Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.O>[C:11]([C:13](=[C:8]([CH3:9])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1
Yield: 69.9 %

Procedure:
A mixture of p-fluoroacetophenone (100 g, 0.72 mole), ethyl cyanoacetate (81.8 g, 0.72 mole), ammonium acetate (13 g, 0.17 mole) and acetic acid (34.7 g, 0.57 mole) is refluxed for 24 hours in benzene (200 mL) with a continuous removal of water by a Dean Stark trap. The cooled mixture is diluted with benzene (150 mL) and extracted with water (2×300 mL). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to a brown oil. Kugelrohr distillation (125°-127°/0.03 Torr.) affords 108.4 g (64.3%) of product as a yellow green oil.
Reaction SMILES: P(OCC)(OCC)([O:3][C:4]1([CH:8]2[CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1)=O.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[C:26]([S:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39]([CH:41]4[CH2:43][CH2:42]4)=[O:40])=[CH:34][CH:33]=3)[N:25]=2)[CH:19]=1.[CH3:44]CN(C(C)C)C(C)C>CO>[CH3:17][C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[C:28]([N:6]3[CH2:5][C:4]([CH:8]4[CH2:9][CH2:10]4)([O:3][CH3:44])[CH2:7]3)[N:27]=[C:26]([S:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39]([CH:41]4[CH2:43][CH2:42]4)=[O:40])=[CH:34][CH:33]=3)[N:25]=2)[CH:19]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)n[nH]1
Reactant: CCOP(=O)(OCC)OC1(C2CC2)CNC1
Solvent: CO
Product: COC1(C2CC2)CN(c2cc(Nc3cc(C)[nH]n3)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)C1
Temperature: 65 °C

Procedure:
3-Cyclopropylazetidin-3-yl diethyl phosphate (103 mg, 0.36 mmol) was added to a solution of N-(4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (96 mg, 0.24 mmol) and DIPEA (0.40 ml, 2.32 mmol) in methanol (5 ml), and the mixture was heated to 65° C. for 16 hours. The volatile components of the mixture were then removed in vacuo and the residue purified mass directed preparative HPLC, eluted with Acetonitrile/water/TFA to give the product as a white solid after freeze drying (6.3 mg, 5.3%). DMSO-d6: 0.34 (2H, m), 0.55 (2H, m), 0.81 (4H, d), 1.14 (1H, m), 1.81 (1H, m), 1.99 (3H, s), 3.26 (3H, s), 3.79 (4H, m), 5.37 (1H, s), 5.71 (1H, br s), 7.49 (2H, d), 7.71 (2H, d), 9.34 (1H, s), 10.39 (1H, s). ES+ 492
Reaction SMILES: C[CH:2](Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:22](N(CC)CC)C.Cl.[CH3:30][NH:31][C:32](=[O:37])[CH2:33][CH2:34][NH:35][CH3:36]>C1(C)C(C)=CC=CC=1.C(OCC)C>[ClH:20].[CH3:30][NH:31][C:32]([CH2:33][CH2:34][N:35]([CH3:36])[CH2:2][C:3]([N:5]([C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:22])=[O:4])=[O:37]
Reactant: CCN(CC)CC
Reactant: CNCCC(=O)NC
Reactant: CC(Cl)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CNC(=O)CCN(C)CC(=O)N(C)c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 155.2 %

Procedure:
A mixture of 16.1 g of 2-(methyl-chloroacetamido)-5-chlorobenzophenone, 10 g of triethylamine and 7.6 g of 3-methylaminopropionic acid methylamide hydrochloride in 500 ml of anhydrous xylene is heated to reflux for 12 hours whilst stirring. The triethylamine hydrochloride which has precipitated is filtered off with suction after cooling and, after extracting three times by shaking with water, the organic phase is dried over anhydrous potassium carbonate, filtered and evaporated in vacuo. The oily crude base thus obtained (18 g) is dissolved in 800 ml of anhydrous diethyl ether and filtered and 17.0 g of 2-(5-methylaminocarbonyl-N-methyl-3-methyl-3-aza-pentanamido)-5-chlorobenzophenone hydrochloride (77% of theory), with a melting point of 151°-153°, are obtained by passing dry hydrogen chloride into the solution.
Reaction SMILES: [C:1](Cl)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].Cl[C:15](Cl)=[C:16](Cl)Cl.[CH3:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+]>O>[CH3:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:15][CH3:16])[C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:10]
Reactant: O=C(Cl)CCCCCCCC(=O)Cl
Reactant: ClC(Cl)=C(Cl)Cl
Reactant: CCCCCCNC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCN(C)C(=O)CCCCCCCC(=O)N(C)CCCCCC
Reaction time: 0.21 h

