Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH:9]=1)(C)(C)C.N1C=CC=CC=1.F.C(OC([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccn(-c2cccc(Cl)c2)c(=O)c1
Agent: F
Agent: O=C([O-])OC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1cc(CO)ccn1-c1cccc(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-(3-chlorophenyl)-1H-pyridin-2-one (5.11 g, 14.6 mmol) in acetonitrile (75 ml) in a teflon beaker was added hydrogen fluoride-pyridine (2.5 ml, 87.5 mmol) and stirred for 3 hours. The reaction mixture was neutrallized with solid and aqueous sodium dicarbonate and then the solvent evaporated in vacuo. The resulting solid residue was extracted with EtOAc, dried (MgSO4), filtered and the solvent was evaporated in vacuo. This residue was chromatographed (silica gel, 80-100% EtOAc:hexane gradient elution) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:14]([OH:34])([PH2:32]=[O:33])[CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C:16](O)=[O:17])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:36][C@H:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH3:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:42]([O:41][C:39](=[O:40])[CH:37]([NH:36][C:16](=[O:17])[CH:15]([C:14]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13])([OH:34])[PH2:32]=[O:33])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH3:38])([CH3:45])([CH3:44])[CH3:43]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(NC(=O)OCc1ccccc1)C(O)([PH2]=O)C(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C(Cc1ccc(-c2ccccc2)cc1)C(O)([PH2]=O)C(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
The compound from step 1 (0.9 g) is solubilised in 10 ml of DMF in nitrogen, and t-butyl alaninate hydrochloride (450 mg), 2.5 ml of DIEA (6 eq) and 1.98 g of TBTU (3 eq) are successively added. The mixture is stirred for 15 min at ambient temperature and the reaction is processed as in step 4 of example 3. 1.10 g of expected product (97%) is obtained.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH:25]([C:27]#[N:28])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)[OH:32]>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:25]([C:27](=[O:32])[NH2:28])[CH3:26])=[O:23])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C#N)cc1
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(N)=O)cc1

Procedure:
A mixture of 5 g. (12.1 m moles) 1-cyanoethyl 4-(hexadecylamino)benzoate in 100 ml. 75% sulfuric acid is heated at 50° C. for 20 hours. The cooled solution is diluted with water, filtered, and the residue is dried to yield the amide as a white amorphous solid.
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C>ClCCl.CCOCC.O.[BH4-].[Zn+2].[BH4-]>[Cl:1][CH:2]([CH:8]([OH:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(Cl)C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-chloro-3-oxo-3-phenylpropionate (CI, EXAMPLE 1, 6.8 g, 30 mmol) in dichloromethane (68 ml) is cooled to −5° and a solution of zinc borohydride (0.4 M, 38 ml, 15 mmol) in ether is added dropwise over 30 mins. After the addition, the reaction mixture is stirred at 0° for 30 mins and then poured into a cold solution (0°) of acetic acid (5 ml) in water (15 ml). The resulting mixture is extracted with dichloromethane (30 ml×2). The combined organic extracts are washed with water (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed (silica gel; ethyl acetate/hexane, (5/95 to 25/75) to give the title compound which is a 1:9 mixture of anti and syn isomers as determined by NMR.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=[O:12])=[CH:6][CH:5]=1.C1C[N:19]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:19])=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(OC(F)(F)F)cc1
Yield: 57.3 %

Procedure:
4-(Trifluoromethoxy)phenylacetic acid (2 g, 9.085 mmol) was dissolved in DMF (20 ml, dry) and PyBOP (4.728 g, 9.085 mmol) was added. The mixture was stirred in an ice-bath and ammonia gas was bubbled in for 5 mins. The ice-bath was removed and the mixture was stirred at rt overnight and then evaporated in vacuum. Water (50 ml) was added into the residue and it was extracted with EtOAc (20 ml×3). The extracts were combined, washed with saturated aqueous NaHCO3 (15 ml), water (20 ml×3), brine (15 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20 g/70 ml), eluting with DCM, then MeOH/DCM (1:99), to give the title compound (1.14 g, 57%) as a white solid. Mass Spectrum: M−H+ 218. 1H NMR (400 MHz, CD3OD): δ 3.53 (s, 2H), 7.20 (d, 2H), 7.38 (d, 2H). 13C NMR (100 MHz, CD3OD): 42.5, 121.9 (q, J=253 Hz), 122.1, 131.8, 136.3, 149.4, 176.2.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:12]([O:10][C:9]([CH:4]1[CH2:5][NH:6][CH2:7][CH2:8][NH:3]1)=[O:11])[CH3:13]
Reactant: O=C(O)C1CNCCN1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CNCCN1
Yield: 26 %

