [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (0.05 g, 0.17 mmol), 2-bromo-N,N-diethylethylamine hydrobromide (0.133 g, 0.511 mmol) and diisopropylethylamine (0.089 mL, 0.511 mmol) were added to a microwave tube and the mixture was heated for 10 min at 150° C. The mixture was filtered and purified by preparatory LCMS. LCMS Method: 2: RT: 2.07 min; MI: 393 [M+1]. NMR (DMSO, 300 MHz): 0.81 (d, 4H), 1.10 (t, 6H), 2.04 (brs, 1H), 2.89 (m, 6H), 3.33 (t, 2H), 6.75 (d, 2H), 7.20 (dd, 1H), 7.53 (m, 1H), 7.64 (m, 1H), 7.92 (d, 2H), 8.18 (s, 1H), 11.00 (s, 1H)
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:27]=[CH:28][CH:29]=2)[N:5]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:6](=[O:21])[C:7]=1[C:8]1[NH:13][C:12]2[CH:14]=[CH:15][C:16](I)=[CH:17][C:11]=2[S:10](=[O:20])(=[O:19])[N:9]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N(CC(O)=O)C.[CH3:54][NH:55][S:56]([CH3:59])(=[O:58])=[O:57]>C(OCC)(=O)C.[Cu]I.CN(C)C=O>[OH:1][C:2]1[C:3]2[N:4]([CH:27]=[CH:28][CH:29]=2)[N:5]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:6](=[O:21])[C:7]=1[C:8]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([N:55]([CH3:54])[S:56]([CH3:59])(=[O:58])=[O:57])=[CH:17][C:11]=2[S:10](=[O:20])(=[O:19])[N:9]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Reactant: CNS(C)(=O)=O
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)c(O)c2cccn21
Yield: 31.4 %

Procedure:
4-Hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (Example 6a, 0.188 g, 0.357 mmol), potassium triphosphate (0.379 g, 1.78 mmol), sarcosine (0.019 g, 0.214 mmol), and copper (I) iodide (0.017 g, 0.089 mmol) were combined. Anhydrous N,N-dimethylformamide (7 mL) was added followed by N-methyl-methanesulfonamide (0.39 g, 3.57 mmol). The solution was degassed while stirring under vacuum and the flask purged with nitrogen. The mixture was stirred at 100° C. for 1 h. Additional copper (I) iodide (0.1 g, 0.525 mmol) was added. The mixture continued to stir at 100° C. for 3 h. Upon cooling, the mixture was diluted with ethyl acetate (200 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to a solid. Purification by flash column chromatography (5% ethyl acetate in dichloromethane) followed by trituration from ethyl acetate and collection by vacuum filtration afforded the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.057 g, 0.112 mmol, 31% yield) as a pale yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.97 (6H, d, J=6.4 Hz), 1.59 (2H, q, J=7.6 Hz), 1.73 (1H, septet, J=6.5 Hz), 3.01 (3H, s), 3.31 (3H, s), 4.41 (2H, t, J=7.9 Hz), 6.70-6.72 (1H, m), 7.04 (1H, d, J=4.5 Hz), 7.69-7.76 (2H, m), 7.88 (1H, d, J=2.3 Hz), 7.91 (1H, s), 13.79 (1H, bs). LC-MS (ESI) calcd for C21H25N5O6S2. found 507.12. found 508.4 [M+H+].
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:38])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH2:34][C:35](O)=[O:36])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl.C([N:42]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.N>O.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:38])[N:8]([C:27]2[N:28]=[CH:29][C:30]([O:33][CH2:34][C:35]([NH2:42])=[O:36])=[CH:31][N:32]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ncc(OCC(=O)O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ncc(OCC(N)=O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
Process 2: The dichloromethane (3 mL) solution of 2-{2-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]pyrimidin-5-yl oxy}acetic acid (51 mg, 0.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (29 mg, 0.15 mmol) and 1-hydroxybenzotriazol-hydrate (21 mg, 0.15 mmol) was stirred at room temperature for 1 hr. Ammonia (28% aqueous solution, 0.5 mL) was added thereto and stirred at room temperature for 4 hrs. The reaction mixture was added water and extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (chloroform/methanol) to obtain 2-{2-{4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl}pyrimidin-5-yl oxy}acetamide (35 mg, 69%) as a colorless and transparent oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1([O:23][C:24](=O)[NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)C=CC=CC=1>>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:24]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[CH2:16][CH2:15]1)=[O:23]
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Product: O=C(Nc1nccs1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from 1-benzo[1,3]dioxol-5-ylmethyl-piperazine and thiazol-2-yl-carbamic acid phenyl ester in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 7.30 (d, J=4.0 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J=3.8 Hz, 1H), 6.77 (s, 2H), 5.97 (s, 1H), 5.96 (s, 2H), 3.62 (bs, 4H), 3.53 (s, 2H), 2.54 (bs, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)C.[ClH:28]>C(OCC)C>[ClH:28].[CH3:24][C:22]1[O:21][N:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=3[CH:15]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)no1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(-c2ccc3c(c2)CCNCC3)no1
Reaction time: 12 h
Yield: 81 %