Procedure:
10.5 grams of azeloylchloride were placed in a container holding 140 milliliters of tetrachloroethylene and dissolved. To the resulting mixture were added 9.2 grams of N-methyl-N-hexylamine, and 1.6 grams of NaOH dissolved in 200 milliliters of water. The completed mixture was agitated for 10-15 minutes; afterwards the organic layer was separated, washed with a dilute aqueous HCl solution. Following this the organic layer was washed with a 10% aqueous Na2CO3 solution and then washed with water. The washed organic layer was dried by contacting with MgSO4 and then the tetrachloroethylene was removed by application of a vacuum.
Reaction SMILES: N([C:3]1[N:4]=[C:5]([NH2:21])[C:6]2[N:7]=[CH:8][N:9]([C:19]=2[N:20]=1)[C@@H:10]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]1[OH:12])N.Cl.[CH:23]([CH:25]([CH:31]=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=O.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C=NC2C1=NC([N:52]1[CH:56]=[C:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH:54]=[N:53]1)=NC=2N>C(O)C>[OH:12][C@@H:11]1[C@H:13]([OH:14])[C@@H:15]([CH2:16][OH:17])[O:18][C@H:10]1[N:9]1[CH:8]=[N:7][C:6]2[C:19]1=[N:20][C:3]([C:56]1[C:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:54][NH:53][N:52]=1)=[N:4][C:5]=2[NH:21]/[CH:23]=[C:25](\[CH:31]=[O:32])/[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)/C(C=O)=C/Nc1nc(-c2n[nH]cc2C(=O)OCC)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 10 °C

Procedure:
A reaction vessel is charged with 2-hydrazinoadenosine (450 g) and absolute ethanol (11376 g). HCl (7.47 g) and ethyl 2-formyl-3-oxopropionate (1557 g) are added. The mixture is heated to reflux and sampled until the level of residual 2-hydrazinoadenosine in the mixture is not more than 0.50% and the level of the compound of formula (3) is not more than 2.5%. The mixture is slowly cooled to approximately 10° C. The product, the compound of formula (4) is isolated by filtration and washed with absolute ethanol (5121 g). The product is dried under vacuum at up to 40° C. until residual ethanol is not more than 5000 ppm to give ethyl (2E)-3-({9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-[4-(ethoxycarbonyl)-pyrazolyl]purin-6-yl}amino)-2-formylprop-2-enoate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.CI>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: CCOC(=O)Cc1ccc(-n2nc(-c3cccs3)cc2N)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(-n2nc(-c3cccs3)cc2N)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)acetate (0.244 g, 0.745 mmol) in THF (7.5 ml), thoroughly cooled to −78° C., was added KHMDS in PhMe (1.79 ml, 0.894 mmol, 0.500 M). The resulting very dark mixture was stirred at −78° C. for 1 h and then treated with MeI (0.056 ml, 0.894 mmol). The reaction was stirred with gradual warming to RT overnight. The completed reaction was quenched by addition of 3M HCl, diluted with EtOAc and the layers separated. The aqueous was extracted with EtOAc (2×) and the combined organics were washed with satd. NaHCO3 (1×), brine (1×), dried (MgSO4), filtered, and concentrated to yield ethyl 2-(4-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)propanoate (0.25 g) of crude which was used without further purification in the next reaction. MS (ESI) m/z: 342.3 (M+H+).
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[NH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[OH-].[Na+]>>[CH3:4][N:5]([CH2:1][C:8]1[NH:7][CH:11]=[CH:10][CH:9]=1)[CH3:6]
Reactant: CNC
Reactant: c1cc[nH]c1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)Cc1ccc[nH]1
Yield: 90.5 %

