Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C@@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16](=[O:25])[N:15]1[C:26](=[O:35])[CH2:27][CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[CH2:37][C@@H:27]([C:26]([N:15]1[C@H:14]([CH3:13])[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16]1=[O:25])=[O:35])[CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30 mL THF at −78° C. was added n-butyllithium (1.6 M soln in hexanes, 7.6 mL, 12.1 mmol), and the mixture stirred 10 minutes at which time oxazolidinone 137 (3.2 g, 10.1 mmol) in 10 mL THF was added dropwise. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was added quickly dropwise at −50° C., and the mixture was allowed to warm slowly to 10° C. over 3 hours. The mixture was partitioned between Et2O and sat. NH4Cl (aq), the phases were separated, and the organic phase dried (MgSO4), and concentrated. The residue was purified by flash chromatography (16:1 to 8:1 hexanes:EtOAc) to provide 2.65 g (61%) of ester 138 as a colorless crystalline solid, mp=84–86° C. [α]D23+17.1 (c=1.00, CHCl3); 1H NMR (CDCl3): δ 7.34 (m, 5H), 5.62 (d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8 Hz, 1H), 4.29 (m, 1H), 2.67 (dd, J=9.8, 16.4 Hz, 1H), 2.40 (dd, J=5.1, 16.4 Hz, 1H), 1.69 (m, 1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08 (m, 1H), 0.88 (m, 9H); 13C NMR (CDCl3) δ 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. Anal. Calcd for C25H37NO5: C, 69.58; H, 8.64; N, 3.25. Found: C, 69.37; H, 8.68; N, 3.05.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=C)[N:4]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[C:10]2[C:9]([CH:11]=[O:31])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2c1c(C)cn2S(=O)(=O)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2cccc(C=O)c12
Reaction time: 0.83 h
Yield: 134.5 %

Procedure:
OsO4 (29 mg, 0.12 mmol) was added to a stirred mixture of 3-methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole (342 mg, 1.15 mmol; Intermediate 30) and 2,6-lutidine (268 μL, 2.3 mmol) in dioxane (15 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.984 g, 4.6 mmol) in water (5 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 50 min, combined with an earlier batch of this intermediate (followed this experimental and starting with 3-methyl-1-(phenylsulfonyl)-4-vinyl-1H-indole, 70 mg; Intermediate 30), extracted with water (30 mL) and DCM (2×30 mL). The organic layers were combined, dried, filtered and concentrated to give the title compound (463 mg, 89%) as a black solid. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[C:6]([C:13]#[N:14])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.O.C(=O)([O-])[O-:19].[Na+].[Na+].OO>CC(C)=O>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[C:6]([C:13]([NH2:14])=[O:19])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(C#N)c(CC(OC)OC)c1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cnc(C(N)=O)c(CC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a 1 L round-bottomed flask was added 3-(2,2-dimethoxyethyl)-5-methoxypicolinonitrile (8.550 g, 38.5 mmol), water (480 ml), and acetone (120 ml). An aqueous solution of sodium carbonate (3M; 154 ml, 462 mmol) was added followed by hydrogen peroxide (35 wt. % solution in water; 138 ml, 1347 mmol). The tan mixture was stirred vigorously at rt for 2 h. The organic solvent was removed uncle reduced pressure and the aqueous residue was extracted with DCM (3×). The combined organic fractions were dried over sodium sulfate. The filtrate was concentrated under reduced pressure to afford 3-(2,2-dimethoxyethyl)-5-methoxypicolinamide (8.200 g, 34.1 mmol, 89% yield) as an off-white solid that was advanced without further purification. MS m/z=263.2 (M+Na)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]2=[O:24])=[CH:2]1.C(N(CC)CC)C.[CH2:32](Cl)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].[O:45]1CCCC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]2=[O:24])=[CH:2]1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccccc23)C1=O
Reactant: CCCCCCCCCCCCCl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N1CCN(CCc2c[nH]c3ccccc23)C(=O)C1CC(=O)OCC
Reaction time: 0.5 h

