Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CO[N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl.C1C[O:38][CH2:37]C1>>[CH3:37][O:38][CH2:30][NH:5][C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: C1CCOC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Product: COCNC(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of sodium hydride (164 mg, 4.10 mmol) in 5 mL of THF was added a mixture of 5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (1.50 g, 3.42 mmol) and chloromethyl methyl ether (0.388 mL, 5.13 mmol) in 5 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 1.50 grams of the title compound as a white solid: (M++H) expect 482.0, found 482.0.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]([O:9][CH3:10])=[CH:5][N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[N:3]=1.[C:21]1([N:27]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC([O-])=O.[K+]>C(O)CCC.O>[CH3:10][O:9][C:6]1[C:7](=[O:8])[C:2]([C:31]2[N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:28]=[CH:29][CH:30]=2)=[N:3][N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:5]=1
Reactant: COc1cn(-c2cccc3cccnc23)nc(Br)c1=O
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: COc1cn(-c2cccc3cccnc23)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 81.5 %

Procedure:
A mixture of 3-bromo-5-methoxy-1-quinolin-8-ylpyridazin-4(1H)-one (70 mg, 0.217 mmol), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (88.1 mg, 0.326 mmol), KOAc (42.6 mg, 0.434 mmol) and PdCl2{P(t-Bu)2(Ph-p-NMe2)}2 (7.7 mg, 0.0109 mmol) in BuOH (1.1 mL) and water (0.1 mL) was heated to reflux for 16 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100 and AcOEt/MeOH=100/0 to 70/30) and recrystallized with AcOEt/hexane to yield the title compound (69.9 mg, 81% yield) as a white solid: mp 189-192° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.76 (3H, s), 6.98 (1H, s), 7.31-7.49 (6H, m), 7.58-7.73 (2H, m), 7.78 (1H, d, J=1.9 Hz), 8.14 (1H, d, J=8.3 Hz), 8.54 (1H, d, J=7.9 Hz), 8.67 (1H, s), 8.99 (1H, d, J=4.1 Hz). Anal. Calcd for C23H17N5O2: C, 69.86; H, 4.33; N, 17.71. Found: C, 69.61; H, 4.37; N, 17.57.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]>>[CH2:12]([Si:2]([Cl:4])([Cl:3])[Cl:1])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5].[Cl:1][Si:2]([Cl:4])([Cl:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:2]([Cl:4])([Cl:3])[Cl:1]
Reactant: C=CCCCCC=C
Reactant: Cl[SiH](Cl)Cl
Product: C=CCCCCCC[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)CCCCCCCC[Si](Cl)(Cl)Cl
Temperature: 50 °C

Procedure:
In another experiment, 220 g (1.62 mole) trichlorosilane was added slowly in 20 minutes to a stirred mixture of 660 g (6 mole) 1,7-octadiene at 35° C. Subsequently, the reaction mixture was heated at 50° C. for 24 hours to complete the addition and then fractionally distilled. This resulted in 322 g, i.e., 82%, 7-octenyl trichlorosilane and 24 g, i.e., 12%, 1,8-bis-trichlorosilyl octane.
Reaction SMILES: [C:1]([C:4]1[C:11]([OH:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[I:14]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH3:13])[C:7]([C:8]#[N:9])=[C:10]([I:14])[C:11]=1[OH:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(C#N)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C)c(C#N)c(I)c1O
Temperature: 80 °C
Yield: 62.9 %

