Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@H:11]([C@@H:25]([OH:27])[CH3:26])[C:12]([NH:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C=O)C>[Si:38]([O:27][C@@H:25]([CH3:26])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:28])[C:12]([NH:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)=[O:13])([C:35]([CH3:37])([CH3:36])[CH3:34])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-iodobenzohydrazide (7.3 g, 14.2 mmol) in DMF (60 mL) were added imidazole (3.9 g, 57.3 mmol) and TBSCl (4.3 g, 28.5 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature gradually and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by SiO2 column to give the title compound (8.6 g, 97%), which was used directly in the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([N:12](C(C)C)[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+].[C:31]1(C)[CH:36]=CC=C[CH:32]=1>O>[CH:6]1([N:12]=[C:13]([N:15]([CH:16]([CH3:17])[CH3:18])[CH:31]([CH3:36])[CH3:32])[N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Cc1ccccc1
Reactant: CC(C)NC(C)C
Reactant: CC(C)NC(=O)N(C(C)C)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(C(=NC1CCCCC1)N(C(C)C)C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
Phosphorus oxychloride (96 ml, 1.03 mol) is added dropwise over 30 min period to a toluene (800 ml) solution of cyclohexyl-diisopropylurea (226 g, 1.0 mol). The reaction is stirred 3.5 hours at 50° C., then stirred overnight at room temperature. Diisopropylamine (310 ml, 2.18 mol) is added to the reaction mixture dropwise for over a 2 hour period, then stirred 2 hours at room temperature. The reaction mixture is poured into water (2000 ml). The water layer is extracted with toluene (3×150 ml) and the toluene layer is discarded. Sodium hydroxide (240 g, 6 mol) is slowly added to the aqueous layer in an ice-water bath. Two layers formed and the aqueous layer is extracted with diethylether (2×150 ml). The organic layer and the extracts are combined and dried over Na2 CO3, filtered and concentrated. The residue is further distilled under vacuum (ca. 0.3-0.5 torr) collecting product, cyclohexyl-tetraisopropylguanidine, at 140°-143° C. (250g, 80%) of 99% purity as judged by gas chromatography. 1H NMR (CDCl3) δ 3.75-3.9(m, 1H), 3.37(m, 1H), 3.22-3.31 (m,1H), 1.12-1.77 (m, 10H), 1.22 (d, 6H), 1.14 (d, 6H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:26]1[C:25]2[C:29](=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[NH:28][C:27]1=[O:31])([OH:16])=[O:15]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3cc(Cl)ccc32)c1CCC(=O)O
Temperature: 95 °C
Yield: 72.1 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-chloro-2-oxindole (168 mg) and piperidine (2 drops) in ethanol (2 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for and additional hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 270 mg (72%) of 4-(2-carboxy-ethyl)-3-methyl-5-(6-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: C[I:2].[CH3:3][C:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=2)[N:5]=1.[CH2:19](OCC)C>S1(CCCC1)(=O)=O>[I-:2].[C:16]([CH2:15][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N+:5]([CH3:19])=[C:4]([CH3:3])[C:12]2([CH3:13])[CH3:14])([OH:18])=[O:17]
Reactant: CCOCC
Reactant: CC1=Nc2ccc(CC(=O)O)cc2C1(C)C
Reactant: CI
Solvent: O=S1(=O)CCCC1
Product: CC1=[N+](C)c2ccc(CC(=O)O)cc2C1(C)C
Product: [I-]
Temperature: 48 °C
Yield: 79 %

Procedure:
Methyl iodide (3 ml, 48.19 mmol) was added to a solution of 2,3,3-trimethyl-3H-indol-5-yl-acetic acid (2.5 g, 11.52 mmol) in sulfolan (15 ml). The reaction was heated at 48° C. for 18 hours, then cooled to room temperature. The crude reaction mixture was added dropwise to an excess of diethyl ether and the precipitate was collected by filtration and dried in vacuo to obtain the product as a beige solid (3.27 g, 79% yield). 1H NMR (d6-DMSO): δH 7.85 (d, 1H), 7.70 (s, 1H), 7.50 (d, 1H), 3.95 (s, 3H), 3.75 (s, 2H), 2.75 (s, 3H), 1.50 (s, 6H). MALDI-TOF, m/z 232 (M+=232 for C14H18NO2).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-])=O)[C:12]([N:14]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13]>C(OCC)(=O)C.CO.[Pd]>[NH2:28][C:27]1[CH:26]=[CH:25][C:11]([C:12]([N:14]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:13])=[CH:10][C:9]=1[NH:8][CH2:7][CH2:6][CH:2]1[O:1][CH2:5][CH2:4][O:3]1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCC2OCCO2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCC2OCCO2)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.4 g) in solution in a mixture of ethyl acetate/methanol 2:1 (100 ml), and 10% palladium on carbon (240 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (2.02 g; 89% yield).