Procedure:
2.14 g of the product of Step C of Example 1 were dissolved in a mixture containing 1.4 ml of triethylamine and 25 ml of tetrahydrofuran. 1.5 ml of lauryl chloride were added dropwise and after stirring for 30 minutes, the precipitate was filtered off. The filtrate was concentrated to dryness and the residue was taken up in methylene chloride, washed with water and dried. The solvent was eliminated under reduced pressure at 50° C. to obtain 3.2 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Product: Cc1c(C(=O)NC2CCCN(C(=O)OC(C)(C)C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-{4-fluoro-2-[(S)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 4-amino-azepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A 500 mL round-bottom flask was charged with 4-bromo-2-methylbenzaldehyde (8.00 g, 40.2 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (9.40 g, 50.5 mmol, 1.26 equiv), triethylamine (6.50 g, 64.2 mmol, 1.60 equiv) and dichloroethane (200 mL). The resulting solution was stirred for 30 min at room temperature. Solid sodium triacetoxyborohydride (27.0 g, 127 mmol, 3.17 equiv) was added. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with dichloromethane (3×200 mL) and the organic layers were combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/3) to yield 10.0 g (67% yield) of tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 369 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:5]=[C:4]1[S:23][CH3:24])[CH3:2].S([O-])(O[O-])(=O)=O.[K+].[K+].[OH2:33].C[OH:35]>>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:6]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[N:5]=[C:4]1[S:23]([CH3:24])(=[O:35])=[O:33])[CH3:2]
Reactant: CCn1c(SC)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: O
Reactant: CO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Product: CCn1c(S(C)(=O)=O)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O

Procedure:
A mixture of 3-ethyl-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (300 mg, 0.88 mmol) and OxoneR potassium peroxymonosulfate, 2.54 g, 4.14 mmol) in methanol (71 ml) and water (33 ml) was stirred for 14 h. The solvent was concentrated to about 35 ml, followed by extraction with dichloromethane, drying and evaporation. The resulting white solid was used without purification in the next step.
Reaction SMILES: [Br:1][CH:2]([OH:4])[CH3:3].[N:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[N:12]/[C:13]2[CH:14]=[CH:15][C:16]3[C:17](=[O:27])[NH:18][C:19](=[O:26])[C:20]4[C:25]=3[C:24]=2[CH:23]=[CH:22][CH:21]=4)=[CH:7][CH:6]=1>C(#N)C.CC(C)=O>[Br-:1].[O:26]=[C:19]1[C:20]2[C:25]3[C:24](=[C:13](/[N:12]=[CH:11]/[C:8]4[CH:9]=[CH:10][N+:5]([CH2:3][CH2:2][OH:4])=[CH:6][CH:7]=4)[CH:14]=[CH:15][C:16]=3[C:17](=[O:27])[NH:18]1)[CH:23]=[CH:22][CH:21]=2
Reactant: O=C1NC(=O)c2ccc(/N=C/c3ccncc3)c3cccc1c23
Reactant: CC(O)Br
Solvent: CC#N
Solvent: CC(C)=O
Product: O=C1NC(=O)c2ccc(/N=C/c3cc[n+](CCO)cc3)c3cccc1c23
Product: [Br-]
Temperature: 25 °C

Procedure:
2.34 g (18.75 mmol) of bromoethanol was added dropwise to a solution of 1.13 g (3.75 mmol) of 6-{[(E)-4-pyridinylmethylidene]amino}-1H-benzo[de]isoquinolin-1,3(2H)-dione in 60 mL of acetonitrile or acetone and the solution was then heated at reflux for 1 hour. After concentration to about ⅓ of the amount of solvent and cooling to room temperature, the resulting precipitate was suction-filtered, washed with ethyl acetate and dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[CH:9]([F:11])[F:10].[CH2:12]([S-:14])[CH3:13].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:14][CH2:12][CH3:13])=[CH:4][C:3]=1[CH:9]([F:11])[F:10]
Reactant: CC[S-]
Reactant: Fc1ccc(Br)c(C(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ccc(Br)c(C(F)F)c1
Yield: 28.4 %