Procedure:
The 4-acetyl-5-hydroxy-2-methylbenzonitrile (6.7 g, 38 mmol) was dissolved in acetic acid (80 mL) and the N-Iodosuccinimide (10.0 g, 46 mmol) was added. The reaction was heated to 80° C. in an oil bath and monitored by LC/MS. After heating for 4 hrs the reaction was complete. This was allowed to cool and was concentrated in vacuo to give a dark oil. The oil was taken up in ethyl acetate and washed with water, sodium bicarbonate (3×, until remained slightly basic), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile as pale yellow solid (7.2 g, 62%). LCMS calculated for C10H9INO2(M+H)+: m/z=301.9; found: 301.9.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].[OH-].[Na+]>C(Cl)Cl>[CH3:19][O:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:23]
Reactant: COC(=O)c1ccccc1N
Reactant: COCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1ccccc1C(=O)OC
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 3.02 g (20 mmol) of methyl anthranilate in 30 ml of methylene chloride was added 2.22 g (22 mmol) of triethylamine. Into the mixture, a solution of 2.39 g (22 mmol) of methoxyacetyl chloride in 15 ml of methylene chloride was dropwise added under chilling with ice. The resulting mixture was then stirred for 1 hour. After adding ice, the stirred mixture was made alkaline by addition of 1 N aqueous sodium hydroxide and then extracted with chloroform. The organic portion was collected and washed sequentially with 3 N HCl, 6 N HCl, water and saturated aqueous sodium chloride. The washed chloroform portion was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.6 g of the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[N:10][P:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C)c1NC(=N)c1ccc(C(C)(C)C)cc1
Agent: [Li]CCCC
Product: Cc1cccc(C)c1NC(=NP(c1ccccc1)c1ccccc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.40 g of 4-t-butyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine IV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the sticky residue was treated with 20 mL of pentane. After 1 hour stirring at room temperature, the pentane was removed in vacuo yielding 2.16 g (93%) of off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: Cc1cc(Br)cnc1N1CCNCC1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Yield: 43.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 69 and using 6-fluoro-4-methylnicotinic acid (931 mg) and 1-(5-bromo-3-methylpyridin-2-yl)piperazine (1.5 g), the title compound (1 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:33][C:34]([O:36][C:37](C)(C)C)=[O:35].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a solution of 251 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 6 mL of acetonitrile was added 0.108 mL of t-butyl bromoacetate and 0.36 mL of DIPEA. The reaction was heated at 50° C. for 5 hours and then concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried with sodium sulfate, combined and evaporated. The residue was purified by FC (0-2.5% methanol in methylene chloride) to afford 294 mg of title compound. Mass spec (ESI): 564 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)(=[O:35])=[O:34])=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[C:19]([O:43][CH3:44])[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:44][O:43][C:19]1[CH:18]=[C:17]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[C:32]2[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][N:38]=3)(=[O:34])=[O:35])=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ccc(C)o2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 150 °C

Procedure:
A microwave vial charged with Pd(Amphos)2Cl2 (0.012 g, 0.018 mmol), 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.073 g, 0.351 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 160; 0.075 g, 0.176 mmol), potassium phosphate (0.149 g, 0.703 mmol), 1.5 mL dioxane and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane). Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave the titled compound.
Reaction SMILES: [Br-].[Cl:2][C:3]1[C:4]([C:29]([O:31][CH3:32])=[O:30])=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.C1CN2C(=NCCC2)C1>C(#N)C>[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:6][C:5]2[C:4]([C:29]([O:31][CH3:32])=[O:30])=[C:3]([Cl:2])[CH:28]=[CH:27][CH:26]=2)=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(=O)c1c(Cl)cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: COC(=O)c1c(Cl)cccc1C=Cc1ccc(Br)cc1

Procedure:
To a mixture of. 44.6 g (84.9 mmol) of 3-chloro-2-methoxycarbonylbenzyltriphenylphosphonium bromide and 16.7 g (90.4 mmol) of 4-bromobenzaldehyde was added 150 ml of acetonitrile, and then, 14.8 g (119 mmol) of 1,5-diazabicyclo[4,3,0]-5-nonene was added dropwise to the mixture. Thereafter, the mixture was refluxed for 3 hours.
Reaction SMILES: [CH2:1]1[CH2:5]O[CH2:3][CH2:2]1.C([Li])([CH2:8][CH3:9])C.[B:11](OC)([O:14]C)[O:12]C.Cl>C(OCC)(=O)C>[C:1]1([B:11]([OH:14])[OH:12])[CH:5]=[CH:9][CH:8]=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: C1CCOC1
Reactant: [Li]C(C)CC
Agent: Cl
Solvent: CCOC(C)=O
Product: OB(O)c1ccccc1
Temperature: -71 °C
Reaction time: 2 h