Reaction SMILES: Cl[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:24][CH2:25][CH2:26][F:27])[N:3]=1.[CH3:28][NH2:29]>C1COCC1>[F:27][CH2:26][CH2:25][O:24][C:4]1[N:3]=[C:2]([NH:29][CH3:28])[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]=1[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCCF
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-fluoro-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (1.00 g, 2.30 mmol) and methylamine (2 M in THF; 2.75 mL, 5.50 mmol) in THF (15 mL) in analogy with method described in example 1d.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[C:7]([C:11]1[C:12](=[O:31])[CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2C2C=CC(O)=CC=2)[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:8][CH3:9].FC1[CH:34]=[C:35]([CH2:39][S:40]([CH2:43]C2C=CC=C(F)C=2)(=[O:42])=[O:41])C=CC=1.O>CS(C)=O>[C:7]([C:11]1[C:12](=[O:31])[CH2:13][CH:14]([C:18]2[CH:19]=[CH:20][C:21]([O:4][C:2]3[CH:3]=[CH:34][CH:35]=[C:39]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:1]=3)=[CH:22][CH:23]=2)[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:8][CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CCC(=O)C1=C(O)CC(c2ccccc2-c2ccc(O)cc2)CC1=O
Reactant: O=S(=O)(Cc1cccc(F)c1)Cc1cccc(F)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2ccc(Oc3cccc(S(C)(=O)=O)c3)cc2)CC1=O
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.7 g (15.0 mmol) of potassium t-butoxide in 20 mL of methyl sulfoxide at room temperature was treated with 2.0 g (7.7 mmol) of 2-propionyl-3-hydroxy-5-((4-hydroxyphenyl)-phenyl)cyclohex-2-en-1-one. After 15 minutes of stirring, 2.0 g (11 mmol) of 3-fluorophenylmethylsulfone was added thereto and the solution was heated, under nitrogen, at 120° C. for 7 hours. The mixture was cooled to room temperature, poured into 100 mL of cold water and washed with 30 mL of diether ether and acidified with 1N HCl to pH 4 and extracted thrice with 20 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel. Evaporation of the solvent afforded the above named product as a light green oil. The product was recovered in a yield of 2.5 g (78 percent of theoretical). A small sample was crystallized to reveal the product as a white solid which melted at 109.5°-113.5° C. 1H NMR (CDCl3) δ1.17 (t, J=7 Hz, 3H, --CH2CH3), 2.63-3.65 (m includes s at 3.03 for CH3SO2 --, 10H), 6.97-7.78 (m, 8H, aromaties), 18.1 (s, 1H, enol H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
10% Pd/C (60 mg) was added to a stirred solution of 4-hydroxycinnamic acid (325 mg, 1.98 mmol) in MeOH (15 mL) under an inert atmosphere. Hydrogen gas was then passed through the reaction mixture by means of a hydrogen filled bladder and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was filtered over celite and the celite was washed with MeOH. The filtrate was collected and concentrated under reduced pressure to afford 310 mg (94.5% yield) of 3-[4-hydroxy phenyl]propionic acid as a white solid. 1H NMR (DMSO): δ 7.0 (d, 2H), 6.6 (d, 2H), 2.35 (t, 2H), 2.25 (t, 2H), LC-MS purity: 96.55%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[CH:17]([O-:19])=O.[NH4+:20]>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([NH:20][CH:17]=[O:19])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [NH4+]
Reactant: O=C[O-]
Solvent: O
Product: O=CNC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 170 °C
Reaction time: 10 h

Procedure:
A mixture of 4,4′-difluorobenzophenone (15.0 g, 68.7 mmol) and ammonium formate (35.3 g, 559 mmol) was stirred at 170° C. for 10 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: NC1C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].Cl[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(#N)C.O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(COc2cccc(N)c2)cc1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Nc1ccccc1
Solvent: O
Product: COC(=O)CNc1cccc(OCc2ccc(OC)cc2)c1

Procedure:
A mixture of the aniline (Intermediate 87, 24.6 g, 107.3 mmol), sodium bicarbonate (13.5 g, 161 mmol) and methyl chloracetate (10.1 ml, 118 mmol) in acetonitrile (30 ml) was heated at 90°-100° for 48 h. Water (200 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating in vacuo to leave the crude product as a peach solid. Trituration with ether-hexane (1:1) gave the title compound (Intermediate 88) as a flesh coloured solid (30.3 g; 94%), m.p. 79°-81°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1)=O.O>CC(O)=O>[C:27]([C:24]1[CH:23]=[C:22]([C:20]2[NH:19][C:3]3[C:4]([Cl:18])=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]([F:17])([F:16])[F:15])=[CH:7][C:2]=3[N:1]=2)[O:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)Nc2c(N)cc(-c3ccccc3C(F)(F)F)nc2Cl)on1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2nc3cc(-c4ccccc4C(F)(F)F)nc(Cl)c3[nH]2)on1
Temperature: 100 °C

Procedure:
3-tert-Butyl-isoxazole-5-carboxylic acid [4-amino-2-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide (73.9 mg, 0.168 mmol, prepared as in the previous step) was dissolved in AcOH (1 mL) and the resulting solution was heated to 100° C. for 14 h. The resulting mixture was cooled to room temperature and poured into H2O (20 mL). The aqueous phase was extracted with DCM (3×10 mL) and the combined extracts were washed with sat NaHCO3 solution (20 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was dissolved in POCl3 (1 mL) and heated for 16 h at 100° C. The resulting mixture was cooled to room temperature and poured onto ice (˜20 mL). After the POCl3 had been consumed, the precipitate was isolated by filtration and washed with H2O (2×20 mL). The solid was dissolved in DCM (25 mL) and the solution was dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/hexanes to yield 2-(3-tert-butyl-isoxazol-5-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.8 Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.68 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.30 (s, 1H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C20H16ClF3N4O: 421.1 (M+H); Measured: 421.1.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[BH4-].[Na+].O>C(O)C>[N:12]1[CH:13]=[CH:14][C:9]([NH:8][CH:5]([CH2:6][CH3:7])[CH2:4][OH:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(CC)N(C(=O)OC(C)(C)C)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(CO)Nc1ccncc1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A stirred solution of 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)butyric acid ethyl ester (0.33 g) in ethanol (5 ml) was treated with sodium borohydride (0.12 g) and the stirring was continued for 18 h. Water (1 ml) was added and the mixture was concentrated under reduced pressure. The residue was absorbed on to silica and the resulting powder was loaded on to a flash chromatography column which was eluted with methanol:chloroform:aqueous ammonia (10:89:1). The title compound (0.168 g) was obtained as an oil after evaporation of the product containing fractions.
