Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].Cl[CH2:14][CH:15]1[O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][CH:15]1[O:17][CH2:16]1
Reactant: Oc1ccc2ccccc2c1Br
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1c(OCC2CO2)ccc2ccccc12

Procedure:
A suspension containing 22.3 g of 1-bromonaphth-2-ol, 27.75 g of 1-chloro-2,3-epoxypropane and 27.6 g of potassium carbonate in 200 ml of butanone is refluxed overnight. The inorganic salts are filtered off and drained and the filtrate is then evaporated under vacuum. The oil obtained is distilled under 0.01 mm of mercury.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:8])(=O)C.N.Cl>C(#N)C>[SH:4][CH2:5][CH:6]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: N
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)C(CS)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Benzyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)amino]benzoate (2.0 g) is dissolved in acetonitrile (20 ml), and thereto is added 28% aqueous ammonia (15 ml), and the mixture is stirred at room temperature for one hour. The reaction mixture is adjusted to pH 2.5 with 20% hydrochloric acid under ice cooling and is extracted with ethyl acetate (70 ml). The extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure and the residue is extracted with ethyl acetate (100 ml). The extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give the title compound (0.9 g) as a colorless oily substance.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH:5]1([CH:11]2[CH:15]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[O:14][B:13]([CH:22](Cl)[CH:23]([CH3:31])[CH2:24][CH:25]([CH3:30])[C:26]([CH2:28][CH3:29])=[CH2:27])[O:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1COCC1>[CH:16]1([CH:15]2[CH:11]([CH:5]3[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[O:12][B:13]([CH:22]([CH2:1][CH3:2])[CH:23]([CH3:31])[CH2:24][CH:25]([CH3:30])[C:26]([CH2:28][CH3:29])=[CH2:27])[O:14]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=C(CC)C(C)CC(C)C(Cl)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: C=C(CC)C(C)CC(C)C(CC)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
Ethylmagnesium bromide (3.0 M in diethyl ether, 35.6 mmol) was added dropwise in 20 minutes to a stirred solution of [4R- [2(S*,S*,S*),4α,5β]]-4,5-dicyclohexyl-2-(6-chloro-2-ethyl-3,5-dimethylhexen-6-yl) -1,3,2-dioxaborolane (14.5 g, 35.6 mmol) in THF (200 mL) cooled with a -78° C. bath. The bath was allowed to warm to 20°-25° C. and the mixture was stirred for 24 h. The solution was concentrated under vacuum and ether (200 mL) was added to the residue. The ethereal solution was washed with saturated aqueous ammonium chloride (2∞200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to liquid [4R-[2(S*,S*,S*),4α,5β]]-4,5-dicyclohexyl -2-(2,6-diethyl-3,5-dimethylhexen-6-yl)-1,3,2-dioxaborolane (14a) as a liquid (12.9 g, 90%); 300 MHz 1H-NMR (CDCl3) δ0.87-2.27 (m, 43), 3.81 (m, 2), 4.66 and 4.71 (AB, 2); 75 MHz 13C-NMR (CDCl3): 12.3, 14.1, 17.6, 19.5, 22.0, 25.8, 25.9, 26.1, 27.1, 27.6, 28.2, 28.5, 31.6, 37.4, 43.1, 83.1, 105.8, 156.8. HRMS: calcd for C26H48BO2 [(M+1)+] 403.3747; found, 403.3732.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.404 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.24 g, 41%). MS (ISN) 585.2 [(M−H)−]; mp 237° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1.[Br:14]Br>C(OCC)C>[Br:14][CH:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[C:11]1=[O:12]
Reactant: O=C1CCCOc2cc(Br)ccc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2ccc(Br)cc2OCCC1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (1.2 g, 5 mmol) in diethyl ether (20 mL) at 0° C. was added bromine (257 μL, 5 mmol) dropwise under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, allowed to warm up to RT and stirred for 3 h. Further bromine (50 μL, 0.97 mmol) was added and stirring was pursued for 16 h. The solvent was removed in vacuo and the resultant residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane) to give the title compound as a white solid (1.55 g, 97%). 1H NMR (CDCl3): 7.62 (1 H, m), 7.26 (2 H, m), 4.94 (1 H, dd, J=7.7, 6.7 Hz), 4.43 (1 H, ddd, J=12.7, 5.6, 4.8 Hz), 4.25-4.15 (1 H, m), 2.97-2.86 (1 H, m), 2.51 (1 H, ddt, J=14.7, 7.7, 4.6 Hz).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO>[Pd].O1CCCC1>[C:1]([NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Nc1ccccc1N