Procedure:
The compound (T17) and THF (1,000 ml) were put into a reaction vessel under an atmosphere of nitrogen, and chilled to −71° C. Then, a sec-butyl lithium solution (1.0 M in cyclohexane and n-hexane; 1,000 ml) were added dropwise thereto in the temperature range of −71° C. to −62° C., and the stirring was continued for additional 120 minutes. Subsequently, trimethyl borate (127.6 g) was added dropwise in the temperature range of −70° C. to −59° C., and the stirring was continued for additional 180 minutes. The resulting reaction mixture was allowed to come to 0° C., and then poured into a vessel containing 1N-hydrochloric acid (3,000 ml) and ethyl acetate (3,000 ml) which had been chilled at 0° C. and mixed. The mixture was then allowed to stand to be separated into an organic layer and an aqueous layer. Extraction was carried out and the resulting organic layer was fractionated. The extracts were washed with brine, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, whereby 115.9 g of phenylboronic acid derivative (T18) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1.[C:27]([OH:30])(=O)[CH3:28].[CH2:31](O)C>O.[Zn]>[CH:3]([O:30][CH:27]([CH3:28])[CH3:31])([CH3:26])[CH3:4].[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: CCO
Reactant: CC(=O)O
Reactant: COc1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc2c1
Agent: [Zn]
Solvent: O
Product: CC(C)OC(C)C
Product: COc1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc2c1

Procedure:
The procedure used in Example 216 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, dissolve 890 mg of 4-(5-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 5.9 ml of ethanol and 5.9 ml of water and 5.9 ml of acetic acid, at ambient temperature, add 682 mg of zinc in three stages, and, between each addition, stir for approximately one hour to two hours. Add Celite and filter. The filtrate is concentrated under pressure. The crude product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 by volume). After formation of a paste with diisopropyl ether, in this way we obtain 716 mg of 4-(5-methoxy-1H-benzimidazol-2-yl) -9H-fluorene-9(R,S)-amine, in the form of a beige powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7]C(=C)[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:15]=[O+][O-].CSC.[CH3:21][OH:22]>>[O:22]=[C:21]1[CH2:7][C@@H:3]([C:2]([OH:1])=[O:15])[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1
Reactant: CO
Reactant: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Reactant: O=[O+][O-]
Solvent: CSC
Product: O=C1C[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 1-(SR)-3-methylene-4-(SR)-phenylcyclopentanoic acid (84.8 g, 0.42 mol) from Example 20, Step B in methanol (2.5 L) was cooled to −70° C. in a dry-ice acetone bath. Ozone was bubbled through the solution until the blue color persisted. Excess ozone was removed with a stream of nitrogen and dimethyl sulfide (125 mL, 1.68 mol) was added. The mixture was then allowed to warm to rt over 16 h. Most of the methanol was removed in vacuo and the residue was taken up in ethyl acetate and washed twice with water and brine, dried over sodium sulfate and concentrated. The residue was triturated with hexanes and the solid was filtered and dried to afford the title compound (61.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[Cl:23][C:24]1[C:25](I)=[CH:26][C:27]([F:30])=[N:28][CH:29]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:25]2[C:24]([Cl:23])=[CH:29][N:28]=[C:27]([F:30])[CH:26]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Fc1cc(I)c(Cl)cn1
Product: Cc1ccccc1C(CC(=O)c1cc(F)ncc1Cl)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 5-chloro-2-fluoro-4-iodopyridine (CAS RN: [659731-48-3]) was prepared the title compound as a light yellow oil, MS (ESI−): m/z=430.0014 ([M−H]−, 1Br).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9][C:8]=2[O:24][CH3:25])=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:24][CH3:25])=[CH:4][CH:3]=1
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)ccc1-c1ccc(Cl)s1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(N)ccc1-c1ccc(Cl)s1
Yield: 83.4 %

