Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[O:9]1[CH2:24][CH2:25][O:26][CH:8]1[C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=Cc1ncc(F)cc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)cnc1C1OCCO1
Temperature: 120 °C

Procedure:
To a solution of 5-fluoro-3-nitropicolinaldehyde (12.5 g, 73.48 mmol) in toluene (220 mL) were added p-toluene sulfonic acid (698 mg, 3.67 mmol) and ethylene glycol (20.7 mL, 367.43 mmol) at 25° C. The reaction mixture was heated to 120° C. for overnight and water was removed using dean-stark apparatus. Reaction mass was cooled to 25° C. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-10% EtOAc in hexane to give 2-(1,3-dioxolan-2-yl)-5-fluoro-3-nitropyridine: 1H NMR (400 MHz, DMSO-d6): δ 4.02 (s, 4H), 6.22 (s, 1H), 8.939 (d, 1H, J=1.2 Hz); LC-MS (ESI) m/z 215.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[CH2:8][CH:9]3[CH2:14][N:13]([C:6]=2[CH:5]=1)[CH2:12][CH2:11][NH:10]3)([O-:3])=[O:2].[CH2:17](Br)[CH:18]=[CH2:19].C(=O)(O)[O-].[Na+].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:19]([N:10]1[CH:9]2[CH2:14][N:13]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:7]=3[CH2:8]2)[CH2:12][CH2:11]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCNC(C2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1CCN2CC1Cc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (17.5 g.), allyl bromide (7.6 ml.), sodium bicarbonate (1 teaspoon) and N,N-dimethylformamide (200 ml.) was stirred overnight at room temperature, then concentrated to dryness. The residue was partitioned between dilute aqueous sodium hydroxide and isopropyl acetate. The isopropyl acetate layer was washed with dilute aqueous sodium hydroxide and brine, filtered and concentrated to dryness. The residue was recrystallized from isopropyl alcohol, and the product was combined with corresponding product (2.3 g.) from a previous a preparation. Ethereal hydrogen chloride was added to a solution of the combined products in ethyl acetate affording 4-allyl-9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (10 g.), the compound of Formula IV wherein Q is allyl.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH3:16][O:17][CH2:18][CH:19](O)[CH3:20]>C1(C)C=CC=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:16][O:17][CH2:18][CH:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:20]
Reactant: COCC(C)O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: COCC(C)OC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 53.5 %

Procedure:
To a mixture of 212.0 g of 2,4-dinitrobenzoic acid in 300 ml of toluene were added 4.0 g of toluenesulfonic acid and 180.2 g of 1-methoxy-2-propanol. The mixture was refluxed for 48 hrs and the resulting water removed by azeotropic distillation. After this period the mixture was cooled to room temperture and washed with 500 ml of an aqueous 5% NaHCO3 solution followed by two 150 ml water washings. The toluene was removed at reduced pressure and the resulting oil was washed with hexane to give 152 g (1-methoxy-2-propyl)-2,4-dinitrobenzoate, a tan solid, mp 42° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:14]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 2-methyl-3-nitrophenol (15.3 g, 100 mmol) in DMF (150 mL) was added sodium hydride (60% in mineral oil, 2.6 g, 110 mmol) at 0° C. and the mixture was stirred for 30 minutes at room temperature. Methyl iodide (28.4 g, 200 mmol) was added and the mixture was heated to 80° C. for 5 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 times 100 mL). The combined ethyl acetate phases were dried over sodium sulphate and concentrated under vacuum to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc=5:1). Evaporation afforded the title compound as a yellow solid (14.4 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:40][CH:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[O:39])=[CH:47][CH:48]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 64.7 %

Procedure:
A mixture of 0.0636 g (0.21 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0609 g (0.32 mmole) of toluenesulfonic acid monohydrate, 0.0463 g (0.21 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0661 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-17) as a white solid.
Reaction SMILES: [F:1][C:2]([F:62])([F:61])[C:3]1[CH:4]=[C:5]([CH:58]=[CH:59][CH:60]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:55]=[CH:56][CH:57]=2)[CH2:34][N:35]([CH3:54])[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH3:54][N:35]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:34][C:33]1[CH:55]=[CH:56][CH:57]=[C:31]([C:29](=[O:30])[NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:58]=[CH:59][CH:60]=[C:3]([C:2]([F:1])([F:61])[F:62])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:32]=1
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCOCCOCCOCCC(=O)O)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-((3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-carbamoyl)benzyl)(methyl)amino)ethoxy)ethoxy)ethoxy)propanoate (264 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (2 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 46 mg (13%) of as a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.941-8.924 (d, J=5.1 Hz, 1H), 8.665-8.635 (d, J=9.0 Hz, 1H), 8.436 (s, 1H), 8.159-8.081 (m, 3H), 7.888-7.863 (m, 1H), 7.792-7.563 (m, 7H), 4.720 (s, 2H), 4.533 (s, 2H), 3.895-3.862 (m, 6H), 3.685-3.560 (m, 14H), 3.410 (s, 2H), 2.910 (s, 3H), 2.509-2.468 (m, 2H), 2.020-2.004 (s, 4H), 1.816-1.799 (s, 2H). MS (ES, m/z): 806 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][CH:23]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+:31]>CO>[CH3:8][C:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][CH:23]=2)=[CH:14][CH:15]=1)([CH3:1])[C:3]([O-:5])=[O:4].[Na+:31]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)C(=O)[O-]
Reaction time: 0.5 h
Yield: 97 %

