Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([Br:25])[CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(N)ncnn23)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 164.6 %

Procedure:
To a cooled (−20° C.) solution of 3-(4-amino-pyrrolo[2,1-f][1,2,4]triazine-7-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.19 g, 3.59 mmol) in tetrahydrofuran (35 mL) was added THF solution of 1,3-dibromo-5,5-dimethylhydantoin (0.56 g, 1.97 mmol). The mixture was allowed to stir (−20° C.) for 2 h and then allowed to warm to rt. The reaction was quenched with the addition of 10% aqueous Na2S2O3 solution. The mixture was extracted with ethyl acetate (3×75 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness. The crude material was purified by Biotage® chromatography using a gradient of 50% to 75% ethyl acetate in hexanes to afford 1.33 g (90%) of the desired product. 1H NMR (300 MHz, CD3OD-d4) δ 8.00 (s, 1 H), 7.45 (d, 1 H), 6.94 (d, 1 H), 4.44-4.32 (m, 1 H), 3.65-3.59 (m, 2 H), 3.47-3.38 (m, 2 H), 2.31-2.11 (m, 2 H), 1.45 (s, 9 H); LC-MS [M+H]+=411.7, RT=2.98 min.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11](=[O:13])[CH3:12].[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:14][CH2:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)=[O:13]
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
25 g (143 mmol) of 1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone were dissolved in 750 ml of THF, 64.7 g (172 mmol) of phenyltrimethylammonium tribromide were added, and the mixture was stirred at room temperature for 15 h. The resultant precipitate was filtered, and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate, washed with 2× sat. sodium hydrogencarbonate solution and 1× sat. sodium chloride solution, the organic phase was dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][CH:4]([OH:11])[C:5]([CH3:10])([CH3:9])[C:6](=[O:8])[CH3:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][CH:4]([O:11][S:24]([CH3:23])(=[O:26])=[O:25])[C:5]([CH3:9])([CH3:10])[C:6](=[O:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)C(C)(C)C(O)C=C(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)C(C)(C)C(C=C(Cl)C(F)(F)F)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
733 g (3 mol) of 6-chloro-3,3-dimethyl-4-hydroxy-7,7,7-trifluoro-hept-5-en-2-one, 360 g (3.6 mol) of triethylamine and 1.5 g of 4-(N,N-dimethylamino)pyridine in 1 l of toluene were admixed at 5° C. with 378 g (3.6 mol) of methanesulfonyl chloride. The mixture was subsequently stirred at 25° C. for 3 hours, the precipitate was filtered off, and the filtrate was extracted with dilute hydrochloric acid and with saturated sodium bicarbonate solution. Drying and concentrating the organic phase gave 948 g of product. Melting point: 50°-52° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:47])[S:43](Cl)(=[O:45])=[O:44]>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 36.7 %

Procedure:
To a stirred solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-ylamine (example 220) (0.23 g, 0.5 mmol) in toluene (5 mL) was added triethylamine (0.21 mL) and dimethylsulfamoyl chloride (0.14 g, 1.0 mmol), the reaction mixture was allowed to stir at 70° C. for 22 h, poured into ice-water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (EtOH/hexane) yielded the title compound (0.104 g, 37%) as an off-white solid. MS (ISP) 567.3 [(M+H)+]; mp 113° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[O:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:21]([O:17][C:9]1[N:8]=[C:13]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:12]=[CH:11][CH:10]=1)[C:20]1[CH:6]=[CH:4][CH:5]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(OCc3ccccc3)n2)CC1
