Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH:6]=[C:5]([O:32][CH3:33])[N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[C:12]([OH:14])=[O:13])[CH:6]=[C:5]([O:32][CH3:33])[N:4]=1
Reactant: [H][H]
Reactant: COc1cc(Oc2cccc(-c3ccccc3)c2C(=O)OCc2ccccc2)nc(OC)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(-c3ccccc3)c2C(=O)O)nc(OC)n1

Procedure:
To 10.3 Grams of benzyl 2-(2,6-dimethoxypyrimidine-4-yloxy)-6-phenylbenzoate dissolved in 100 ml of ethyl acetate was added 0.5 g of 10% palladium on activated carbon (water content: about 50%) and the resulting mixture was subjected to catalytic reduction at room temperature under normal pressure (hydrogen pressure) for 3 hours. The palladium on carbon was filtered off and the filtrate obtained was concentrated under reduced pressure to obtain 2-(2,6-dimethoxypyrimidine-4-yloxy)-6-phenylbenzoic acid (the present compound (1)) in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:29])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:29])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[NH:12][C:11](=[S:40])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(F)c(OCCCN3CCOCC3)cc2N1
Product: Fc1cc2c(cc1OCCCN1CCOCC1)NC(=S)CN=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-thione (IIi) was prepared by reacting 0.0053 moles of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (lactam Ii) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: FC(F)O[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14].[F:17][CH:18]([F:29])[O:19]C1C=C2C(C=CN2)=CC=1>>[F:17][CH:18]([F:29])[O:19][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([OH:15])=[O:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)Oc1ccc2cc[nH]c2c1
Reactant: O=C(O)c1c[nH]c2ccc(OC(F)F)cc12
Product: O=C(O)c1c[nH]c2cc(OC(F)F)ccc12

Procedure:
Prepared as for 5-(difluoromethoxy)-1H-indole-3-carboxylic acid starting with 6-difluoromethoxyindole (WO 97/45408 A1). MS (m/e) 227.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:20])([F:21])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH3:7])[CH2:2][CH3:3]
Reactant: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C
Temperature: 0 °C
Yield: 19.3 %

Procedure:
0.98 g (3.1 mmol) of 2-propylthio-4-(3-trifluoromethylpyrazolyl)benzaldehyde (Compound No. V-159 of the present invention) prepared in the same manner as in Example 8 (9) was dissolved in 10 ml of methylene chloride and stirred together with 1.44 g (12.4 mmol) of triethylsilane and 0.63 ml (6.8 mmol) of boron trifluoride diethyl ether complex at room temperature for 22 hours. The reaction mixture was poured into 50 ml of ice-cold water, and 20 ml of methylene chloride was added. The methylene chloride layer was separated, washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the methylene chloride was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.18 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] propyl sulfide (yield 19.3%) as a colorless liquid (nD20 unmeasurable).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)=[O:26].CCCP(=O)=O.CCOC(C)=O>O.CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([C@H:14]([NH:15][C:31]([C:30]2[CH:34]=[CH:35][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=2)=[O:32])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (100 mg, 0.294 mmol, Intermediate 6), 4-(methoxycarbonyl)benzoic acid (52.9 mg, 0.294 mmol), and DMF (2 mL) were added TEA (0.123 mL, 0.881 mmol) and 50% propylphosphonic anhydride in EtOAc (0.175 mL, 0.587 mmol). The solution was stirred at room temperature. After 2 h, the reaction was diluted with water (30 mL), stirred for 30 min, and then filtered. The solids were washed with water and dried in the funnel to give the title compound as a white solid. MS (ESI pos. ion) m/z: 467.0 (M+H).
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[C:17]1([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Reactant: C#Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(-c3ccccc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution (70 ml) of methyl 4-[chloro(hydroxyimino)methyl]benzoate (2.20 g) and ethynylbenzene (1.3 ml) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (3.0 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-tetrahydrofuran to give methyl 4-(5-phenyl-3-isoxazolyl)benzoate (2.47 g, yield 86%) as colorless crystals. melting point: 201–202° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][P:16]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][C:34]=1[C:43]([CH3:46])([CH3:45])[CH3:44])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:19]=1[C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:4])([CH3:3])[CH3:2].C([OH:50])(C)C>O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:8]=[CH:7][C:6]=1[O:15][P:16]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][C:34]=1[C:43]([CH3:46])([CH3:45])[CH3:44])([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:20][C:19]=1[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)O
Reactant: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Solvent: O
Product: CC(C)(C)c1ccc(OP(=O)(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 57.5 °C

