Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27]>O>[OH:27][N:26]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: NO
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: ON=C1CC(c2ccccc2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 3-phenylindan-1-one (80 g), methanol (935 ml), water (90 ml), potassium carbonate (103.8 g), and hydroxylamine HCl (104.3 g) was heated at reflux for 16 hours, then poured into ice-water: the title compound was filtered, washed with water, with a small portion of ether, then dried in air. Yield: 74.7 g; m.p. 133°-139°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[C:15]([C:16]2[C:21]([NH:22][C:23](OCC3C=CC=CC=3)=O)=[CH:20][CH:19]=[C:18]([O:33][CH3:34])N=2)=[CH:14][NH:13][CH:12]=1)=[O:10])[CH3:7].[C:35](=O)(O)[O-].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:15]2[C:16]3[CH:35]=[C:18]([O:33][CH3:34])[CH:19]=[CH:20][C:21]=3[N:22]=[CH:23][C:14]=2[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1c[nH]cc1-c1nc(OC)ccc1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2cnc3ccc(OC)cc3c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 10 mL aliquot DMF is cooled to 5° C. To this is added 2.26 mL (0.024 mol) of phosphorous oxychloride. The mixture is warmed to room temperature, stirred for 15 minutes and cooked to 5° C. To this solution is added dropwise a solution 3.2 g (0.08 mol) of 4-(benzyloxycarbonylamino-6-methoxy-pyridin-2-yl)-1H-pyrrole-3-carboxylic acid ethyl ester dissolved in 15 mL of DMF. The reaction mixture is warmed to room temperature and stirred for 3 hours. The reaction mixture is carefully poured into 100 mL of saturated sodium bicarbonate. The pH is adjusted to 8 with solid K2CO3 and the mixture extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and evaporated. The residue is chromatographed on 150 g of silica gel using ethyl acetate followed by 10/1 chloroform/methanol as the eluant. Appropriate fractions are combined to yield 1.46 grams of 8-methoxy-3H-pyrrolo [2,3-c]quinoline-1-carboxylic acid ethyl ester. 1H NMR (CDCl3) δ9.10 (s, 1H), 8.35 (d, 1H), 8.10 (s, 1H, 7.2 (s, 1H), 7.05 (d, 1H), 4.4 (q, 2H), 4.10 (s, 3H), 1.40 (t, 3H). Mass spectrum: m/e=260 (p+1). TLC (ethyl acetate) Rf=0.3.
Reaction SMILES: O.[C-:2]#[N:3].[Na+].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1C=CC=CC=1>[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][C:2]#[N:3])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)cc1
Yield: 95.7 %

Procedure:
In a 100 ml four-necked flask, there were placed 3.2 g of water, 1.23 g (0.025 mole) of sodium cyanide and 0.16 g of triethylbenzylammonium chloride, and a solution prepared by dissolving 5.3 g (0.023 mole) of 4-benzyloxybenzyl chloride in 6 g of benzene was further added thereto under stirring. Then, the resultant mixture was heated at a temperature of 80° C. for 5 hours under stirring to permit a reaction. After completion of the reaction, the formed organic layer is washed with water and dried over anhydrous sodium sulfate, followed by distilling off benzene to obtain 4.83 g (0.022 mole) of 4-benzyloxyphenylacetonitrile.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:19][C:13]1[CH:12]=[C:11]([N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Cc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of 4-(trifluoromethyl)-1H-pyrazole (1.0 g, 7.0 mmol) and 4-fluoro-2-methylbenzonitrile (1.16 g, 8.50 mmol) in acetonitrile (8 mL) was slowly added potassium carbonate (1.96 g, 14.2 mmol) at room temperature. The reaction was heated to 80° C. and stirred overnight. The reaction was cooled to room temperature and poured into water. The layers were separated and the aqueous was extracted with ethyl acetate (3×15 mL). The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (710 mg, 40%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.26 (s, 1H), 7.94 (s, 1H), 7.72-7.74 (m, 2H), 7.61-7.64 (m, 1H), 2.64 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:46][CH3:47])[C:38]2[O:43][CH2:42][O:41][CH2:40][C:39]=2[C:44]=1[F:45])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:45][C:44]1[C:39]2[CH2:40][O:41][CH2:42][O:43][C:38]=2[C:37]([O:46][CH3:47])=[CH:36][C:35]=1[CH:21]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)COCO2
