Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O.C(N(CC)CC)C.CN(C)C=O>[CH2:34]([O:33][C:31]([CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:7]3[S:6][C:5]4[N:4]=[CH:3][CH:2]=[N:1][C:10]=4[NH:9][C:8]=3[CH:11]=2)[CH2:30][CH2:29]1)=[O:32])[CH3:35]
Reactant: O=C(O)Cc1ccc2c(c1)Nc1nccnc1S2
Reactant: CCOC(=O)C1CCN(CCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(CCCNC(=O)Cc2ccc3c(c2)Nc2nccnc2S3)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 68.3 %

Procedure:
To 10 ml of N,N-dimethylformamide were added 0.6 g of 10H-pyrazino[2,3-b][1,4]benzothiazine-8-acetic acid, 0.8 g of ethyl 1-(3-aminopropyl)piperidine-4-carboxylate dihydrochloride, 0.38 g of 1-hydroxybenzotriazole, 1.07 ml of triethylamine and 0.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and the resulting mixture was stirred at room temperature for 22 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of sodium. chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol). The crystals thus obtained were washed with ether and thus 0.72 g of the title compound was obtained as a pale brown powder.
Reaction SMILES: C(Cl)Cl.[C:4](OC(=O)C)(=[O:6])[CH3:5].[OH:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:4]([O:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:6])[CH3:5]
Reactant: O=C(O)c1cc(-c2cccnc2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cccnc2)cc1C(=O)O
Temperature: 25 °C

Procedure:
Methylene chloride (5.0 mL), pyridine (0.25 mL), and acetic anhydride (0.19 mL) were sequentially added to the obtained 2-hydroxy-5-(pyridin-3-yl)benzoic acid, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then pyridine (0.082 mL) and acetic anhydride (0.095 mL) were added thereto, followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-93% chloroform/methanol] to obtain 0.035 g of 2-acetoxy-5-(pyridin-3-yl)benzoic acid as a white solid.
Reaction SMILES: C([O:3][C:4](=[CH:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:5]([F:8])([F:7])[F:6])C.S(=O)(=O)(O)O>CCOCC.O>[C:13]1(=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][C:4]([C:5]([F:7])([F:6])[F:8])=[O:3])[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: CCOC(=CCCN1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCC(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 20 mmole of N-(3-bromopropyl)phthalimide and 22 mmole of triphenylphosphine in 50 ml of benzene is heated at reflux temperature for 2 days. The solid which separates on cooling is filtered, washed with benzene and dried under reduced pressure to give 3-phthalimidopropyl triphenylphosphonium bromide. To a solution of 100 ml of dry liquid ammonia is added finely divided sodium (0.46 g or 2 × 10-2M) and a catalytic amount of ferric nitrate. When the blue sodium solution turns gray 10 g or 2 × 10-2M of finely powdered 3-phthalimidopropyltriphenylphosphonium bromide is added. After stirring for 15 minutes the ammonia is evaporated under a stream of nitrogen. To the residue is added 100 ml of anhydrous benzene and the solution is boiled for about 10 minutes under nitrogen. The solid residue is filtered pff and to the filtrate, containing salt free 3-phthalimidopropylidene triphenylphosphorane is added 6.6 g of 5 × 10-2M of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature under nitrogen for 12 hours. Concentration of the solvent leaves a residue which is distilled under high vacuum to afford 2-ethoxy-1,1,1-trifluoro-5-phthalimidopent-2ene. A solution of 3 g of 2-ethoxy-1,1,1-trifluoro-5-phthalimidopent- 2-ene in 50 ml of ether is treated with a solution of 1 M of sulfuric acid in 50 ml of water. The reaction mixture is stirred for one half hour at 25° C. The ether phase is separated, washed with brine, and dried over magnesium sulfate and concenrated to give trifluoromethyl 3-phthalimidopropyl ketone.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:57])=[C:19]([C:21]2([CH:54]([F:56])[F:55])[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][C:23]([NH:30]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)=[N:22]2)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(=N)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O1CCOCC1>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:57])=[C:19]([C:21]2([CH:54]([F:56])[F:55])[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][C:23]([NH2:30])=[N:22]2)[CH:20]=1