Temperature: 55 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A solution of 1-boc-4-hydroxypiperidine (501 mg, 2.49 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 65 mg, 2.74 mmol) and the mixture was heated at 55° C. for 1 hour. The reaction mixture was then cooled to room temperature, a solution of the product of preparation 111 (506 mg, 2.49 mmol) in tetrahydrofuran (3 mL) was added dropwise and the mixture was stirred at room temperature for 45 minutes and at 70° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, afforded the title compound as a white solid in 49% yield, 470 mg. LRMS APCI m/z 385 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: O=C(Nc1ccc(I)c(Cl)c1)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(Cl)c3)cn2)CC1
Temperature: 95 °C

Procedure:
A solution of 6-Chloro-N-(3-chloro-4-iodo-phenyl)-nicotinamide (100 mg, 0.26 mmol), ethyl isonipecotate (60 mg, 0.38 mmol), diisopropyl ethyl amine (0.14 mL, 0.77 mmol) and a catalytic amount of DMAP in dioxane, in a sealed tube was heated at 85° C. for 19 h. Followed addition of another portion of ethyl isonipecotate (60 mg, 0.38 mmol) and the mixture was heated at 95° C. for 24 h. The mixture was then cooled, the solvent was evaporated and the residue was purified with a silica gel column and 20-40% EtOAc in hexanes to afford the product. HRMS m/z calcd for C20H21N3O3ClI [M+H]+: 514.0389. Found: 514.0387.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].OC([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](N(C)C(=O)CC2)CC3)CC1)C.C(Cl)(=O)CCCCCCCCC=C>>[CH3:24][C:25]([CH3:30])([CH3:29])[C:26]([O:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3])=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: C=CCCCCCCCCC(=O)Cl
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(OC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing substantially the same procedure as described in Example 6, but substituting 20-hydroxy-5α-4-azapregn-1-ene-3-one and trimethylacetyl chloride for the 20-hydroxy-4-methyl-5a-4-azapregnan-3-one and 10-undecenoyl chloride, respectively, used therein, the title compound was obtained. MS M-1 calculated for C25H39NO3, mw=402.53; observed m/e 401.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:2]3[CH2:3][CH2:4][CH:5]([C:8]4[C:9](=[O:18])[NH:10][C:11]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:6][CH2:7]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 46 %

Procedure:
Title compound was prepared from 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as off-white solid in 46% yield. MS m/e (M+H)+=574.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 11.76 (s, 1H), 8.36 (s, 1H), 7.70 (d, J=5.80, 1H), 7.61 (d, J=7.63, 1H), 7.43 (t, J=7.63, 1H), 7.28 (d, J=7.93, 1H), 7.24 (s, 1H), 7.15 (t, J=7.32, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=16.79, 1H), 4.55 (d, J=12.21, 1H), 4.13 (m, 1H), 3.87 (m, 1H), 3.58 (d, J=13.12, 1H), 3.15 (m, 2H), 3.03 (m, 3H), 2.88 (m, 1H), 2.63 (m, 1H), 2.34 (d, J=16.17 1H), 1.91 (d, J=1.22, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[OH:4].C(=O)([O-])[O-].[K+].[K+].F[C:26]1[CH:40]=[CH:39][C:29]([C:30]([C:32]2[CH:37]=[CH:36][C:35](F)=[CH:34][CH:33]=2)=[O:31])=[CH:28][CH:27]=1.C1(C)C=CC=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[OH:4].[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])[C:29]1[CH:39]=[CH:40][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1cc(C(C)(C)c2ccc(O)cc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Polymerization was carried out similar to the P(BPZ-BNZPH) polymerization, except methylbisphenol-A (10.0000 g, 39.00 mmol), potassium carbonate (10.782 g, 78.00 mmol), 4,4′-difluorobenzophenone (8.5102 g, 39.00 mmol), toluene (50 g) and N,N-dimethylacetamide (85 g) were used. The yield was about 15.34 g. The number average molecular weight of the polymer was about 8.2K.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25]>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:25][CH2:24][CH:23]([O:26][CH3:27])[O:22][CH3:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CNC(=O)c1ccc(OC(C)=O)cc1)OC