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
After adding 21 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 105 mg of {2-(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (74 mg) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]=O)[S:5][C:6]=1[CH3:7].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([CH:8]=[N:11][OH:12])[S:5][C:6]=1[CH3:7]
Reactant: NO
Reactant: Cc1nc(C=O)sc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(C=NO)sc1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4,5-dimethylthiazole-2-carbaldehyde (987 mg, 7.0 mmol) in 1,4-dioxane (35 mL) was added hydroxylamine hydrochloride (1.45 g, 21 mmol) and K2CO3 (3.8 g, 28 mmol). The resulting mixture was stirred at 100° C. for 2 hours and then diluted with EtOAc (150 mL), washed with H2O (30 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was used for next step without further purification. LCMS m/z (M+H) 157.1 found, 157.1 required.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:35][CH2:36]1)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 33.6 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-fluoro-N-isopropyl-4-(piperazin-1-yl)benzamide hydrochloride (138 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-fluoro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (71.4 mg, 0.153 mmol, 33.6% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6.57 Hz, 6 H) 1.82-2.01 (m, 3 H) 2.12-2.24 (m, 1 H) 2.46-2.50 (m, 4 H) 2.98-3.15 (m, 4 H) 3.35-3.44 (m, 3 H) 3.54-3.64 (m, 1 H) 3.92-4.14 (m, 2 H) 6.98 (d, J=1.77 Hz, 1 H) 7.03 (t, J=8.84 Hz, 1 H) 7.56-7.66 (m, 3 H) 8.09 (d, J=7.83 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C25H31FN6O2, 467; found, 467.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C=O)c1cccc(O)c1
Yield: 56 %

Procedure:
A mixture of 38.9 g. (0.153 mole) of 2-(3-benzyloxyphenyl)-2-methylpropanal, 20 g. 5% Pd/C/50% water, 1.0 sodium bicarbonate and 150 ml. ethanol was shaken overnight under 55 psi of hydrogen. The reaction was filtered through diatomaceous earth, the filter cake washed with ethanol and the combined filtrate evaporated. The residue was reduced as above for another 8 hours. Another 10 g. portion of catalyst was added and the reaction continued overnight. The reaction was worked-up as above and the residue purified via column chromatography on 500 g. of silica gel eluted with 25% ether-hexane to yield 14 g. (56%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: Cn1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (600 mg), 2-chloromethyl-1-methyl-1H-benzimidazole (360 mg), potassium carbonate (550 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (730 mg, yield: 84%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1C(OC)=O.O>CN1CCCC1=O.CN1CCNCC1>[NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:4]=2[S:5][CH:6]=1
Reactant: COC(=O)c1sc2ccc([N+](=O)[O-])cc2c1N
Agent: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1csc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