Reactant: COc1ccc(C(NC2=NC(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)(C(F)F)CCS(=O)(=O)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: N=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: NC1=NC(c2cc(N)ccc2F)(C(F)F)CCS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A solution of {(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-yl}-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (207 mg, 263 μmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (1.01 ml, 13.1 mmol). The orange colored solution was stirred at room temperature for 1 hour. In order to cleave the intermediate benzophenonimine, hydrochloric acid (1M, 2.63 ml) and dioxane (10 ml) were added. The mixture was stirred at 23° C. for 4 hours. For the workup, the reaction mixture was poured into an aqueous solution of sodium carbonate (1 M) followed by the extraction with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a 110:10:1-mixture of dichloromethane, methanol and ammonium hydroxide as the eluent. The (RS)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-ylamine (72 mg, 85% yield) was obtained as a light brown foam. MS (ISP): m/z=322.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])/[CH:4]=[CH:5]/[N+:6]([O-:8])=[O:7].[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH:4]([S:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][N+:6]([O-:8])=[O:7]
Reactant: COC(/C=C/[N+](=O)[O-])OC
Reactant: SCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: COC(OC)C(C[N+](=O)[O-])SCc1ccccc1
Yield: 86 %

Procedure:
A solution of (1E)-3,3-dimethoxy-1-nitroprop-1-ene (3.03 g, prepared according to Terahedron 2002, 58, 5773-5778), benzylmercaptan (2.54 ml) and piperidine (0.25 ml) in toluene (20 ml) was stirred at room temperature for 48 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (4.78 g, yield 86%) as a yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH2:9])=[O:8].[CH3:10][O:11][C:12]([NH:14][C@@H:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17])=[O:13].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[C:16](=[O:17])[C@@H:15]([NH:14][C:12](=[O:13])[O:11][CH3:10])[CH:19]([CH3:21])[CH3:20])(=[O:8])[NH2:9]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To the product of Example 116A (21.6 g, 144 mmol), the product of Example 116B (29.1 g, 166 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.6 g, 180 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL, 578 mmol) was dissolved in dichloromethane (960 mL) and stirred at room temperature for 18 hrs. The resultant solution was then concentrated to a residue, water was then added and the solution extracted with a 25% isopropanol in chloroform solution (2×2000 mL) the organic layer washed with brine then the organic extract dried over MgSO4, then concentrated to a yellow oil which was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane to provide 25 g (64%) of the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (m, 2H), 6.81 (s, 1H), 4.24 (dd, J=8.1, 4.4 Hz, 1H), 4.00 (t, J=8.4 Hz, 1H), 3.75 (m, 1H), 3.55 (m, 1H), 3.50 (s, 3H), 2.02 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H), 0.92 (d, J=6.7 Hz, 3H), 0.86 (d, J=8.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9](N)[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4].[BrH:17].N([O-])=O.[Na+]>O.Br.O.[Cu]Br>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([Br:17])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4]
Reactant: Br
Reactant: COC(=O)n1c(C)cc2c(N)c(Cl)ccc21
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)n1c(C)cc2c(Br)c(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Amino-5-chloro-2-methyl-indole-1-carboxylic acid methyl ester (2.04 g, 8.54 mmol) is suspended in a 4.8% solution of HBr in water (75 ml). After cooling to 0° C., a solution of sodium nitrite (1.23 g, 17.94 mmol) in water (30 ml) is slowly added during 20 minutes. After 30 minutes at 0° C., it is slowly added to a solution of copper(I) bromide (25.1 g, 175 mmol) in 48% HBr/H2O (75 ml), while the temperature is kept below 5° C. After the addition is complete, the suspension is stirred at RT for 2 hours and then at 85° C. for 5 minutes. After cooling to RT, the mixture is extracted with CH2Cl2/MeOH (95:5, 800 ml). The organic layer is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 4:1) affords the title compound. 1H NMR (DMSO, 400 MHz) δ 2.61 (s, 3H), 4.03 (s, 3H), 6.56 (s, 3H), 7.46 (d, J=9 Hz, 1H), 8.05 (d, J=9 Hz, 1H); ES-MS: 303 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:16])[CH2:14][CH2:13][S:12][C:11]([NH2:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:16])[CH2:14][CH2:13][S:12][C:11]([NH:15][C:23](=[O:25])[CH3:24])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]1(c2ccc(F)c(Br)c2)CCSC(N)=N1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1=N[C@](C)(c2ccc(F)c(Br)c2)CCS1
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of (S)-4-(3-bromo-4-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine (550 mg, 1.8 mmoles, 1.0 equiv) in tetrahydrofuran (20 mL) is added pyridine (720 mg, 9.0 mmoles, 5 equiv) and acetic acid anhydride (220 mg, 2.2 mmoles, 1.2 equiv). After 10 minutes, the reaction is poured into water and the aqueous mixture is extracted with dichloromethane. The organic phase is separated and washed with 1N HCl and saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (83% yield): MS (m/z) 345, 347 (M+1).