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 4-(chlorocarbonyl)phenyl acetate (110 g, 553.87 mmol) in CH2Cl2 (500 mL) was cooled in an ice bath and treated with triethylamine (115 mL, 830 mmol, 1.5 equiv.) and 2,2-dimethoxyethanamine (63.36 mL, 581.56 mmol, 1.05 equiv.). The reaction mixture was allowed to warm to ambient temperature and the reaction was followed by TLC (CH2Cl2). The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and filtered. The filtrate was washed with water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water, dilute mono-potassium phosphate (pH=5.4, pH of solution about 7), water, and brine, dried, and concentrated to give 120 g (81% th.; 109% pract.) of 4-(2,2-dimethoxyethylcarbamoyl)phenyl acetate as a light brown waxy solid with no further purification; 1H NMR (CDCl3) δ 7.79 (d, 2H), 7.15 (d, 2H), 6.32 (br. t, 1H), 4.47 (t, 1H), 3.58 (d, 2H), 3.41 (s, 6H), 2.30 (s, 3H) ppm.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:12][CH2:13][CH2:14][CH2:15][B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:29]([O:28][C:26]([NH:25][C:6]([CH2:5][OH:4])([CH2:12][CH2:13][CH2:14][CH2:15][B:16]1[O:17][C:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[O:20]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(COC(C)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(CO)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of ethyl 2-(acetoxymethyl)-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (12.0 g, 26.3 mmol) in ethanol (100 mL) was treated with solid potassium carbonate (3.62 g, 26.3 mmol) and stirred for 2 h. The solution was filtered and the filtrate was evaporated to dryness. The resulting residue was dissolved in ethyl acetate (150 mL) and washed successively with water (50 mL) and saturated aqueous sodium chloride (50 mL). Organic layer was concentrated and purified using a combiflash system (120 g column, eluting with 20-30% ethyl acetate in heptanes) to give ethyl 2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (7.0 g, 78%). 1H NMR (CDCl3) δ 5.25 (bs, 1H), 4.00 (m, 2H), 3.91 (d, J=11.3 Hz, 1H), 3.60 (d, J=11.3 Hz, 1H), 1.53-1.46 (m, 1H), 1.23 (s, 9H), 1.21-1.15 (m, 1H), 1.06 (m, 7H), 1.03 (s, 12H), 0.90 (m, 1H), 0.54 (t, J=7.8 Hz, 2H). MS found for C20H38BNO7 m/z[438(M+Na)]
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][CH2:9][CH:8]2[C:11](=[CH2:12])[CH:3]1[CH2:4][CH2:5][CH:6]([OH:13])[CH2:7]2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>P(=O)(O)(O)O.CCOCC>[C:15]([O:13][CH:6]1[CH2:5][CH2:4][CH:3]2[C:11](=[CH2:12])[CH:8]([CH2:9][CH2:10][C:2]2([CH3:14])[CH3:1])[CH2:7]1)(=[O:17])[CH3:16]
Reactant: C=C1C2CCC(C)(C)C1CCC(O)C2
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOCC
Product: C=C1C2CCC(C)(C)C1CCC(OC(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 3-necked flask which was equipped with a reflux condenser, there were placed, under N2-atmosphere, 0.9 g (4.6 mmoles) of 7,7-dimethyl-10-methylene-bicyclo[4.3.1]decan-3-ol, 8 ml of acetic anhydride and 1 drop of phosphoric acid. The reaction mixture was stirred overnight at room temperature. Then 50 ml of H2O were added and the solution stirred one more night at room temperature. The resulting mixture was taken up in ether, washed to neutrality with brine and dried over Na2SO4. After filtration and concentration in vacuo, the product was distilled in a bulb-to-bulb apparatus at 150° C. (10 Pa). There were obtained 1.09 g of a colorless oil in 99% of the theoretical yield. The thus-obtained mixture was composed of 2 isomers (71/29) which were separated by gas chromatography on a chemically inert CARBOWAX® column having a length of 5 meters.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12](I)[CH:13]=[C:8]2[N:7]=1)C.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][O:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:16][N:15]1[C:9]2=[N:10][CH:11]=[C:12]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:13]=[C:8]2[N:7]=[C:6]1[NH2:5]