Procedure:
2-Methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}-propionic acid, ethyl ester 2.5 g, 63.2 mmol) was dissolved in MeOH (200 mL) and 2N NaOH (100 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously for 6 h. The solvents were removed, and the residual solids were triturated with water. The suspended solids were then collected and triturated with pentane to produce a white solid (2.38 g, 97%). mp 199-200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.93 (m, 2H), 7.46-7.49 (m, 3H), 6.73 (d, J=9.0 Hz, 2H), 6.69 (d, J=9.0 Hz, 2H), 4.12 (t, J=6.4 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 1.26 (s, 3H); MS(EI): 390 (M+H), 366 (M−Na).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:5][CH:4]=1)#[N:2].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:15][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]([CH3:14])=[N:11][CH:12]=1
Reactant: Cc1nccn1-c1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ncc(Cl)n1-c1ccc(C#N)cc1

Procedure:
A solution of 1-(4-cyanophenyl)-2-methylimidazole (3 g, 16.4 mmol) and N-chlorosuccinimide (2.18 g, 16.3 mmol) in chloroform (180 ml) was heated at reflux for 4 hours, then washed with water, dried over magnesium sulphate and evaporated to a yellow solid. Trituration with ether left a pale-yellow solid (2.38 g, 67%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14].I[CH2:16][CH3:17].O>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:16][CH3:17]
Reactant: CCI
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add potassium carbonate (2.20 g, 15.92 mmol) to 2-bromobenzenethiol (2.00 g, 10.58 mmol) in acetone and stir at room temperature. After 10 minutes, add iodoethane (1.82 g, 11.67 mmol) with stirring. After 18 hours, add water and extract with ethyl acetate. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:19])=[C:6]([C@@:8]([C:14]#[C:15][CH:16]2[CH2:18][CH2:17]2)([C:10]([F:13])([F:12])[F:11])[OH:9])[CH:7]=1.[C:20](Cl)(Cl)=[O:21].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:19][C:20](=[O:21])[O:9][C@:8]([C:14]#[C:15][CH:16]3[CH2:17][CH2:18]3)([C:10]([F:12])([F:13])[F:11])[C:6]=2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
(S)-5-Chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) below -10° C. Phosgene (~8.0 kg, 80 mol) was directly fed below the surface over about 1 h, keeping the temperature below 0° C. The resulting slurry was warmed to 20-25° C. and held 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution stirred about 30 min. Heptanes (97 kg) was added and ~140 L of solvent was distilled under reduced pressure. Heptanes (97 kg) and THF (22 kg) were added and the solution washed with 5% aqueous sodium bicarbonate (15 L), followed by water (15 L). The solution was warmed to 50° C. and filtered into a clean reactor, followed by a 40 kg heptanes rinse. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10° C. The product was filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid. HPLC: 99.8 area %: mp 139-141° C.; [a]25D -94.1° (c 0.300, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J 32 2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282 MHz, DMSO-d6) δ -81.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:23](=[O:32])[N:24]([CH3:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C=1>>[CH3:13][C:11]([CH3:12])([CH3:14])[CH2:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:23](=[O:32])[N:24]([CH3:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)=[O:15]
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: CC(C)(C)CC(=O)Nc1ccc(O)cc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)C)cc1)c1ccccc1
Yield: 77 %