Procedure:
1-Bromo-2-(difluoromethyl)-4-fluorobenzene (Preparation 50, 772 mg, 3.43 mmol) and sodium ethanethiolate (352.7 mg, 3.77 mmol) in DMSO (5 mL) was heated at 50° C. for 18 hours. On cooling, water (70 mL) was added to the reaction mixture, the product was extracted with EtOAc (20 mL×3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel column chromatography eluting with heptane to afford the title compound as a colourless oil (260 mg, 28%).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[CH3:13][O:12][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=[CH:11][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: COc1c(Br)ccc2c1CCCC2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)ccc2c1CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a stirred mixture of 6-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene, (15 g, 62.21 mmol) in THF (150 mL) cooled to 0° C. was added n-butyllithium (43.14 mL, 69.03 mmol, 1.6M solution in hexanes) over 5 min. The reaction mixture was stirred for 1 h then cooled to −78° C., and triisopropyl borate (21.72 mL, 17.7 g, 94.14 mmol) was added dropwise over 0.25 h. The mixture was allowed to warm to room temperature with stirring then poured into 1N HCl (100 mL). The product was extracted with ethyl acetate (4×100 mL), the combined organic extracts dried over anhydrous sodium sulfate, and filtered. After concentrating the filtrate in vacuo at ambient temperature, the oily yellow residue was partially dissolved in diethyl ether, triturated with hexane, and the resulting precipitate filtered and washed with hexane to afford 1.64 g (13%) of the title compound 1-methoxy-5,6,7,8-tetrahydronaphthalene-2-boronic acid as an off-white crystalline solid (MW 206.05, C11H15BO3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26](=[O:39])[N:27]([CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[N:6][CH:7]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26](=[O:39])[N:27]([CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][N:36]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:37][CH2:38]4)[CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[N:6][CH:7]=1
Reactant: O=C(Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2cccn(CCN3CCNCC3)c2=O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(CCn2cccc(-c3ccc(C(=O)Nc4c(O)cccc4C(=O)Nc4ccc(Cl)cn4)cc3)c2=O)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazin-1-ylethyl)-1,2-dihydropyridin-3-yl]benzoyl}amino)benzamide (130 mg) was dissolved in pyridine (5 mL), and with cooling with ice, methanesulfonyl chloride (51 μL) was added, followed by stifling at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, then azeotroped with toluene. An aqueous saturated sodium hydrogencarbonate solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 5%), then by silica gel column chromatography (methanol/chloroform=0% to 5%). The resulting compound was dissolved in ethyl acetate, and 4 N hydrochloric acid/ethyl acetate was added, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-{2-[4-(methylsulfonyl)piperazin-1-yl]ethyl}-2-oxo-1,2-dihydropyridin-3-yl)benzoyl]amino}benzamide hydrochloride (47 mg) as a yellow white solid.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:8]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=1[NH2:10])#[N:7].[N:19]([O-])=O.[Na+].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C.O>[C:6]([C:8]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][C:9]=1[NH:10][N:19]=[N:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:7]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1NN=Nc1ccccc1

Procedure:
A cooled solution of 3.6 ml. of concentrated sulfuric acid and 3.6 ml. of water is added to 3.0 g. (0.016 mol.) of 2-cyano-5-trifluoromethylaniline. The slurry is cooled (ice bath) and stirred and a solution of 1.1 g. (0.016 mol.) of sodium nitrite in 6 ml. of water is added dropwise. The resulting mixture is then added to a solution of 3 ml. of aniline in 120 ml. of ethanol. Additional aniline (6 ml.) is added and the reaction mixture is stirred for 15 minutes. The mixture is poured into 500 ml. of water and the precipitate is collected by filtration, washed with water and recrystallized from hexane to give 3-(2-cyano-5-trifluoromethylphenyl)-1-phenyltriazene, m.p. 139°-141°.
Reaction SMILES: [CH:1](=O)CCCCC.[CH:8](=O)[CH2:9]CCCCC.[CH2:16]([C:19]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:20][OH:21])[CH2:17][CH3:18]>>[CH2:16]([C:19]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:20][OH:21])[CH2:17][CH2:18][CH3:1].[CH2:16]([C:19]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:20][OH:21])[CH2:17][CH2:18][CH2:8][CH3:9]
Reactant: CCCCCCC=O
Reactant: CCCCCC=O
Reactant: CCCC(CO)(CO)CO
Product: CCCCC(CO)(CO)CO
Product: CCCCCC(CO)(CO)CO

