Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([F:47])=[CH:20][C:21]=1[C:22]1[C:27]2[S:28][C:29]([C:31]3[C:36]([F:37])=[CH:35][N:34]=[C:33]([NH:38][CH2:39][CH2:40][N:41]4[CH2:45][CH2:44][NH:43][C:42]4=[O:46])[N:32]=3)=[CH:30][C:26]=2[CH:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])(C)(C)C>ClCCl>[F:37][C:36]1[C:31]([C:29]2[S:28][C:27]3[C:22]([C:21]4[C:16]([CH2:15][NH:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[CH:17][N:18]=[C:19]([F:47])[CH:20]=4)=[CH:23][CH:24]=[CH:25][C:26]=3[CH:30]=2)=[N:32][C:33]([NH:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][NH:43][C:42]2=[O:46])=[N:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CCC(F)(F)F)Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Agent: Cl
Solvent: ClCCl
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(-c4cc(F)ncc4CNCCC(F)(F)F)c3s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add hydrogen chloride (2 mL, 1 M in diethyl ether) to a solution of [6-fluoro-4-(2-{5-fluoro-2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophen-7-yl)-pyridin-3-ylmethyl]-(3,3,3-trifluoro-propyl) carbamic acid tert-butyl ester (0.136 g, 200.68 μmol) in dichloromethane (3 mL). Stir the mixture overnight at room temperature. Evaporate the solvent and suspend the resulting solid in dichloromethane and treat with 30% aqueous potassium carbonate. Wash the organic phase with saturated aqueous sodium chloride and load the organic solution onto a 25 g silica gel loading column with dichloromethane and elute onto a 40 g silica gel column with a gradient from dichloromethane to ethyl acetate and then from ethyl acetate to 10% methanol in ethyl acetate to give the title compound. Purify the material further by HPLC (HPLC Conditions: 38-42% CH3CN/10 mM NH4HCO3, pH 10 at 20 mL/min on XBride® MS C18 19×100 mm) Collect the appropriate fractions and concentrate it. Co-evaporate the residue with two portions absolute ethanol, one portion toluene, and transfer to a 10 mL round bottom with dichloromethane. Convert the material to a solid using dichloromethane hexane co-evaporation to give the title compound 45 mg (39%) as a yellow solid. MS (ES) m/z 578 [M+1]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: C1COCCN1
Product: O=C1Nc2ncnc(N3CCOCC3)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Yield: 35 %

Procedure:
The title compound (35% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and morpholine according to the procedure described for Example 14. MS-EI 453 [MZ+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:10]1=[O:29]>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:10]1=[O:29]
Reactant: COc1ccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N2CC(C(=O)O)N(C)C2=O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-2-(methyloxy)pyridine (0.259 ml, 1.998 mmol) in 1,4-dioxane (20 ml) was added cesium carbonate (2604 mg, 7.99 mmol), Xantphos™ (87 mg, 0.150 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and the reaction was stirred at reflux overnight. After cooling the solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution, water and then brine and passed through a hydrophobic frit. The organic layer was reduced under vacuum and the residue was purified by Flashmaster automated silica gel chromatography eluting with 0-30% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (272 mg, 43.4% yield). LC/MS [M+H]+=308. (ii) Trifluoroacetic acid (1 ml) was added to a solution of 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (270 mg, 0.878 mmol) in dichloromethane (2 ml) and the solution was stirred at room temperature overnight. The reaction mixture reduced to dryness under vacuum azeotroping with toluene and then dried under heated vacuum overnight to give 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.88 mmol). LC/MS [M+H]+=252.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:49]([OH:51])=[O:50])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:45](=[O:48])[CH:46]=[O:47])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35](=[O:43])[NH:36]C(=O)C(Cl)(Cl)Cl)=[CH:30][CH:29]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:44])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CO.Cl>O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:49]([OH:51])=[O:50])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:45](=[O:48])[CH:46]=[O:47])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35](=[O:43])[NH2:36])=[CH:32][CH:33]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:44])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3ccc(OC(=O)NC(=O)C(Cl)(Cl)Cl)cc3)C2=O)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3ccc(OC(N)=O)cc3)C2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-[3-{4-(3-tert-Butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-[4-{N-(2,2,2-trichloroacetyl)carbamoyloxy}phenyl]acetic acid (550 mg.) was suspended in water (5 ml.), and to the suspension there were added sodium bicarbonate (250 mg.) and methanol (1 ml.). The mixture was stirred at ambient temperature for 7 hours. The reaction mixture was adjusted to pH 2 with dilute hydrochloric acid and the precipitating material was collected by filtration. The material was washed with water and then dried to give 2-[3-{4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-(4-carbamoyloxyphenyl)acetic acid.
Reaction SMILES: [C:1]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:14]COC)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].Cl>CO>[C:1]([CH:5]1[C:13]2[C:12]([OH:14])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1cccc2c1C(C(C)(C)C)OC2
Agent: Cl
Solvent: CO
Product: CC(C)(C)C1OCc2cccc(O)c21
Temperature: 50 °C
Reaction time: 10 h
Yield: 104 %