Procedure:
To a solution of tert-butyl-(2-nitrophenyl)-amine (1.27 g, 6.5 mmol), 5% palladium on carbon (0.5 g), and sodium borohydride (0.49 g, 13.1 mmol) in tetrahydrofuran (20 mL) was added methanol (10 mL) in a dropwise manner. Upon completion of the reaction, it was filtered through a pad of Celite and the filtrate was poured into a saturated aqueous solution of ammonium chloride (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo to give N-tert-butyl-benzene-1,2-diamine which was used in the next step without further purification. A solution of N-t-butyl-benzene-1,2-diamine (1.1 g, 6.7 mmol) and carbonyldiimidazole (1.63 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred at room temperature for 12 hours. Upon completion, the reaction was poured into a 1 N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 50% ethyl acetate in hexane) to give 1-tert-butyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS (ES) m/z 191.1.
Reaction SMILES: C(O)(=O)C.O[CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[O:20]=[C:21]([CH:28]1[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH2:36][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[O:33])[CH2:29]1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH:18]1[C:19]2[CH:6]([CH:22]([C:21](=[O:20])[CH:28]3[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH2:36][C:37]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[O:38])=[O:33])[CH2:29]3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)CC(=O)C1CC(C(=O)OCCC(=O)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)C1CC(C(=O)OCCC(=O)c2ccccc2)C1)C1c2ccccc2Oc2ccccc21
Reaction time: 168 h

Procedure:
Acetic acid (20 ml) was added to a stirred suspension of 9-hydroxyxanthene (3.96 g, 20 mmol) and ethyl 3-oxo-3-[3-(phenacylmethyloxycarbonyl) cyclobutyl]propanate (6.0 g, 18 mmol) in ethanol (20 ml) at room temperature. A clear solution formed and was allowed to stand for 7 days at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[C:26]3[C:18](=[CH:19][N:20]=[C:21]4[C:25]=3[CH:24]=[CH:23][N:22]4S(C3C=CC=CC=3)(=O)=O)[NH:17][N:16]2C)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])([N:15]2[C:26]3[C:18](=[CH:19][N:20]=[C:21]4[C:25]=3[CH:24]=[CH:23][NH:22]4)[N:17]=[N:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1Nc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2N1C1(C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(n2nnc3cnc4[nH]ccc4c32)CC1
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A mixture of 4-(6-benzenesulfonyl-2-methyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.37 g, 0.75 mmol) in THF/methanol containing aqueous sodium hydroxide (3.75 mmol) was stirred for 16 hours. The solvent was evaporated under vacuum to a small volume, the residue dissolved in DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to afford 240 mg (90%) of 4-methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-piperidine-1-carboxylic acid tert butyl ester. LCMS (Method I, ESI): RT=3.20 min, m+H=357.3; 1H NMR (400 MHz, DMSO) δ: 12.46 (s, 1H), 9.06 (s, 1H), 7.63 (t, 1H), 6.86 (m, 1H), 3.62 (m, 2H), 3.33 (m, 2H), 2.71 (m, 2H), 2.12 (m, 2H), 1.85 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[CH:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
To a solution of (2R)-2-amino-N-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]butanamide (Intermediate 17, 40 mg, 0.11 mmol) in dry DCM (5 ml) TEA (0.042 ml, 0.3 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (23.7 mg, 0.08 mmol) in dry DCM (3 ml) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (22 mg) as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(C)(C)C>>[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1ccc2nccc(Br)c2c1
Product: N#Cc1ccc2nccc(N3CCC(N)CC3)c2c1