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccn5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.7 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.250 g, 0.42 mmol), 2-(tributylstannyl)pyridine (0.235 g, 0.63 mmol), copper(I) iodide (0.040 g, 0.21 mmol) and triethylamine (0.130 g, 1.26 mmol) in N,N-dimethylformamide (5 mL) was added bis(triphenylphosphine)palladium(II) dichloride (0.018 g, 0.042 mmol). The mixture was irradiated in a microwave reactor at 140° C. After 1.5 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated. The residue was purified by prep-HPLC to afford 0.025 g (13%) of the product as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=4.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.84-7.76 (m, 1H), 7.74-7.72 (m, 1H), 7.32-7.29 (m, 1H), 7.12 (d, J=6.0 Hz, 1H), 7.00-6.77 (m, 3H), 6.82 (d, J=8.5 Hz, 1H), 6.83-6.74 (m, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H) ppm; (M+1)=469.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Br)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1([C:44](=[O:46])[CH3:45])[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:40]2[CH2:41][CH2:42][CH2:43][N:37]([C:44](=[O:46])[CH3:45])[CH2:38][CH2:39]2)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCCNCC1
Reactant: COc1ccc(-c2cc(NC(=O)C(C)CCCBr)n(C(=O)OC(C)(C)C)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)n(C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
5-(5-Bromo-2-methyl-pentanoylamino)-3-(4-methoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (280.0 mg, 0.6 mmol, 1.0 eq) was dissolved in DCM (3 mL). Triethylamine (80 μL, 0.6 mmol, 1.0 eq) and 1-[1,4]-diazepan-1-yl-ethanone (158 μL, 170.0 mg, 1.2 mmol, 2.0 eq) were added and the mixture was stirred at room temperature for 24 hours, then at 50° C. for 16 hours. NaHCO3 saturated solution was added and the organic layer separated and collected. Evaporation of the solvent gave a crude product purified using SiO2 column (elution DCM, DCM:MeOH 99:1 to 96:4) obtaining the title product (181.3 mg, yield 54%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+]>>[NH2:16][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:15]([OH:18])=[O:19]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1
Agent: [Na+]
Product: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1

Procedure:
A mixture of 1.0 g. (0.004 mole) of 7-benzoylindolin-2-one was added to 30 ml. of 3N sodium hydroxide and the basic solution was refluxed for 45 minutes under nitrogen. The mixture was filtered and the filtrate was neutralized with glacial acetic acid. The precipitate was filtered off, washed with water and dried. The material melted at 122° C. (dec.). The yield was 0.8 g. (72%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:27]C)[N:11]=1)[CH3:9])(C)(C)C.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:27])[N:11]=1)[CH3:9]
Reactant: COc1cccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccc(O)c2c(=O)n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-tert-butyl(1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (100 mg, 0.25 mmol) in DCM (3 mL) at −78° C. was added BBr3 (1M/DCM, 0.63 mL, 0.63 mmol). The reaction was stirred at −78° C. for 20 min, then warmed to ambient temperature. After stirring 10 minutes at ambient temperature, MeOH (5 mL) was added. The reaction was concentrated in vacuo. Purification by flash chromatography (12 g silica, 0-100% EtOAc/DCM then 0-30% MeOH/DCM) provided (S)-2-(1-aminoethyl)-5-hydroxy-3-phenylquinazolin-4(3H)-on as an orange residue. ES/MS 282.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl.[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Agent: Cl
Product: Cc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 8 with 4-chlorophenyl hydrazine.HCl substituted for phenyl hydrazine and 2-amino-5-(2-N-t-butylaminosulfonylphenyl)pyridine was used in the coupling step. There was obtained the title compound; HRMS (M+H)+: calc. 468.089714; found 468.088873.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O[CH:11]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.6 (M+H)+.