Procedure:
A mixture of 35% aqueous formaldehyde solution (3.2 ml, 40.7 mmol) and dimethylamine hydrochloride (3.44 g, 42.4 mmol) was added to pyrrole (2.72 g, 40.47 mmol) at room temperature with stirring over a 20-minute interval, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, 10% aqueous sodium hydroxide solution (18 ml) was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (10:1) as the eluent to afford 2-(N,N-dimethylaminomethyl)pyrrole (4.55 g, quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OC)c([N+](=O)[O-])c2)CC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(O)c([N+](=O)[O-])c2)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 1-(4-methoxy-3-nitro-phenyl)-cyclopropane-carboxylic acid methyl ester (10.0 g, 39.8 mmol) in CH2Cl2 (100 mL) was added BBr3 (12.0 g, 47.8 mmol) at −70° C. The mixture was stirred at −70° C. for 1 hour, then allowed to warm to −30° C. and stirred at this temperature for 3 hours. Water (50 mL) was added dropwise at −20° C., and the resulting mixture was allowed to warm room temperature before it was extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/EtOAc 15:1) to afford 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (8.3 g, 78%). 1H NMR (CDCl3, 400 MHz) δ 10.5 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.59 (dd, J=2.0, 8.8 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 3.64 (s, 3H), 1.68-1.64 (m, 2H), 1.20-1.15 (m, 2H).
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1([CH3:12])[O:10][CH2:9][CH:8]([OH:11])[CH2:7][O:6]1.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(N(CC)CC)C>[C:13]([O:11][CH:8]1[CH2:9][O:10][C:5]([CH3:12])([CH3:4])[O:6][CH2:7]1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(C)OCC(O)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a CH2Cl2 (200 mL) solution of 2,2-dimethyl-1,3-dioxan-5-ol (17.0 g, 0.13 mol) at 0° C., triethylamine (20 mL) was added slowly. The reaction flask was flushed with nitrogen for 5 minutes. Methacryloyl chloride (13.5 g, 0.13 mol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then filtered, washed with a water solution of NaHCO3 (1M, 2×200 mL) and distilled water (2×200 mL). The filtrate was dried over MgSO4. 1,4-hydroquinone (10 mg) was added as an inhibitor and solvent was removed. The oil was dissolved in ethyl acetate (50 mL) and passed through a silica gel plug. Solvent was removed and the product was purified by distillation, yielding a colorless oil product (18.5 g, 71%). 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 1.41 (s, 3H), 1.92 (s, 3H), 3.77 (d, 1H), 3.82 (d, 1H), 4.05 (d, 1H), 4.10 (d, 1H), 4.71 (m, 1H), 5.56 (s, 1H), 6.12 (s, 1H). 13C NMR (75.5 MHz, CDCl3) δ 19.2, 20.6, 23.0, 61.6, 63.2, 99.3, 123.2, 124.5, 138.1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][CH2:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B5OC(C)(C)C(C)(C)O5)[CH:26]=4)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:20]=3)[N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:14]=2[CH:13]=[CH:12][CH:11]=1.Br[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][C:59]=1[CH3:60].O>O1CCOCC1.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>[CH3:7][O:8][CH2:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:54]5[CH:55]=[N:56][CH:57]=[CH:58][C:59]=5[CH3:60])[CH:26]=4)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[N:20]=3)[N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:52])[CH3:50])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccncc1Br
Reactant: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(B4OC(C)(C)C(C)(C)O4)cc13)n2COCC[Si](C)(C)C
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: C1COCCO1
Solvent: O
Product: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(-c4cnccc4C)cc13)n2COCC[Si](C)(C)C
Temperature: 90 °C