A solution of 23.00 g (91.26 mmol) of methyl 3-amino-5-nitrobenzo[b]thiophene-2-carboxylate (J. Hetero. Chem, 34(4), 1163 (1997)) in 100 mL of 1-methyl-2-pyrrolidinone and 30 mL of 1-methylpiperazine is heated at 180° C. for 2 hours. The reaction is cooled to room temperature and poured into water. The resultant solid is collected by filtration and washed with water. The solid is dissolved in a mixture of ethyl acetate and diethyl ether and the solution is washed with water twice. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether and hexane are added to the residue and the dark red solid is collected by filtration to provide 11.17 g (63%), mp 155–158° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCCCO1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Temperature: 25 °C
Yield: 85 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.20 g) was heated with anhydrous potassium carbonate (0.315 g) in dry DMF (5 mL) at 60° C. for 1 hour and cooled to room temperature. 2-(Bromomethyl) tetrahydro-2H-pyran (73 uL) was added and the reaction mixture heated at 50° C., overnight. The reaction mixture was quenched into water (50 mL) and extracted into ethyl acetate (25 mL, 3 times). The combined organic layers were separated and passed through a hydrophobic frit to dry, then stripped to dryness and the pale yellow gum (145 mg), which turned to a white solid when triturated with methanol, was purified by MDAP to give the title compound (6 mg) (˜85% pure).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1nccc(N2CCN(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(tert-butoxycarbonyl)-4-(1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl)piperazine (700 mg) was stirred in dichloromethane (20 ml) and triethylarnine (1.34 ml) and cooled in an ice-bath. 4-chlorobenzenesulphonylchloride (0.56 g) was added and reaction allowed to warm to room temperature and then stirred overnight. The mixture was evaporated and the residue was purified by chromatography on silica gel using in gradient of dichloromethane to 8% methanol in dichloromethane as eluent to give a foam. This was triturated with diethylether to give 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperazine a colourless solid 1.05 g ;m.p. 183-184° C.; NMR (CDCl3): 8.15 (m, 1H), 7.7 (m, 2H), 7.55 (m, 2H), 6.3 (m, 1H), 3.65 (m, 4H), 3.45 (m, 4H), 3.35 (m, 4H), 3.05 (m, 4H), 2.5 (s, 3H).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C[N:27]1CCOCC1.N>C1COCC1>[C:9]([O:13][C:14](=[O:15])[NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23](=[O:25])[NH2:27])[CH2:18]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isobutylchloroformate (2.06 g, 15.0 mmol) was added dropwise with cooling in an ice-methanol bath to a solution of 3-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (3.15 g, 13.0 mmol) and N-methylmorpholine (1.52 g, 15.0 mmol) in THF (40 mL). After stirring for 30 mins, methanolic ammonia (7M, 5 mL) was added. The mixture was allowed to warm to room temperature, and left to stand overnight. The residue remaining on evaporation of solvent was partitioned between aq. NH4Cl (150 mL) and DCM (150 mL). The solid suspended in the organic layer was collected, the filtrate evaporated, and the combined solids crystallised from methanol to afford 2.07 (66%) of (3-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester as colourless plates. 1H NMR (400 MHz, MeOD) δ: 6.65-6.59 (m, 1H), 3.40-3.28 (m, 1H), 2.35-2.23, (m, 1H), 2.01-1.92 (m, 1H), 1.91-1.80 (m, 2H), 1.80-1.71 (m, 1H), 1.42 (s, 9H), 1.40-1.21 (m, 3H), 1.19-1.05 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:18](OC(C)(C)C)(=[O:26])[C:19](OC(C)(C)C)=[O:20].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:19](=[O:20])[C:18]([OH:26])=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1
Reactant: CC(C)(C)OC(=O)CCNc1ccccc1F
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 84 h
Yield: 47.8 %

Procedure:
To a solution of the title compound of Example C (5.41 g, 22.6 mmol) in dry THF (100 ml) was added di-tert-butyl oxalate (4.57 g, 22.6 mmol), followed by potassium tert-butoxide (5.07 g, 45.2 mmol) and the resulting dark yellow solution was stirred for 84 h at room temperature. The reaction mixture was then acidified with 1N HCl to pH=3, followed by the addition of H2O (35 ml) and the mixture was then extracted with CH2Cl2. The combined organic layers were dried with MgSO4, filtered and dried to give a solid which was chromatographed on silica gel eluting with 1/1/98 MeOH/HOAc/CH2Cl2 to give the title compound (3.166 g, 48%). Anal calcd for C15H16NO4F: C, 61.43; H, 5.50; N, 4.78. Found: C, 61.16; H, 5.50; N, 4.77.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](CO)[C:12](O)=[C:11](C)[C:10]=1[CH3:19])C1C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]([O:30][CH3:31])([O:28][CH3:29])[CH3:27])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:32])[CH2:24][CH2:25][C:26]1([CH3:27])[O:28][CH2:29][C:13]2[CH:14]=[C:9]([OH:8])[C:10]([CH3:19])=[C:11]([CH3:12])[C:31]=2[O:30]1)[CH3:21]
Reactant: CCOC(=O)CCC(C)(OC)OC
Reactant: Cc1c(OCc2ccccc2)cc(CO)c(O)c1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1(C)OCc2cc(O)c(C)c(C)c2O1
Reaction time: 48 h

Procedure:
To a solution of 4-benzyloxy-6-hydroxymethyl-2,3-dimethyl-phenol (52 mg, 0.20 mmol), prepared as in Example 29, in 0.5 mL of dry DMF was added the above dimethyl ketal, 4,4-dimethoxy-pentanoic acid ethyl ester (420 mg, 2.2 mmol) and 5 mg of pyridinium p-toluene sulfonate (PPTS). The mixture was stirred for 48 h and concentrated. The crude product was purified on silica gel column chromatography (8:1 hexane/EtOAc) to afford a clear oil containing the desired product and starting ketal material. This mixture was then dissolved in EtOH (5 mL) and hydrogenated in the presence of 10 mg of Pd/C for 1.5 h at atmosphere pressure. After filtration the solution was concentrated and purified by chromatography (5:1 hexane/EtOAc) to afford 3-(6-hydroxy-2,7,8-trimethyl-4H-benzo[1,3]dioxin-2-yl)-propionic acid ethyl ester as a light brown sticky oil (38 mg). 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.29 (s, 1H), 4.77 (s, 1H), 4.72 (q, J=14.9, 2H), 4.13 (q, J=7.2, 2H), 2.57-2.52 (m, 2H), 2.22-2.16 (m, 2H), 2.16 (s, 3H), 2.10 (s, 3H), 1.47 (s, 3H), 1.27 (t, J=7.2, 3H); 13C-NMR δ (ppm): 173.8, 147.2, 142.5, 126.0, 122.8, 116.5, 107.5, 99.5, 60.5, 33.9, 28.6, 21.8, 14.2, 11.9, 11.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl.CS(C)=O>[Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Fc1cccc(CNc2cccc(-c3cc(NC4CCNCC4)ncc3Cl)n2)c1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of 5′-chloro-N6-(3-fluorobenzyl)-N2′-(piperidin-4-yl)-2,4′-bipyridine-2′,6-diamine (Example 6, 16 mg, 0.039 mmol), dichloromethane (0.5 ml), and TEA (0.022 ml, 0.155 mmol) was cooled to 0° C. This cooled mixture was then diluted with a solution of 0.03 ml of dichlormethane with ethanesulfonyl chloride (6.99 mg, 0.054 mmol). The reaction mixture then was warmed to ambient temperature and stirred for 1 hour, followed by LCMS. The reaction mixture solvent was removed under reduced pressure, to yield a residue which was dissolved in 0.75 ml DMSO, filtered, purified by prep LC and then lyapholized to yield 9.9 mg of the title compound, as a TFA salt. LCMS (m/z): 504.2 (MH+), retention time=0.77 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.32 (t, J=7.33 Hz, 3H) 1.47-1.67 (m, 2H) 2.08 (d, J=10.84 Hz, 2H) 2.96-3.12 (m, 4H) 3.75 (d, J=12.89 Hz, 2H) 3.80-3.92 (m, 1H) 4.65 (s, 2H) 6.83 (s, 1H) 6.92 (d, J=9.08 Hz, 1H) 6.95 (d, J=7.62 Hz, 1H) 7.01 (t, J=8.64 Hz, 1H) 7.11 (d, J=9.96 Hz, 1H) 7.19 (d, J=7.62 Hz, 1H) 7.30-7.41 (m, 1H) 7.75-7.85 (m, 1H) 8.06 (s, 1H)