Procedure:
The title compound (262 mg, 77% yield) was prepared from N-(4-hydroxyphenyl)-3,3-dimethyl-butyramide (275 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=341 (M+1); Rt=4.15 min.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]1[NH:21][C:22]([O:24]C(C)(C)C)=[O:23])(=O)=O>N1C=CC=CC=1>[N+:18]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH2:10][CH2:11][CH:6]2[O:24][C:22](=[O:23])[NH:21][CH:7]2[CH:8]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NC1C=C(c2ccncc2[N+](=O)[O-])CCC1OS(C)(=O)=O
Solvent: c1ccncc1
Product: O=C1NC2C=C(c3ccncc3[N+](=O)[O-])CCC2O1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
The mixture of 2-(tert-butoxycarbonylamino)-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv.) in pyridine (0.21M) was stirred at 110° C. for 10 min in microwave. Pyridine was removed under reduced pressure. The residue was dissolved in ethyl acetate, and washed with sat NaCl. The organic was dried with MgSO4, filtered and concentrated to give 5-(3-nitropyridin-4-yl)-3,3a,7,7a-tetrahydrobenzo[d]oxazol-2(6H)-one (85%), which was used in the next step without further purification. LC/MS (m/z): MH+=262.1, Rt=0.49
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([CH2:46][O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][CH:10]=2)[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Reactant: ClCc1cccnc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3cccnc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate [Example 55 (b)] with 3-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-4-{4-[2-(pyridin-3-ylmethoxy)-ethoxy]-phenyl}-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][S-:23].[Na+]>COCCOC>[F:16][C:5]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[S:23][CH3:22]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1nc(N)nc(-c2ccco2)c1F
Yield: 36.1 %

Procedure:
A stirred solution of 260 mg (0.80 mmol) trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester and 560 mg (7.99 mmol) sodium methanethiolate in 10 ml dry DME under argon was heated at 50° C. for 2 hours. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/2) followed by trituration in ether/hexane afforded 65 mg (36%) 5-fluoro-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine as a white crystalline solid. EI-MS m/e (%): 225 (M+, 100), 180 (28).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:44](O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:44][C:39]1[CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([N:14]5[CH2:15][CH2:16][O:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:36]=[C:37]([CH3:41])[N:38]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCOCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M286) (377 mg, 0.615 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (211 mg, 69%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=O)[C:3]([O:5][CH3:6])=[O:4].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:9])[CH2:7][N:13]1[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: COC(=O)C(C)(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Stir a solution of methyl 2,2-dimethyl-3-oxo-propanoate (30.88 g, 237.31 mmoles) and tert-butyl piperazine-1-carboxylate (34.00 g, 182.55 mmoles) in DCM (500 mL) at room temperature for 20 minutes. Add acetic acid (2 equiv); 20.92 mL, 365.09 mmoles) followed by sodium triacetoxyborohydride (1.4 equiv; 54.17 g, 255.56 mmoles) over 0.5 h and stir the resulting mixture stirred at room temperature overnight. Carefully quench with water (250 mL) and transfer the mixture to a separating funnel with DCM (300 mL). Wash the resulting organic layer with brine. Dry over MgSO4, filter and evaporate to give tert-butyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)piperazine-1-carboxylate. (58 g, 100%). MS (m/z): 301.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[C:8]2[C:9]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]=3[CH:17]=[CH:18][CH:19]=2)(=[O:6])=[O:5].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH2:20]([N:12]1[C:13]2[C:9]3[C:8](=[CH:19][CH:18]=[CH:17][C:10]=3[C:11]1=[O:16])[C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=2)[CH3:21]
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)c2cccc3c(S(C)(=O)=O)ccc1c23
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
To 25 ml of N,N-dimethylformamide is added 0.48 g of 60% sodium hydride followed by the dropwise addition of a solution of 1.976 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3) in 50 ml of N,N-dimethylformamide. Stirring is continued for 20 minutes followed by heating at 50° C. for 10 minutes then cooling at room temperature. A solution of 1.872 g of ethyl iodide in 25 ml of N,N-dimethylformamide is added dropwise and stirring continued for 1.5 hours. The reaction mixture is poured over cracked ice and the solid collected, dried and crystallized from ethyl acetate to give 1.03 g of the desired product as a solid, m.p. 199°-203° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[C:6]([OH:8])[CH:7]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26](=[O:27])[O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][C:6]=2[OH:8])=[CH:15][CH:14]=1)[CH3:17]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCc1ccc(Cc2ccc(N)cc2O)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2O)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.6 %

Procedure:
To a solution of 5-amino-2-(4-ethylbenzyl)phenol (0.25 g) in tetrahydrofuran (10 mL) was added N-benzyloxycarbonyloxy-succinimide (0.41 g), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give benzyl N-[4-(4-ethylbenzyl)-3-hydroxyphenyl]carbamate (0.40 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH2:46][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[CH:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1])[CH3:41]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 31.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-diethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.9 mg) was obtained.