Procedure:
A mixture of 2-piperazinecarboxylic acid dihydrochloride (5.06 g, 0.025 mol), ethanol (100 ml) and concentrated sulphuric acid (6.0 ml) was heated at reflux temperature for 6 days. Toluene (10 ml) was added, and the resulting mixture was concentrated in vacuo to 213 of its original volume. Cold, saturated aqueous potassium carbonate (80 ml) was added and the mixture was extracted with toluene (3×100 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuc, affording 1.0 g (26%) of 2-piperazinecarboxylic acid ethyl ester as an oil. The oil crystallised upon standing at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:30][CH2:31][C:32]([C:34]2[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=2)=[O:33])CCN2CCC3(C4C(=CC=CC=4)N(S(C)(=O)=O)C3)CC2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:42][C:43]1C=C([Mg]Br)C=C(C)[CH:48]=1.BrC1C=C(C)C=C(C)C=1.[Mg]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:48][CH:43]=[CH2:42])[CH2:30][CH2:31][C:32]([C:34]2[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: Cc1cc(C)cc(C(=O)CC[C@@H](CCN2CCC3(CC2)CN(S(C)(=O)=O)c2ccccc23)c2ccc(Cl)c(Cl)c2)c1
Agent: Cc1cc(C)cc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC[C@H](CCC(=O)c1cc(C)cc(C)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1.42 g (4.50 mmol) of (N-Methoxy-N-methyl)-(4-(S)-(3,4-dichlorophenyl)-6-heptenyl)-amide (prepared in Example 134) was dissolved in 20 mL of dry THF. To it added 10 mL THF solution of 3,5-dimethylphenylmagnesium bromide prepared from 1.8 g (9.6 mmol) of 5-bromo-m-xylene and 463 mg of magnesium turnings. After stirring for 2 hr at rt, the reaction was quenched with saturated aqueous ammonium chloride solution. THF was removed under reduced pressure. The residual material was diluted with ethyl acetate. The organic phase was separated, aqueous phase was extracted twice with ethyl acetate. Combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated, chromatographed on silica gel eluting with a gradient of hexane ethyl acetate=10:1 to 5:1 to give 1.57 g of 4-(S)-(3,4-dichlorophenyl)-1-(3,5-dimethylphenyl)-hept-6-ene-1-one (97%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([NH:12][C:13]2[C:14]([N:19]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]3=[O:26])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C(OCC)(=O)C.O>[CH3:25][C:21]1([CH3:24])[CH2:22][CH2:23][N:19]([C:14]2[C:13]([NH:12][C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[N:9]=3)=[O:11])=[CH:17][N:16]([CH3:18])[N:15]=2)[C:20]1=[O:26]
Reactant: CC(=O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(O)c1cccc(C(=O)Nc2cn(C)nc2N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a mixture of 6-acetyl-N-(3-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide (32 mg) and methanol (5.0 mL) was added sodium borohydride (5.3 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and water was added thereto. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether, and dried under reduced pressure to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH2:37][CH3:38])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH2:37][CH3:38])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCOc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