Procedure:
To a solution of 1-tert-butyl-7-(methoxymethoxy)-1,3-dihydroisobenzofuran (Intermediate 4, 260 mg, 1.10 mmol) in Methanol (10 mL) a 6N aqueous solution of hydrogen chloride (0.18 ml, 1.10 mmol) was added and the reaction mixture was stirred for 10 hours at 50° C. Volatiles were removed under reduced pressure and the residue was partitioned between water (10 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (220 mg) as white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1.C(OCC)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1oc2ccccc2c(O)c1C(c1ccccc1)c1ccccc1

Procedure:
To a mixture of 324 mg of 4-hydroxycoumarin and 368 mg of commercially available diphenylcarbinol in 30 mL of dioxane is added 0.37 mL of boron trifluoride etherate. After 100 hours at room temperature the reaction solution is diluted with 40 mL of diethyl ether and washed with water. The organic phase is dried (magnesium sulfate) and concentrated under reduced pressure. The residue is flash column chromatographed with 20% to 80% ethyl acetate in hexanes to give 587 mg of the title product.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:19])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][CH2:9][C@H:8]([NH2:7])[CH2:20][CH:21]=[CH2:22]
Reactant: C=CC[C@H](COCc1ccccc1CBr)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@@H](N)COCc1ccccc1CBr
Yield: 96.4 %

Procedure:
A solution of compound 18j (2.8 g, 7.3 mmol) in TFA/DCM (25 mL, v/v=1/4) was stirred at rt for 1 hr. The mixture was concentrated under reduced pressure to give compound 18k (2.0 g, 98% yield), which was used without purification. LCMS (m/z): 285.1 (MH+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.S(Cl)(Cl)=O.C(Cl)(Cl)(Cl)Cl.[CH2:17]([OH:19])[CH3:18]>>[C:4]([O:19][CH2:17][CH3:18])(=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7]
Reactant: CCO
Reactant: O=C1C=CC(=O)O1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C/C(=O)O

Procedure:
Maleic anhydride (100.0 g, 1.02 mole) was dissolved in anhydrous ethanol (60 ml, excess) by heating the mixture in an erlenmeyer flask on a steam bath. Thionyl chloride (1.0 ml) was added using a syringe and the mixture heated with stirring for ten minutes. To the turbid mixture was added carbon tetrachloride (100 ml) and the liquid quickly filtered through a Buchner funnel having a coarse glass frit. The solid was discarded. The filtrate was allowed to cool during which the time the ethyl hydrogen fumarate product (92 g, 63%) crystallized.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][C:15](=[O:17])[NH:14][CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].CN1C[CH2:39][CH2:38][C:37]1=[O:41].[H-].[Na+].BrCCCO[Si](C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][C:15](=[O:17])[N:14]([CH2:39][CH2:38][CH2:37][OH:41])[CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CN1CCCC1=O
Reactant: O=C1NCC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)O1
Agent: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])O
Agent: [H-]
Product: O=C1OC2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C(c2ccccc2)CN1CCCO
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 609.7 %

Procedure:
To a solution of 2.43 g (5 mmol) 9-(3,5-bis-trifluoromethyl-benzoyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one in N-methylpyrrolidone 0.436 g (0.5 mmol) of a 55% sodium hydride suspension in mineral oil was added at room temperature under argon. After 15 min. 1.27 g (5 mmol) of (3-bromopropoxy)-tert-butyldimethylsilane was added. The reaction mixture was stirred at 100° C. under argon overnight. After cooling a solution of saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate. The organic layer was dried over (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, Hexane/ethylacetate=2:1) to yield 1.66 g (50%) of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[NH3:38]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:7])[NH2:38]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)O
Reactant: N
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]phenyl]propionic acid (2.40 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture is heated at 80° C. for 90 min. After cooled to room temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (1.35 g, 56%). HRMS calcd for C27H35NO5: 453.5786. Found: 453.5784. MA calcd for C27H35NO5: C, 71.50%; H, 7.78%; N, 3.09. Found: C, 71.52%; H, 7.76%; N, 3.12%.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:9]([F:17])[C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:22]O>>[Br:6][C:7]1[C:8]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:9]([F:17])[C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:22])=[O:13]
Reactant: CO
Reactant: C[Si](C)(C)c1c(Br)cc(C(=O)O)c(F)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c([Si](C)(C)C)c(F)c1F
Temperature: 25 °C

Procedure:
Sulfuric acid (1.88 mL, 22.3 mmol) was added to a solution of the benzoic acid from step B (5.3 g, 17.1 mmol) in methanol (34 mL) at room temperature. The resulting mixture was stirred at reflux overnight. The mixture was allowed to cool to room temperature then concentrated. The resulting residue was dissolved in EtOAc then washed with saturated NaHCO3 (aq), water, then saturated NaCl (aq). The organics were dried over MgSO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 to afford the title compound as a white solid. 1H NMR (600 MHz, CDCl3): δ 7.78 (dd, J=5.4, 1.0 Hz, 1H); 3.93 (s, 3H); 0.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)ccc1CCc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1cc(O)ccc1CCc1ccc(F)cc1
Yield: 98.5 %