Reaction SMILES: C([Cl:4])(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]([C:19]#[N:20])=[N:14][N:15]([CH3:18])[C:16]=1[CH3:17]>C(O)C>[ClH:4].[CH3:17][C:16]1[N:15]([CH3:18])[N:14]=[C:13]2[C:12]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]=[C:19]2[NH2:20]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccccc2N)c(C#N)nn1C
Solvent: CCO
Product: Cc1c2c(nn1C)c(N)nc1ccccc12
Product: Cl
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of acetyl chloride (0.150 g, 1.9 mmol) in ethanol (6.4 mL) was stirred for 15 minutes. 4-(2-Aminophenyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile (0.270 g, 1.27 mmol) was added, and the reaction was heated at reflux under a nitrogen atmosphere for two hours. A precipitate formed. The mixture was allowed to cool to ambient temperature and then cooled to 0° C. The solid was isolated by filtration, washed with diethyl ether, and dried to provide 285 mg of 1,2-dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride as a white solid, mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>C(Cl)Cl.O>[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[N:13][C:5]=1[O:4][C:3]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=1[F:1]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1F
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(NCc1ccccc1Cl)c1cccnc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.1 %

Procedure:
To a stirred solution of 2-(2,4-difluoro-phenoxy)-nicotinic acid (0.300 grams, 1.19 mmole) and NMM (0.133 grams, 1.31 mmole) in dry methylene chloride (15 ml) at −10° C. was added isobutyl chloroformate (0.202 grams, 1.31 mmole). After 20 minutes at −10° C. 2-chlorobenzylamine (0.202 grams, 1.43 mmole) was added and the mixture was allowed to warm to room temperature over night. The mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give a clear oil that was purified by chromatography on silica gel eluting with 30% ethyl acetate/hexane to give a solid. Recrystalization from ethyl acetate/hexane gave a solid (0.295 g). M.P. 122-124° C.; Anal. calcd. for C19H13N2O2F2Cl: C, 60.89; H, 3.50; N, 7.47. Found: C, 60.77; H, 3.44; N, 7.38.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][C:14]1[CH:15]=[C:16]([C:31]2[S:35][C:34]([C:36]3([OH:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)[CH:17]=[C:18]([NH:20][C:21]2[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=2)[CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:8]([O:12][C:6](=[O:7])[NH:5][S:2]([N:39]1[CH2:38][CH2:37][C:36]([OH:42])([C:34]2[S:35][C:31]([C:16]3[CH:17]=[C:18]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][N:22]=4)[CH:19]=[C:14]([CH3:13])[CH:15]=3)=[CH:32][N:33]=2)[CH2:41][CH2:40]1)(=[O:4])=[O:3])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Reactant: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(=O)(=O)NC(=O)OC(C)(C)C)CC3)s2)c1
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
At 0° C., chlorosulfonyl isocyanate (14.95 μL, 0.172 mmol) in DCM (0.6 mL) was added to tert-butanol (16.47 μL, 0.172 mmol), after stirred for 30 min, 4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (50 mg, 0.115 mmol) and triethylamine (48.0 μL, 0.344 mmol) were added and the reaction aged for 20 min and ice bath removed. After stirred for 2 h, the crude reaction mixture was directly subject to column chromatography on silica gel (0-100% ethyl acetate in hexanes) to afforded 58 mg (0.094 mmol, 82%) tert-butyl({4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}sulfonyl)carbamate. MS ESI: [M+H]+ m/z 615.1. 1H NMR (600 MHz, CDCl3): δ 8.64 (d, J=4.8 Hz, 1H); 7.87 (s, 1H); 7.84 (s, 1H); 7.31 (s, 1H); 7.03 (s, 1H); 7.01 (d, J=4.8 Hz, 1H); 3.81 (d, J=12 Hz, 2H); 3.47 (m, 2H); 2.36 (s, 3H); 2.25 (m, 2H); 2.00 (d, J=12 Hz, 2H); 1.50 (s, 9H). rhSYK activity=+++