A mixture of {1-benzyl-3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol (0.70 g), activated manganese dioxide (2.0 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.65 g, yield 90%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 144-145° C.
Reaction SMILES: Cl[Si](C)(C)C.O[C:7]1([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=2)[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]([CH3:16])([CH3:15])[CH2:8]1.[I-].[Na+].C(O)(=O)C>C(#N)C.[Zn]>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]([CH3:15])([CH3:16])[CH2:8][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CC(=O)c1ccc(C2(O)CC(C)(C)CC(C)(C)C2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
38.1 ml of chlorotrimethylsilane are added over 45 minutes to a solution of 40.45 g of 1-[4-(hydroxy-3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (compound V′.1) and 56.21 g of sodium iodide in 230 ml of anhydrous acetonitrile. During the addition, the temperature is maintained between 35° C. and 40° C. After stirring for 2 hours, 40 ml of acetonitrile and 39.4 ml of acetic acid are added. Next, 29.4 g of finely powdered zinc are added portionwise with stirring and at room temperature. The mixture is refluxed with vigorous stirring for 4 hours. After cooling to room temperature, the reaction medium is filtered through Celite and then washed with saturated aqueous sodium bicarbonate solution. The organic phase is concentrated under reduced pressure and the oil obtained is purified by chromatography on a column of silica gel, eluting with a 95/5 (v/v) cyclohexane/ethyl acetate mixture; yield=68%; m.p.=54° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[Br:38][C:39]1[C:40]([NH2:46])=[N:41][CH:42]=[C:43]([Br:45])[N:44]=1>CN(C)C=O.ClCCl>[Br:38][C:39]1[C:40]([NH:46][C:14]([CH:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[N:41][CH:42]=[C:43]([Br:45])[N:44]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOCC1C(=O)Nc1ncc(Br)nc1Br
Temperature: 50 °C
Yield: 70.6 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (1.500 g, 6.49 mmol) and 1,1′-carbonyldiimidazole (1.578 g, 9.73 mmol) in N,N-dimethylformamide (2 mL) and dichloromethane (6 mL) was stirred 4.5 h at room temperature under nitrogen. N,N-Diisopropylethylamine (2.260 mL, 12.97 mmol) was added followed by 3,5-dibromopyrazin-2-amine (3.28 g, 12.97 mmol). The resulting mixture was stirred and heated at 50° C. under a reflux condenser under nitrogen for 2 d. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted 3 times with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexanes) to give the desired product (2.136 g, 4.58 mmol, 71% yield) as a slightly yellow foam-solid. MS (ESI) m/z 467 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5](O)[C:4]=2[CH:3]=1.[O:17]=[C:18]([CH:25]1[CH2:28][CH:27]([C:29]([O:31][CH2:32][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])=[O:30])[CH2:26]1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C.C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([CH:19]([C:18](=[O:17])[CH:25]3[CH2:28][CH:27]([C:29]([O:31][CH2:32][C:33]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:34])=[O:30])[CH2:26]3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC(=O)C1CC(C(=O)OCC(=O)c2ccccc2)C1
Reactant: OC1c2ccccc2Sc2ccc(Cl)cc21
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)C1CC(C(=O)OCC(=O)c2ccccc2)C1)C1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 60 °C