Procedure:
Methyl 2-(4-fluorophenethyl)-5-methoxybenzoate (33.8 g, 117 mmol) and pyridine hydrochloride (170 g) were heated at 220° C. for 2 hours. The black reaction mixture was cooled, poured into 2N HCl (1 L), and the pale-brown solid extracted with ethyl acetate (2×450 ml). The extracts were washed with 2N HCl (500 ml), brine (200 ml), dried (MgSO4) and evaporated to give 2-(4-fluorophenethyl)-5-hydroxy benzoic acid (30 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].[OH-:15].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][C:6]([CH3:7])([CH3:5])[C:9]([OH:13])=[O:15]
Reactant: [OH-]
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCC(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (15 g, 0.064 mole), acetone (140 ml) and sodium hydroxide (14.5 g, 0.36 mole) was stirred and heated to reflux. Chloroform (12 g, 0.1 mole) was added to the mixture dropwise over a period of 15 minutes. Refluxing was continued for 3 hours and the acetone was evaporated in vacuo. The residue was treated with ice water containing hydrochloric acid. The produce was extracted with ether. The ether extract was washed with water, then with brine and finally dried over MgSO4. The ether was evaporated in vacuo and the residue chromatographed on a column containing silica gel (320 g) and eluted with methylene chloride/tetrahydrofuran/acetic acid 50/1/1. The appropriate fractions were combined and evaporated in vacuo to give 10 g of 2-(2,3-dichloro-4-butyrylphenoxy)-2-methylpropionic acid which was identified by NMR and the purity confirmed by thin layer chromatography.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:29])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[N:36]1([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>CCOC(C)=O.CCCCCC>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:48][C:45]4[CH:44]=[CH:43][C:42]([CH2:41][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:47][CH:46]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])[CH:15]=1)=[O:29]
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-2-methyl-benzamide (prepared below, 100 mg, 0.251 mmol) and THF (2.5 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (44.2 mg, 0.251 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with acetone (˜5 mL) to afford the title compound in 56% yield (0.078 g, 0.1401 mmol).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([CH3:5])([CH3:4])[CH3:3].C(OCC)C.[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[C:27]([S:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37](Br)=[CH:36][N:35]=3)=[C:28]([Cl:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCOC(C)=O.[Cl-].[Zn+2].[Cl-].C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[C:27]([S:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:36][N:35]=3)=[C:28]([Cl:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Reactant: CC(C)(C)C[Mg]Cl
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)Cc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)nc1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a stirred solution of 1.0 M neopentyl magnesium chloride in diethyl ether (50 mL, 50 mmol) at −78° C. under nitrogen, add via syringe a solution of 0.5 M zinc chloride in THF (100 mL, 50 mmol). Warm gradually to ambient temperature and transfer via syringe of this solution (25 mL, ˜8.33 mmol) to a stirred solution of 3-tert-butoxycarbonyl-6-(5-bromo-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.62 mmol) in THF (2 mL) at ambient temperature. Add dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (50 mg, 0.061 mmol) and heat at 65° C. for 6 h. Cool to ambient temperature, dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(2,2-dimethyl-propyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (69 mg, 24%). MS (APCI+) m/z: 501 (M+H)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 375 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[N:4][CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[CH:5]=[N:4][CH:3]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Clc1cncc(Nc2ccc3[nH]ccc3c2)n1
Reactant: OB(O)c1ccnc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cc(-c2cncc(Nc3ccc4[nH]ccc4c3)n2)ccn1
Yield: 24 %

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-1H-indol-5-amine (0.05 g, 0.205 mmol), 2-fluoropyridine-4-boronic acid (0.057 g, 0.4 mmol), sodium carbonate (0.112 g, 1.025 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) in DME:water (3:2, 3 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield the title compound (0.015 g, 24%) as a yellow solid. 1H NMR (CD3OD) δ 8.47 (s, 1H), 8.35-8.33 (d, J=5.29 Hz, 1H), 8.16 (s, 1H), 8.01-8.00 (d, J=5.13 Hz, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.45-7.43 (d, J=8.64 Hz, 1H), 7.35-7.33 (dd, J=10.33, 1.72 Hz, 1H), 7.29 (d, J=2.95 Hz, 1H), 6.48-6.47 (d, J=2.58 Hz, 1H); MS (API-ES/Positive); m/z: 306 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]3[C@@H:18]([C:26]([OH:28])=[O:27])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29](OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CO>[CH3:29][O:27][C:26]([C@@H:18]1[C@@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[O:17]1)=[O:28]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CO
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Yield: 74.2 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (3.018 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.66 g) in methanol (120 ml) was heated under reflux for 17 h. The resulting mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (150 ml). The solution was washed with 0.5M aqueous citric acid solution (3×25 ml) and brine (50 ml), dried (magnesium sulphate), and evaporated in vacuo to give a white foam. Purification by column chromatography on silica gel, eluting with ethyl acetate:cyclohexane (1:1), gave the title compound as a white solid (2.32 g).