Reaction SMILES: [CH2:1]([Cl:5])[C:2]([OH:4])=[O:3].[C:6]1([CH:12]=[CH:13][C:14]2[CH:15]=[C:16]([OH:24])[C:17]([CH:21]([CH3:23])[CH3:22])=[C:18](O)[CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:5][CH2:1][C:2]([O:4][C:18]1[CH:19]=[C:14]([CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:24][C:2](=[O:3])[CH2:1][Cl:5])[C:17]=1[CH:21]([CH3:23])[CH3:22])=[O:3]
Reactant: O=C(O)CCl
Reactant: CC(C)c1c(O)cc(C=Cc2ccccc2)cc1O
Product: CC(C)c1c(OC(=O)CCl)cc(C=Cc2ccccc2)cc1OC(=O)CCl
Yield: 72 %

Procedure:
This material was synthesized from anhydrous chloroacetic and 5-(2-Phenylethenyl)-2-i-propyl-1,3-benzenediol obtained in example 11 in 72% yield by the same procedure as described in example 12. 1HNMR (CDCl3, ppm): δ 1.30 (d, J=7.0 Hz, 6H), 3.08 (hept, J=7.0 Hz, 1H), 4.39 (s, 4H), 6.96 (d, J=17 Hz, 1H), 7.14 (d, J=17 Hz, 1H) 7.17 (s, 2H), 7.2-7.5 (m, 5H).
Reaction SMILES: CS(O[C@H:6]1[C@H:11]2[CH2:12][C@H:8]([C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[N:10]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[N:24]([C@H:6]1[C@H:11]2[CH2:12][C@H:8]([C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[N:10]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OS(C)(=O)=O)C2)N1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](N=[N+]=[N-])C2)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-[(methylsulfonyl)oxy]-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-1 (232 mg) in dimethylformamide (2.0 mL) and water (0.4 mL), was added sodium azide (108 mg). The mixture was stirred at 80° C. for 1 hr. The resulting mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (4:1) to give the target compound (175 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([F:29])[CH2:25]1)=[O:23])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:19](=[O:21])[CH3:20])[CH3:18])[CH2:13][CH2:12]1)[CH3:10])(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([O-:35])=[O:34].[C:19]([N:17]([CH3:18])[CH:14]1[CH2:13][CH2:12][CH:11]([C@H:9]([CH3:10])[C@H:8]([NH3+:7])[C:22]([N:24]2[CH2:28][CH2:27][C@H:26]([F:29])[CH2:25]2)=[O:23])[CH2:16][CH2:15]1)(=[O:21])[CH3:20]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N(C)C1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1
Solvent: ClCCl
Product: CC(=O)N(C)C1CCC([C@H](C)[C@H]([NH3+])C(=O)N2CC[C@H](F)C2)CC1
Product: O=C([O-])C(F)(F)F

Procedure:
To a solution of the material prepared in Step D (0.012 g, 0.028 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 3 h at ambient temperature the reaction was concentrated in vacuo, affording the title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 5.41 (s, 0.5H as a single rotamer), 5.36 (s, 0.5H as a single rotamer), 5.31 (0.5H as a single rotamer), 5.26 (0.5H as a single rotamer), 4.28 (m, 1H), 4.06 (dd, J=5.5 Hz, J=9.0 Hz, 1H), 4.00 (dd, J=5.5 Hz, J=9.0 Hz, 1H), 3.78 (m, 6H), 3.64 (m, 2H), 3.51 (m, 1H), 2.90 (s, 1.5H as a single rotamer), 2.79 (s, 1.5H as a single rotamer), 2.31 (m, 2H), 2.13 (s, 3H), 2.07 (s, 3H), 1.98 (m, 2H), 1.70 (m, 6H), 1.30 (m, 2H), 0.93 (m, 3H); LC/MS 328.3 (M+1).