Procedure:
2-Chloro-9-hydroxythioxanthene (0.72 g, 2.89 mmol) was allowed to react with ethyl 3-oxo-3-(3-phenacyloxycarbonylcyclobutyl)propanoate (0.8 g, 2.41 mmol) in acetic acid (4 ml) and ethanol (4 ml) for 4 days and then heated at 60° C. for 4 hours. Worked up following procedure described in Example 6(i) to give a yellow oil. The crude product was purified by chromatography on flash silica eluting with chloroform then chloroform-methanol (99.5:0.5 then 99:1) to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:16])[CH2:12][CH2:13]OC)([CH3:9])[CH2:3][CH:4]([N:6]([CH3:8])[CH3:7])[CH3:5].[OH-].[Na+].C1(C=CC(O)=CC=1)O.C(=O)=O>>[CH3:9][C:2]([NH:10][C:11](=[O:16])[CH:12]=[CH2:13])([CH3:1])[CH2:3][CH:4]([N:6]([CH3:8])[CH3:7])[CH3:5]
Reactant: COCCC(=O)NC(C)(C)CC(C)N(C)C
Agent: O=C=O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Product: C=CC(=O)NC(C)(C)CC(C)N(C)C
Temperature: 80 °C

Procedure:
A mixture of 144.7 parts (0.63 mole) of N-(1,1-dimethyl-3-dimethylaminobutyl)-3-methoxypropionamide, 1 part of solid sodium hydroxide and 1 part of hydroquinone is charged to a reaction flask fitted with a condenser with a Dry Ice-cooled receiver, a stirrer and temperature control means. The pressure in the flask is reduced to less than 5 mm. and the flask is heated to 80°C. Vigorous reaction begins and liquid condenses in the receiver. After about one-half hour, the temperature is increased to 90°C. and this temperature is maintained for 3 hours. The product is distilled and the desired N-(1,1-dimethyl-3-dimethylaminobutyl)acrylamide is obtained at 80°-91°C./ 0.3-0.4 mm. The yield is 109.1 parts, or 87.4% of the theoretical amount, and the nitrogen percentage is the calculated 14.1%.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=O)C(C)(C)C.[OH-].[Na+].CCOC(C)=O>C1COCC1.CO>[C:44]([O:43][C@@H:9]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[CH2:8][OH:7])([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 40 °C

Procedure:
The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)ethyl pivalate (10 mg, 0.015 mmol), 2N NaOH (150 μL) in THF/MeOH (1:1, 1 mL) was heated at 40° C. After reaction finished, the reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C34H32ClN3O2S: 582.2 (M+H+); Found: 582.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.F[C:17]1[C:22]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][N:18]=1>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([O:15][C:17]3[C:22]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: Cc1ccc(NC2CCC(O)CC2)nc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC2CCC(Oc3ncccc3C3CCOCC3)CC2)nc1
Yield: 60 %

Procedure:
4-(5-methyl-pyridin-2-ylamino)-cyclohexanol (50 mg) was added to a solution of 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine, as prepared in preparation 1a, (50 mg) in DMSO (15 mL) and the reaction mixture was stirred until TLC analysis confirmed the absence of starting materials. Then the mixture was diluted with water (10 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography (EtOAc:Petrol ether=1:1) to provide (5-methyl-pyridin-2-yl)-{4-[3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclohexyl}-amine (0.03 g, yield 60%) as a solid. [M+1] 368. IC50 (uM): 0.057.
Reaction SMILES: CN.[CH3:3][C:4]([C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[C:16]([CH3:27])([S:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH3:17])[O:11][N:10]=1)([CH3:8])[C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.[N:36]1(OC(N(C)C)=[N+](C)C)[C:40]2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:17][C:16]([S:18]([CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)(=[O:19])=[O:20])([CH3:27])[C:15]([NH:14][C:12]1[O:11][N:10]=[C:9]([C:4]([CH3:8])([C:5](=[O:6])[NH:36][CH3:40])[CH3:3])[CH:13]=1)=[O:28]
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 65 h
Yield: 23 %

Procedure:
2 Methyl amine (2M solution in THF, 0.125 mL, 0.25 mmol) is added to a solution of 2-Methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (50 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (57 mg, 0.15 mmol) in DMF (1 mL), followed by the addition of N,N-diisopropylethylamine (0.056 mL, 0.32 mmol). The reaction mixture is stirred at room temperature for 65 h. After this time, more O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (100 mg, 0.26 mmol) and methylamine (2M solution in THF, 0.125 mL, 0.25 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hour at room temperature. After this time, the reaction mixture is diluted with water and extracted with ethyl acetate twice. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by preparative LC-MS affords 12 mg of the title compound. Yield: 23%; m/z 402 [M+H].
Reaction SMILES: C([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:9](=[O:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1.[Li+].[OH-].Cl>C1COCC1>[CH2:18]([CH:29]([NH:8][C:9](=[O:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC(Cc1ccccc1)NC(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.2 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[benzyl(hexyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.080 g, 0.17 mmol) in THF (8.6 mL) was added 4.3 mL of a 0.10 M LiOH solution and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 2M HCl and extracted with ethyl acetate (3×25mL). The combined organic phase was washed with brine (25 μL), dried over Na2SO4, and concentrated in vacuo to afford 0.068 g (90%) of a colourless oil.