Procedure:
Starting from 4-bromo-6-cyanoquinoline (commercial) and piperidin-4-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (382 mg, 69% over two steps).
Reaction SMILES: O.[OH-].[Na+:3].[NH2:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[C:11](Cl)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1(C)C=CC=CC=1>[Na+:3].[C:11]([NH:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:9])=[O:8])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCCS(=O)(=O)[O-])OCc1ccccc1
Temperature: 25 °C

Procedure:
To 1000 ml of water in the RBF charge 192 gm of (3.0 eq) of sodium hydroxide under cooling followed by 200 gm of Taurine and dissolve it until clear solution is obtained. Cool to 0° C. to 5° C., and Charge 50% CBZ-Cl in toluene at 0° C. to 5° C. After completion of addition, maintain at room temperature for 14 h. Separate the toluene layer and wash the aqueous layer with 2×200 ml of ethyl acetate. Add slowly 27 gm of sodium hydroxide in 60 ml of water to the aqueous layer and adjust pH to 12-14. Cool to 0° C. to 5° C. and a white solid separates from the solution. Filter the solid and dry the solid at 60-70° C. Weight of the solid: 320 g
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.OC([C:19]1[S:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][N:23]=1)C1CC1>CC(C)=O>[O:3]=[C:2]1[CH2:4][CH:1]1[C:19]1[S:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][N:23]=1
Reactant: CC(C)=O
Reactant: NS(=O)(=O)c1cnc(C(O)C2CC2)s1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: NS(=O)(=O)c1cnc(C2CC2=O)s1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Jones' reagent (0.63 mL, 1.69 mmol, 2.67M) was added dropwise to a 0° C. solution of 2-(1-hydroxy-1-cyclopropylmethyl)-5-thiazole sulfonamide (0.33 g, 1.4 mmol) in acetone (5 mL). The ice bath was removed and the solution stirred for 30 min. The reaction was quenched with a few drops of isopropanol and the acetone removed in vacuo. The residue was taken up in water and extracted with EtOAc. The combined extracts were dried (MgSO4), concentrated and purified by flash chromatography using 30% EtOAc/hexane to give 0.23 g (72%) of 2-(1-ketocyclopropyl)-5-thiazole sulfonamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[C:28]([S:30][CH3:31])[CH:27]=[C:26]([CH:32]([CH3:34])[CH3:33])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:9]=[CH:14][CH:15]=[CH:16][C:17]=3[CH:10]([C:11]([NH:25][C:24]3[C:26]([CH:32]([CH3:34])[CH3:33])=[CH:27][C:28]([S:30][CH3:31])=[CH:29][C:23]=3[CH:20]([CH3:22])[CH3:21])=[O:13])[C:4]=2[CH:3]=1
Reactant: CSc1cc(C(C)C)c(N)c(C(C)C)c1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Product: CSc1cc(C(C)C)c(NC(=O)C2c3ccccc3COc3ccc(Br)cc32)c(C(C)C)c1
Yield: 76.1 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.84 g of 2,6-diisopropyl-4-methylthioaniline in place of aniline to obtain 1.25 g of Compound 44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Nc1ccccc1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccccc3)nc21
Temperature: 195 °C

Procedure:
A mixture of 0.134 g (0.33 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (5.40 mmol) of aniline was heated with stirring in a 195° C. oil bath to reflux. The resulting solution was maintained at reflux for 5 minutes. Most of the excess aniline was evaporated at reduced pressure. The residual gum was dissolved in 15 mL of ethyl acetate. After filtration of a relatively small amount of insoluble material, the solution was filtered through a layer of silica gel to remove violet color. The filtrate was concentrated to 2 mL volume. Petroleum ether was added until slight turbidity. The crystals that separated on inducement were filtered and washed with 50% ether/petroleum ether; wt 0.068 g; mp 223°-225° C.
Reaction SMILES: Cl.[CH:2]1([NH2:15])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:2]1([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: NC1CCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: O=C(NC1CCCc2c1[nH]c1ccccc21)c1ccccc1