Procedure:
7-(5-Methyl-isoxazol-3-yl)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (1.9 g, 5.8 mmol) was treated with ethanol (20 ml) followed by a saturated ethanolic hydrochloride solution (20 ml). The mixture was stirred for 12 h until a precipitate was observed. Diethyl ether (100 ml) was added and the precipitate filtered and dried in vacuo to give the title compound as a colourless solid (1.25 g, 81%).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][C:11]2[N:12]=[C:13]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH3:28])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:31]>CCOCC.O1CCOCC1>[ClH:31].[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[C:10]3[CH2:9][NH:8][CH2:30][CH2:29][C:11]=3[N:12]=[C:13]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH3:28])[N:14]=2)=[CH:21][CH:20]=1
Reactant: CC1CCCN1c1nc2c(c(-c3ccc(F)cc3)n1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1CCCN1c1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (0.193 g, 0.47 mmol) in Et2O (2 mL) was added 4 M HCl in dioxane (2.5 mL). After 16 h, the mixture was concentrated and the residue was triturated with Et2O to give the title compound (0.124 g, 76%) as a white solid. MS (ESI): mass calcd. for C18H21FN4, 312.4; m/z found, 313.4 [M+H]+. 1H NMR (DMSO-d6): 9.54 (m, 2H), 7.64 (dd, J=8.5, 5.5, 2H), 7.37 (t, J=8.8, 2H), 4.23-4.04 (m, 3H), 3.58-3.36 (m, 4H), 3.03-2.95 (m, 2H), 2.08-1.96 (m, 2H), 1.93-1.85 (m, 1H), 1.71-1.64 (m, 1H), 1.21 (d, J=6.3, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([O:14]C)=[O:13])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CC(O)=O>CO>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([OH:14])=[O:13])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)nc(C(=O)OC)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc(C)nc(C(=O)O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of 68 4 mg (0.155 manol) 6-butyl-4-methoxycarbonyl-2-methyl-5-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrimidine in 5 mL methanol was added ~0.300 mL 10% NaOH. After stirring at room temperature for 2.5 hours, the mixture was acidified with ~0.500 mL HOAc. Volatiles were removed in vacuo. The crude material was redissolved in methanol along with a couple of drops of TFA, then was HPLC'd using the following conditions: Rainin Dynamax® C-18 column, 25×2.14 cm w/Guard Column; gradient of acetonitrile in water 5 to 100% over 40 minutes at 5 mL/minute; gradient held at 82% for 7 minutes. A yield of 66.1 mg (100%) of the title compound was obtained. Rf 0.14 in 1/30/69 NH4OH/MeOH/CH2Cl2, visualized by UV; 1H-NMR (300 MHZ, CDCl3): δ~9.7-8.8 (v br s 2H) 7.97 (m, 1H), 7.52 (m, 2H), 7.37 (m, 1H), 7.00 (br s, 4H), 4.51 (br s, 2H), 2.86 (3 line m, 2H), 2.75 (br s, 3H), 1.62 (m, 2H), 1.36 (m, 2H), 0.88 (3 line m, 3H); MS(FAB) m/e 429 (M+1).
Reaction SMILES: C(OP([CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[H-].[Na+].[C:19]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O>C(COC)OC>[C:19]1(=[CH:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)C=CCP(=O)(OCC)OCC
Reactant: O=C1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C=CC=C1CCCCCC1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
6.7 ml of ethyl 4-(diethoxyphosphoryl)-2-butenoate are dissolved in 7 ml of dimethoxyethane and the solution is then poured onto 1.3 g of 60% sodium hydride in 40 ml of dimethoxyethane. After stirring for 45 minutes, the mixture is cooled to 10° C., 3.2 ml of cycloheptanone are then added dropwise and the mixture is allowed to return to RT. After stirring for 4 hours, the mixture is poured onto cold water and then extracted with ether, and the extracts are dried and evaporated. The residue is chromatographed on silica, eluting with DCM. 1.9 g of the expected compound are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[O:8]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9]1.O>CN(C)C=O>[OH:8][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCCCCC1CO1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(O)Cn1ccnc1
Yield: 75 %

Procedure:
Imidazole (40.8 g) in 100 ml of dimethyformamide at room temperature was treated with sodium hydride (4.8 g of 50% dispersion in mineral oil). Once a solution was obtained, 1,2-epoxyoctane (40 g) was added dropwise at room temperature and the resulting mixture placed in an oil bath and warmed to 70° for 6 hours with stirring. The resulting cooled solution was then added to 600 ml of water and extracted with ether (4×400 ml). The combined extracts were washed twice with concentrated aqueous potassium hydroxide, dried (MgSO4) and concentrated. The resulting ethereal solution was stored at 0° and the resulting precipitate filtered to give 45.93 g of 1-(2-hydroxyoctyl)imidazole, m.p. 44°-45.5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:39](=[CH:43]\[CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)/[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31](/[C:39](=[CH:43]\[CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)/[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2ccccn2)cc1Cl
Temperature: 0 °C
Yield: 25.4 %

Procedure:
A solution of triphenylphosphine (266 mg, 01.01 mmol) in methylene chloride (11 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (204 mg, 1.15 mmol). The reaction mixture was stirred at 0° C. until the reaction mixture became homogeneous. The resulting light purple reaction mixture was then treated with (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid (prepared in Example 9, 222 mg, 0.68 mmol), and the reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-aminopyridine (95 mg, 1.01 mmol) and pyridine (0.098 mL, 1.22 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75/25 hexanes/ethyl acetate) afforded (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-acrylamide (70 mg, 25%) as a yellow glassy solid: EI-HRMS m/e calcd for C20H21ClN2O3S (M+) 404.0961, found 404.0962.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14](=O)[CH2:15][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Si:20]([O:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:14]1[S:38][C:2]([NH2:1])=[C:3]([C:4]2[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=2[O:11][CH3:12])[N:13]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1N
Temperature: 95 °C
Yield: 33 %

Procedure:
A mixture of N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethylsilyloxy)-3-methylbutanamide (327 mg, 0.76 mmol), Lawesson's reagent (308 mg, 0.76 mmol) and pyridine (2.5 mL) was heated to 95° C. for 18 hours. DCM was added, the organics washed with sodium hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (DCM) to afford 107 mg (33%) of 2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine LCMS (ESI) m+H=427.3.