Procedure:
A stirred mixture of 2.5 g (0.007 mole) of 2-[4-(5-chlorothien-2-yl)-3-methoxyphenyl]-1H-isoindol-1,3(2H)-dione and 0.4 g (0.007 mole) of hydrazine hydrate in 30 ml of absolute ethanol was heated at reflux for one hour. The mixture was cooled and the solvent evaporated under reduced pressure to leave a residue. The residue was subjected to column chromatography on silica gel, eluting with methylene chloride to yield 1.4 g of 4-(5-chlorothien-2-yl)-3-methoxyaniline.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:39][C:40](OC(C)=O)=[O:41]>C(Cl)Cl>[C:40]([N:16]1[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]2[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:18]=2[CH2:17]1)(=[O:41])[CH3:39]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2c(nc(C(C)C)c(C(OC(C)(C)C)C(=O)O)c2-c2ccc(F)cc2)C(C)(C)C1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1)(0.012 g, 0.028 mmol) and Et3N (0.139 ml, 1 mmol) in CH2Cl2 (5 mL) was added Ac2O (0.026 ml, 0.280 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-(6-acetyl-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (0.011 g, 76% yield) as white powder and mixture of rotomers. 1H NMR (500 MHz, CDCl3) δ ppm 7.41-7.54 (1H, m), 7.11-7.23 (3H, m), 4.91 (1H, br. s.), 4.49 (0.7H, d, J=17.4 Hz), 4.28 (0.3H, d, J=16.5Hz), 4.08 (0.7H, d, J=17.7 Hz), 3.93 (0.3H, d, J=16.8 Hz), 3.39-3.52 (2H, m), 3.15-3.27 (1H, m), 2.15 (2H, s), 1.95 (1H, s), 1.27-1.39 (9H, m), 1.15 (3H, d, J=5.5Hz), 0.90 (3H, s), 1.00 (6H, s). LCMS (M+H) calcd for C27H36FN2O4: 471.27. found: 471.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]2[C:11]([CH2:12][C:13]#N)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1.[OH-:17].[K+].C[OH:20].O>>[CH3:1][O:2][C:3]1[S:4][C:5]2[C:11]([CH2:12][C:13]([OH:20])=[O:17])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: CO
Reactant: COc1nc2c(OC)ccc(CC#N)c2s1
Agent: [K+]
Solvent: O
Product: COc1nc2c(OC)ccc(CC(=O)O)c2s1

Procedure:
A solution of (2,4-dimethoxy-1,3-benzothiazol-7-yl)-acetonitrile (3.61 g, J. Med. Chem., 1987, 30, 1166) and potassium hydroxide (3.45 g) in methanol:water (2:1, 150 ml) was heated to reflux for 6.5 hours. The reaction was cooled and the solvents evaporated under reduced pressure. Water (50 ml) was added and the aqueous layer extracted with diethyl ether. The aqueous layer was then acidified to pH4/5 with acetic acid and extracted with ethyl acetate. The combined organic layers were washed (water and brine), dried (MgSO4) and the solvent evaporated under reduced pressure to yield the subtitled compound which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1.[CH:24]1C=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:20]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: c1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 38.5 g. of methyl 4-hydroxyphenylacetate, 3.8 l. of benzene and 0.9 g. of p-toluenesulfonic acid is heated to the boiling point and about 20 ml. of solvent are distilled to remove moisture, it is then cooled to room temperature and treated with 130 ml. of freshly distilled dihydropyran. The reaction mixture is kept at room temperature for 1 hour and washed with 10% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride and filtered through neutral alumina, thus obtaining the pure methyl 4-(tetrahydropyran-2-yloxy)phenylacetate.
Reaction SMILES: C(ON=O)CC(C)C.[F:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=1.[I:24]CI.O>C(#N)C>[F:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([I:24])=[CH:15][CH:14]=1
Reactant: ICI
Reactant: Nc1ccc(Oc2ccccc2F)cc1
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: O
Product: Fc1ccccc1Oc1ccc(I)cc1
Temperature: 55 °C
Yield: 91.7 %

Procedure:
Add isoamylnitrite (2.45 g, 2.5 Eq.) to 4-(2-fluoro-phenoxy)-phenylamine (1.70 g, 8.37 mmol) and diiodomethane (7.84 g, 3.5 Eq.) in acetonitrile (10 mL) while stirring at 55° C. under a nitrogen atmosphere. Slowly heat mixture to 75° C. and heat at this temperature for 3 hours. Cool to room temperature and pour into water, and extract the desired material into ethyl acetate. Wash this organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 2.41 g of an oil. Purify the material by silica gel chromatography (Prep. 2000) eluting with hexane/methylene chloride 9:1 to provide 1.60 g of the title compound as a thin oil. Mass spectrum (m/e): 314.0 (M*): (Bruker 300) 1H NMR (CDCl3) δ 7.55-7.60 (2H, d), 7.02-7.20 (4H, m), 6.69-6.72 (2H, d).