Procedure:
tris(2,4-Di-tert.butylphenyl)phosphite (5146 g; Irgafos® 168, Ciba Specialty Chemicals) and isopropanol (IPA, 7890 g) are mixed in a reaction vessel and heated to 55-60° C. At this point the mixture is a slurry of approximately 39.0% solids. The peroxide (549 g, 50 weight-% solution of H2O2 in water, 1 equivalent) is added for 2-3 hours while maintaining the pot temperature (reaction is exothermic). After the peroxide addition, the mixture is maintained for 1 hour at 60° C. The reaction mass is homogeneous and the completeness of reaction is checked by LC (>97.0% conversion). Water (1355 g) is added, and the reaction mass is seeded to induce crystallization. Cooling slowly in 2 steps to 45° C. and then to 20° C. completes crystallization. The product is filtered (25μ screen), then dried at 70° C. under full vacuum with a nitrogen sweep.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].Cl>ClCCl>[C:16]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([Cl:5])=[CH:7][CH:8]=1)(=[O:18])[CH3:17]
Reactant: Clc1cccc2ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To aluminum chloride (54.5 g) and dichloromethane (250 ml) was dropwise added 1-chloronaphthalene (47 ml) under ice-cooling over 10 minutes. The obtained reaction mixture was stirred for 20 minutes and acetyl chloride (25 ml) was dropwise added over 40 minutes. The reaction mixture was stirred at room temperature for 4 hours and with refluxing for 20 minutes. The reaction mixture was cooled to room temperature, poured into 1N hydrochloric acid (300 ml), extracted with dichloromethane, washed with saturated brine and dried over magnesium sulfate. The solvent was distilled away and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give 37.3 g of a red-brown liquid (yield 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:12]2([CH:15]=[O:16])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=CC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: O=CC1(c2ccc(F)nc2)CCOCC1
Temperature: 110 °C
Yield: 23.6 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (2.0 g, 11.36 mmol) in dioxane (35 mL) was added tetrahydro-2H-pyran-4-carbaldehyde (2.59 g, 22.73 mmol), Pd(OAc)2 (0.25 g, 1.14 mmol), cesium carbonate (7.41 g, 22.73 mmol), and water (10.24 μL, 0.57 mmol), xantphos (0.98 g, 1.70 mmol). The mixture was purged with nitrogen for 5 min, the resulting mixture was heated to 110° C. in an oil bath for 15 h. The mixture was diluted with ethyl acetate, and was washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-80% ethyl acetate in heptane to give 4-(6-fluoropyridin-3-yl)tetrahydro-2H-pyran-4-carbaldehyde (560 mg, 2.68 mmol, 23.5% yield) as red color oil. LCMS (m/z): 210 (MH+), 0.45 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=[C:18]([NH2:27])[C:17]=2[N:16]=[C:15]1[CH2:28][CH2:29][O:30][CH3:31].Cl.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)C.O.C(N(CC)CC)C>[NH2:27][C:18]1[C:17]2[N:16]=[C:15]([CH2:28][CH2:29][O:30][CH3:31])[N:14]([CH2:13][CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:26]=2[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCCN)CCCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: O
Product: COCCc1nc2c(N)nc3c(c2n1CCCNC(=O)c1ccccc1)CCCC3
Yield: 57.6 %

Procedure:
Benzoyl chloride (900 mg, 6.40 mmol) was added in a single portion to a cooled (0° C.) solution of 1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.9 g, 6.26 mmol) and triethylamine (2 mL) in 1-methyl-2-pyrrolidinone (100 mL). When analysis by HPLC indicated that the reaction was complete, it was diluted with diethyl ether (1 L). The product was salted out by adding 3.3 eq. of a 1.0 M solution of hydrochloric acid in diethyl ether. The solid was isolated by filtration and then dissolved in water. The solution was neutralized using solid potassium carbonate and then extracted with dichloromethane. The extract was concentrated under reduced pressure to provide a solid. This material was recrystallized from 1,2-dichloroethane, slurried with diethyl ether, filtered and then dried in a vacuum oven to provide 1.47 g of N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzamide as a white solid, m.p. 167.8-169.6° C. Analysis: Calculated for C23H29N5O2: % C, 67.05; % H, 7.22; % N, 17.00. Found: % C, 67.17; % H, 7.24; % N, 16.98.
Reaction SMILES: [CH2:1]([CH2:4][SH:5])[CH2:2][NH2:3].Cl.Cl.O[CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15].[BrH:16]>>[BrH:16].[BrH:16].[CH3:15][C:14]1[N:13]=[CH:12][NH:11][C:10]=1[CH2:9][S:5][CH2:4][CH2:1][CH2:2][NH2:3]
Reactant: NCCCS
Reactant: Cc1[nH]cnc1CO
Agent: Br
Agent: Cl
Product: Cc1nc[nH]c1CSCCCN