Reaction SMILES: [CH:1]([N-:4][CH:5]=[CH:6][N-:7][CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2].[Li+].[Li+].[Cl:13][SiH:14](Cl)Cl>CCCCCC>[Cl:13][SiH:14]1[N:7]([CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C=C[N-]C(C)C
Reactant: Cl[SiH](Cl)Cl
Agent: [Li+]
Solvent: CCCCCC
Product: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
In an argon atmosphere, a dilithium(N,N′-diisopropyl-1,2-vinylenediaminide) solution prepared according to the procedure and reagent quantities described in Reference Example-7 was added to a hexane (200 mL) solution containing 25.00 g (184.6 mmol) of trichlorosilane, and the mixture was stirred at room temperature for 16 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained oily material was distilled under reduced pressure (distillation temperature: 64° C./4.4×102 Pa) to obtain 2-chloro-1,3-diisopropyl-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)Cl) as a colorless liquid (yielded amount: 12.96 g, yield: 34%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([S:12]([NH2:15])(=[O:14])=[O:13])[C:8]([OH:11])([CH3:10])[CH3:9])=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](OCC)(OCC)OCC)[CH3:23]>C(O)(=O)C>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:8]([CH3:9])([CH3:10])[O:11][C:25]([O:24][CH2:22][CH3:23])=[N:15][S:12]2(=[O:13])=[O:14])=[CH:5][CH:6]=1
Reactant: CC(C)(O)C(c1ccc(-c2ccccc2)cc1)S(N)(=O)=O
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Product: CCOC1=NS(=O)(=O)C(c2ccc(-c3ccccc3)cc2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 3.14 g of 1-biphenyl-4-yl-2-hydroxy-2-methylpropane-1-sulfonamide in 75 ml of tetraethoxymethane and 15 ml of acetic acid was stirred at 100° C. for 24 hours. The conversion was checked by LCMS. Since it was incomplete, the reaction mixture was admixed with a further 15 ml of acetic acid and stirred at 120° C. for 4 hours. Subsequently, a further 20 ml of tetraethoxymethane were added and the reaction mixture was stirred at 120° C. for 5 hours. Since, by checking with LCMS, no further conversion had been achieved, the solvent was removed under reduced pressure and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (1.04 g) with a molecular weight of 359.5 g/mol (C19H21NO4S).
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:3]1[N:4]=[C:5]2[C:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12]([C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[O:1])[N:4]=2)[NH:9][CH:10]=1)=[O:17]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(C(O)c3ccncc3)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(C(=O)c3ccncc3)nc12

Procedure:
1-[2-(Hydroxy-pyridin-4-yl-methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was treated with Dess-Martin periodinane, following general procedures described in these Examples. MP=218-220 C, (M+H)+=309.
Reaction SMILES: C(OC(=O)[N:7]([CH:17]1[CH2:25][CH2:24][C:23]2[C:19](=[CH:20][N:21]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[N:34]=4)[N:29]=[CH:28][CH:27]=3)[N:22]=2)[CH2:18]1)[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(OC(=O)NC1CCC2C(=CN(C3C4C(=CC=C(OC)N=4)N=CC=3)N=2)C1)(C)(C)C.[H-].[Na+].BrCCOC1C=CC=CC=1>CN(C=O)C.CCOC(C)=O.O>[CH3:37][O:36][C:33]1[N:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[N:21]1[CH:20]=[C:19]2[C:23]([CH2:24][CH2:25][CH:17]([NH:7][CH2:8][CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18]2)=[N:22]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N(CCOc3ccccc3)C(=O)OC(C)(C)C)C4)c2n1
Agent: BrCCOc1ccccc1
Agent: COc1ccc2nccc(-n3cc4c(n3)CCC(NC(=O)OC(C)(C)C)C4)c2n1