Procedure:
An aqueous 2M sodium carbonate solution (0.11 mL, 0.23 mmol) was added to a solution of 3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 12c (60 mg, 0.09 mmol), 3-bromo-4-methyl-pyridine Compound 13a (10 μl, 0.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.01 mmol) in dioxane (1 mL) in a reaction tube. The reaction tube was sealed and heated to 90° C. overnight. After cooling to room temperature, the crude mixture was poured into water (30 mL) and was extract with DCM (2×25 mL). The combined organic layer was dried over sodium sulfate and concentrated. Silica gel chromatography (10% to 50% ethyl acetate/hexanes) gave 3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-5-(4-methyl-pyridin-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 13b (54 mg, 95%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 9.17 (d, 1H, J=1.5 Hz), 8.92 (d, 1H, J=1.5 Hz), 8.71 (m, 2H), 7.87 (m, 2H), 7.61 (m, 2H), 6.50 (s, 2H), 6.23 (s, 2H), 5.17 (s, 2H), 4.04 (t, 2H, J=6 Hz), 3.86 (t, 2H, J=6 Hz), 3.66 (s, 3H), 2.62 (s, 3H), 1.18 (t, 2H, J=6 Hz); 1.05 (t, 2H, J=6 Hz), 0.18 (s, 9H), 0.05 (s, 9H); MS (ESI) m/z: 631 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]=[C:10]=[O:11])=[C:4]([F:12])[CH:3]=1.[NH:13]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:14]1[C:15](O)=[O:16].[OH-].[Na+]>ClC1C=CC=CC=1.O>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:15](=[O:16])[CH:14]3[CH2:18][CH2:19][CH2:20][CH2:21][N:13]3[C:10]2=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)C1CCCCN1
Reactant: O=C=Nc1cc(O)c(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: O=C1C2CCCCN2C(=O)N1c1cc(O)c(Br)cc1F
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
4-Bromo-2-fluoro-5-hydroxyphenyl isocyanate (3 g) was dissolved in chlorobenzene (5 ml), and a solution of pipecolic acid (1.7 g) and sodium hydroxide (0.56 g) in water (5 ml) was added thereto, followed by stirring at room temperature (ca. 20° C.) overnight. The aqueous layer was washed with ether, made acidic with an aqueous hydrochloric acid solution and heated under reflux for 2 hours. After allowed to cool, the resulting mixture was extracted with methylene chloride (300 ml). The extract was washed with sodium bicarbonate solution, dried and concentrated. The residue was recrystallized from ether to give 1.75 g of 2-(4-bromo-2-fluoro-5-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1,3(2H,8aH)-dione. M.P., 196°-199° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]4[O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[C:36]([O:35][C:33]([NH:32][CH:4]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]4[O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:40])=[O:2])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(CSc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CSc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoic acid methyl ester (0.150 g, 0.27 mmol) in THF (2 mL) and methanol (2 mL) was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring at room temperature for 1 h the solution was acidified with 10% HCl to pH 2 and diluted with ethyl acetate (25 mL). After being seperated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoic acid (110 mg, 75%) as white solid. 1H NMR (CDCl3), δ 8.18 (d, J=7 Hz, 2H), 8.14 (dd, J=1, 7 Hz, 2H), 7.98 (d, J=9 Hz, 2H), 7.82 (d, J=9 Hz, 2H), 7.72 (m, 4H), 7.51 (m, 3H), 3.90 (m, 1H), 3.48 (dd, J=4, 12 Hz, 1H), 3.30 (m, 1H), 1.47 (s, 9H). LCMS 440 (M+−100).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:26][C:9]2[N:10]([CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[CH3:27][NH2:28]>C(O)C>[C:19]1([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]3[N:10]([CH3:25])[C:9]4[CH2:26][CH:6]([C:4]([NH:28][CH3:27])=[O:3])[CH2:7][C:8]=4[C:16]=3[CH:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Temperature: 100 °C
Reaction time: 144 h
Yield: 69.8 %

Procedure:
In a 50 ml sealed tube, was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-4-methylcyclopent[b]indole-2-carboxylic acid ethyl ester (10 g, 0.03 mole) in 25 ml absolute ethanol, followed by methylamine (40% aqueous solution, 10 ml, 0.13 mole). After stirring at 100° C. for six days, the mixture was cooled. A tan solid precipitated, which was collected and dried to give 7.0 g of the product as a solid, m.p. 176°-177° C. A sample of this solid was recrystallized from ethanol/ether (1:1) to give white crystals, m.p. 181°-182° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[CH:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)([CH3:13])[CH3:12].[ClH:26]>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.C(OCC)(=O)C>[ClH:26].[CH:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:21][CH:20]=1)([CH3:13])[CH3:12]
Reactant: CC(C)NCCCOc1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(OCCCNC(C)C)cc1
Temperature: 80 °C

Procedure:
2-Methylphenyl boronic acid (0.42 g) was added to a solution of N-isopropyl-3-(4-bromophenoxy)propylamine (1.0 g) and tetrakis triphenylphosphine palladium (100 mg) in aqueous 2M sodium carbonate (8.4 ml) and dimethoxyethane (5 ml). The mixture was heated at 80° C. for 18 hours, cooled to ambient temperature and diluted with ethyl acetate. The reaction mixture was washed with dilute sodium hydroxide solution, brine, dried (MgSO4) and evaporated. The residue was purified by dry flash column chromatography on silica gel (Merck 60H, Art No 7736) using a 5:95 v/v mixture of methanol and dichloromethane to give an oil. This oil was treated with ethereal hydrogen chloride to give a solid which was recrystallised from isopropyl alcohol to give N-isopropyl-3-[4-(2-methylphenyl)phenoxy]propylamine hydrogen chloride (0.38 g) as a solid, m.p. 157°-158° C.; microanalysis, found: C, 71.6; Hi 8.2; N, 4.4; Cl, 10.8%; C19H25NO. HCl requires: C, 71.3; H, 8.19; N, 4.38; Cl, 11.1%; NMR([CD3 ]2SO): 1.27(6H,d), 2.14(2H,m), 2.22(3H,s), 3.05(2H,t), 3.29(1H,m), 4.13(2H,t), 7.01(2H,d) and 7.12-7.30(6H,m); m/z 284(M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[F:33]>>[F:33][C:18]1[CH:19]=[C:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH:21]=[CH:22][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]2([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]2)[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC(F)F)c2OC)COC1
Temperature: 80 °C
Yield: 23 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (146 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (25 mg, 23%).