Procedure:
2-n-Butyl-2-hydroxymethyl-propan-1,3-diol and 2-n-pentyl-2-hydroxymethyl-propan-1,3-diol were prepared from n-hexanal and n-heptanal respectively in a manner analogous to that described for the synthesis of 2-n-propyl-2-hydroxymethyl-propan-1,3-diol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:22][CH:21]=3)=[O:18])=[CH:7][C:6]=2[CH:35]=1.B([O-])([O-])O[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:48]([O:47][CH2:46][CH2:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:22][CH:21]=4)=[O:18])=[CH:7][C:6]=3[CH:35]=2)=[CH:43][CH:42]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CC(C)CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
In toluene/ethanol/water (=10/1/1, 31.5 ml) was dissolved 7-bromo-1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.66 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.35 g) and potassium carbonate (0.37 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was heated to reflux for 16 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1). The purified residue was dissolved in ethyl acetate and filtered to give a solution. The solvent was removed under reduced pressure, followed by recrystallization from isopropyl ether/ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 87) (74 mg).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[OH:14].[OH-].[Na+]>O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Methyl chloroformate (16.35 ml, 0.173 mol) was added to a solution of 2,4difluorophenol (25 g, 0.192 mol) and sodium hydroxide (8.1 g, 0.203 mol) in water (140 ml). The mixture was stirred at ambient temperature for 2 hours and then extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the volatiles removed by evaporation to give 2,4-difluoro-1-methoxycarbonyloxybenzene (32 g, 89%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C@H:24]([CH3:46])[CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:20]=[C:19]([S:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=2[F:56])[N:18]=1>>[N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH:15][C:17]3[CH:22]=[C:21]([O:23][C@H:24]([CH3:46])[CH2:25][O:26][C:27]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=[C:19]([S:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=4[F:56])[N:18]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(C(=O)N2CCC2)o1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C(=O)N3CCC3)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 5-(azetidin-1-ylcarbonyl)furan-2-sulfonamide (the product of step iii) (0.40 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product of Example 13, step iii) (0.41 g) according to the procedure outlined in Example 1, step iv). Yield: 0.25 g
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24](O)=O)=[CH:20][CH:19]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:22][CH:23]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=C(C)c3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CC[C@H](NCc1ccc(C(C)=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 50 mL of N-methylpyrrolidinone containing 0.18 g of N-methylmorpholine was added 0.22 g of phenyl N-phenylphosphoramidochloridate in a single portion. After stirring the mixture at room temperature for 1 hour, 0.20 g of diethyl L-glutamate was added. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure and the residue was triturated with chloroform. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel using a 5% methanol in chloroform mixture as the eluent. This gave 74.6 mg (25%) of the title compound as a pale yellowish solid; NMR (CDCl3, 250 MHz) d 1.22 (t, 3H, J=7.1 Hz), 1.30 (t, 3H J=7.1 Hz), 2.11-2.57 (m, 10H), 4.14 (q, 2H, J=7.1 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.75-4.83 (m, 1H), 6.86 (brs, 1H), 7.18 (brs, 1H), 7.57 (d, 2H, J=8.42 Hz), 7.84 (d, 2H, J=8.42 Hz), 8.50 (d, 1H, J=2.01 Hz), 8.96 (brs, 1H), 10.34 (brs, 1H).