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCCOc3ccccc3)C4)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-carbamic acid tert-butyl ester. To a solution of [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-carbamic acid tert-butyl ester (104 mg, 0.260 mmol) in DMF (2.6 mL) was added NaH (60% in mineral oil, 27 mg, 0.66 mmol) at 0° C. The reaction mixture was warmed to RT and stirred for 30 min. Upon cooling the reaction mixture to 0° C., β-bromophenetole (78 mg, 0.39 mmol) was added. The mixture was warmed to RT, and treated with additional NaH (31 mg, 1.3 mmol) and β-bromophenetole (261 mg, 1.30 mmol). After 30 h, H2O (30 mL) and EtOAc (40 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The crude was purified on SiO2 (0-100% EtOAc/hexanes) to give 65 mg (48%) of the title compound as a white solid. MS (ESI): exact mass calculated for C29H33N5O4, 515.25; m/z found, 516.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (br s, 1H), 8.77 (d, J=5.0, 1H), 8.26 (d, J=9.1, 1H), 8.15 (d, J=5.0, 1H), 7.30-7.27 (m, 2H), 7.18 (d, J=9.1, 1H), 6.97-6.92 (m, 1H), 6.90 (d, J=7.8, 2H), 4.16-4.04 (m, 6H), 3.65-3.59 (m, 2H), 3.09-3.05 (m, 1H), 2.92 (br s, 3H), 2.11 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.B(O)O>>[CH3:23][O:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: COc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cn1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1=Cc2ccc(CCCCOC3CCCCO3)cc2Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1=Cc2ccc(CCCCO)cc2Cc2ccccc21
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A solution of ethyl (±)-3-[4-(2-tetrahydropyranyloxy)-1-butyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (456.0 mg, 1.04 mmole) and p-toluenesulfonic acid monohydrate (60 mg, 0.31 mmole) in absolute EtOH (10 mL) was stirred at RT. After 2 hr, the reaction was quenched with 5% NaHCO3 (1 mL) and concentrated to remove the EtOH. The residue was diluted with H2O (2 mL) and extracted with CH2Cl2. Drying (MgSO4), concentration, and silica gel chromatography (1:1 EtOAc/hexanes) gave the title compound (342.4 mg, 93%) as a colorless oil: TLC (1:1 EtOAc/hexanes) Rf 0.49; 1H NMR (250 MHz, CDCl3) δ 6.85-7.25 (m, 7 H), 4.34 (d, J=15.1 Hz, 1 H), 4.08-4.30 (m, 2 H), 3.75-3.95 (m, 2 H), 3.53-3.72 (m, 2 H), 3.33 (dd, J=15.1, 4.1 Hz, 1 H), 2.95 (dd, J=15.1, 9.4 Hz, 1 H), 2.40-2.75 (m, 4 H), 1.45-1.80 (m, 4 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 353 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH3:3].[S:10](Cl)[Cl:11].N1C=CC=CC=1>C(Cl)Cl>[Cl:11][S:10][N:4]([CH:2]([CH3:3])[CH3:1])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(=O)NC(C)C
Reactant: ClSCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N(SCl)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
To a solution of ethyl (1-methylethyl)carbamate (13.1 g, 0.1 mol) in 100 ml methylene chloride cooled to 0° C. was added sulfur dichloride (11.3 g, 0.11 mol) in one portion. While maintaining the temperature of the mixture at 0° C., pyridine (8.7 g, 0.11 mol) was added dropwise over eleven minutes. After complete addition of the pyridine the temperature was allowed to rise to room temperature and stirring was continued for additional 1.5 hours. The mixture was let stand overnight. Methylene chloride was evaporated under vacuum and 100 ml hexane was added. Filteration of the pyridine hydrochloride and evaporation of hexane resulted in an orange oil which was distilled in a Kugelrohr apparatus to give 12.5 g of the title compound Bp: 64°-80° (bath temperature) at 1.4 mm Hg.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>O1CCOCC1>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: COCc1ccccc1B(O)O
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Solvent: C1COCCO1
Product: COCc1ccccc1-c1ccc(OCc2cccc(C(=O)O)c2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 37 mg, 0.1 mmol) in dioxane (2 mL) was degassed with nitrogen and then added to a reaction vial containing 2-methoxymethylphenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK). The solution was sonicated and degassed and a solution of sodium hydroxide (4 M, 0.2 mL) was added, followed by bis(tri-cyclo-hexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 0.005 mmol) was added. The mixture was degassed and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), and dimethylacetamide (1 mL). 1 M HCl was added until a solid formed. The vial was centrifuged and the solvent was removed. The crude product was washed with water and centrifuged again for 5 min. The water was decanted and the solid was dried in a vacuum oven at 50 degrees to give 3-(2′-methoxymethyl-biphenyl-4-yloxymethyl)-benzoic acid. Mass spectrum MH+=349.