Procedure:
A solution of homocysteamine hydrochloride (22.0 g.) and 4-hydroxymethyl-5-methylimidazole hydrochloride (25.6 g.) in aqueous hydrobromic acid (500 ml.) was heated under reflux for one hour. Concentration under reduced pressure, followed by recrystallisation from methanol-isopropyl alcohol afforded 4-methyl-5-[(3-aminopropyl)thiomethyl]imidazole dihydrobromide (24.5 g.), m.p. 200.5°-202.5°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1.[Cl:30]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:30][C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]3[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=3[C:15]=2[C:7]=1[N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)ccnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CC(C)O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)c(Cl)cnc21
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-4-(3-hydroxypyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (140 mg, 0.34 mmol) and N-chlorosuccinimide (137 mg, 1.02 mmol) in acetonitrile (1.3 mL) and isopropyl alcohol (0.4 mL) was stirred at 35° C. for 5 hours. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate (1 mL), diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid, which was used in the next step without any further purification (100 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2.N1C=CN=C1.C(Cl)Cl.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O>[Si:26]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2)([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: O=Cc1ccc2cccc(O)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A solution of 8-hydroxyquinoline-2-carbaldehyde (10.00 g, 57.75 mmol) and imidazole (8.649 g, 127.0 mmol) in DCM (290 mL, 57.75 mmol) was cooled to 0° C. on an ice bath. TBDMS-Cl (9.574 g, 63.52 mmol) was added and the reaction stirred overnight at ambient temperature. Water was added and the reaction transferred to a separatory funnel. The aqueous phase was extracted 3 times with DCM, the organics combined, followed by washes with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to residue under reduced pressure. The residue was purified by flash column chromatography, eluting with 25% EtOAc/Hexanes to give the product (12.2 g, 74% yield). MS APCI (+) m/z 288.1 (M+1) detected.
Reaction SMILES: [O-][CH2:2]C.[Na+].[Na].[CH:6]1[C:19]2[CH:18]([C:20]([OH:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.CI>O.C(O)C>[CH3:2][O:21][C:20]([CH:18]1[C:19]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:22]
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: O
Solvent: CCO
Product: COC(=O)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sodium ethoxide solution is generated from 21.75 g (0.95 mol) of sodium and 1500 mL of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is added batchwise to this solution and the resulting suspension is stirred for 1 hour at ambient temperature. Then the solid is separated off, washed with 1500 mL of diethyl ether, and the isolated crystals are suspended in 1500 mL of dimethylformamide and 126.73 mL (2.0 mol) of methyl iodide is added with stirring. The solution obtained is left to stand for 24 hours at ambient temperature, then diluted with water to a total volume of 6 L, crystallized, suction filtered, washed with water, and dried. Yield: 167 g of white crystals (74% of theoretical yield); melting point: 82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:19][C:20]([OH:22])=[O:21])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of (R)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid, 3a, (0.08 g, 0.14 mmol) in MeOH (2.6 mL) was added sodium methanolate (2.91 mL of 25% w/v, 13.46 mmol). The reaction was stirred at room temperature for 30 min and then quenched by dilution into aqueous saturated ammonium chloride solution. The MeOH was evaporated in vacuo and the resulting aqueous phase diluted with EtOAc, then extracted with EtOAc (3×). The organics were dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from MeOH provided 52 mg of the desired product 1 as a white powder: 1H NMR (d6-DMSO) δ 12.25 (s, 1H): 12.0 (bs, 1H): 8.8 (s, 1H): 8.3 (s, 1H): 8.25 (s, 1H); 8.1 (s, 1H): 7.45 (d, 1H); 4.75 (t, 1H); 2.5 (m, 2H), 1.0 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.06 minutes (M+H) 392.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(O)CCNCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C1=CCNCC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of of 4-(5-fluoro-2-methoxy-phenyl)-4-hydroxypiperidine (0.56 g, 2.5 mmole) (Intermediate 8) in acetic acid (20 mL) at room temperature was added 2 drops of concentrated sulfuric acid and the resulting solution heated to reflux for 2 days. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The solution was basified with 50% NaOH solution until PH=10, the layers separated and the organic layer was washed with brine (25 mL). The combined aqueous layers were extracted three times with EtOAc (3×25 mL), and the combined organic layers were dried over Na2SO4 and concentrated to afford 0.49 g (95% yield) of 4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
A room temperature solution of 5.04 gms. 4-nitro-benzoic acid in tetrahydrofuran (10 mL) is treated with 5.14 gms. 1′,1′-carbonyl-diimidizole and immediately immersed in an ice bath. The reaction mixture is stirred in the ice bath for 30 minutes, then it is allowed to warm to room temperature. Once at room temperature the reaction mixture is treated with 3 mL piperidine. The reaction mixture is allowed to stir at room temperature ovenight. The reaction is then made basic with the addition of saturated aqueous sodium bicarbonate solution, and the resulting mixture is extracted with ethyl acetate. The organics are separated, dried over anhydrous sodium sulfate, and subsequently evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 50% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 1-(4-nitrobenzoyl)piperidine is isolated as a white solid in the amount of 5.87 gms.