Procedure:
N-(2,3,4,9-Tetrahydro-1H-carbazol-1-yl)benzamide was prepared from 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride and benzoyl chloride in a similar manner as described above to give a pale yellow solid (73% yield). 1H-NMR (CDCl3): δ 8.79 (s, 1H), 7.81-7.75 (m, 2H), 7.54-7.48 (m, 2H), 7.47-7.40 (m, 2H), 7.32 (d, 1H), 7.17 (m, 1H), 7.09 (d, 1H), 6.42 (d, 1H), 5.37 (m, 1H), 2.78 (m, 2H), 2.32 (m, 1H), 2.03-1.91 (m, 3H); MS m/z 289 (M−1).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3Br)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccn1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccccc4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “8” by using 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine and benzenboronic acid as the starting materials. LC-MS (M+H=523, obsd=523). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J=5.1, 0.8 Hz, 1H), 8.08 (s, 1H), 7.76 (s, 1H), 7.54-7.46 (m, 3H), 7.43 (dd, J=5.1, 1.6 Hz, 1H), 7.36 (dddd, J=9.9, 6.5, 2.9, 1.6 Hz, 3H), 5.65 (s, 2H), 3.83 (t, J=6.2 Hz, 2H), 3.79-3.66 (m, 2H), 3.09 (t, J=7.0 Hz, 4H), 3.00 (h, J=6.9 Hz, 1H), 2.92-2.79 (m, 1H), 2.69 (dd, J=20.7, 7.0 Hz, 1H), 1.92 (p, J=7.0 Hz, 2H), 1.59 (dt, J=8.0, 4.5 Hz, 4H), 1.25 (d, J=6.9 Hz, 6H).
Reaction SMILES: ClC1C=C([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N+]=[N-])=[C:12](C(F)(F)F)[CH:11]=2)C=CC=1.[H][H]>C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH2:8])=[O:23])=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(N)cc1

Procedure:
The N-3-chlorophenyl 4-azido-3-trifluoromethylbenzamide compound from Step 18c was reduced under 1 atm of hydrogen in the presence of Pd/ in ethanol to the give the corresponding 4-aminobenzamide, which was used without purification in Step 72b.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-])=O)[C:7]=1[OH:16])(=[O:5])=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:16])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 127.6 %

Procedure:
To a solution of N-methyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (140 mg, 0.53 mmol) in ethyl acetate, was added 10% Pd/C (60 mg). The mixture was flushed with argon, then stirred under a hydrogen atmosphere at balloon pressure for 1.5 hours at room temperature. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated to give the desired product (160 mg, >100%). 1H NMR (DMSO-d6): δ 7.95 (bs, 1H), 6.85 (d, 1H), 6.79 (d, 1H), 2.48 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCCCCCCCCCCC(=O)O
Reaction time: 1 h

Procedure:
To the suspension of 16-hydroxyhexadecanoic acid (0.7 g) in dichloromethane (20 ml) was added triethylamine (1.80 ml). Methanesulfonyl chloride (0.8 ml) was added dropwise to the reaction mixture while it was ice-cooled and stirred. Stirring was continued directly at 0° C. for 1 hour. The reaction mixture was extracted with chloroform, and the chloroform layer was washed with 1% aqueous sodium hydrogen carbonate and then with water, dried with anhydrous sodium sulfate and concentrated. The residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (3:1) to give 16-methanesulfonyloxyhexadecanoic acid (0.74 g). To 16-methanesulfonyloxyhexadecanoic acid (325 mg) dissolved in N,N-dimethylformamide (DMF, 15 ml) was added sodium azide (268 mg), and the mixture was stirred at 80° C. for 12 hours. The reaction mixture, after having been cooled, was then distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate to give 16-azidohexadecanoic acid (235 mg). To the solution of 16-azidohexadecanoic acid (226 mg) in DMF were added N-hydroxysuccinimide (90 mg) and N,N'-dicyclohexylcarbodiimide (160 mg), and the mixture was stirred for 48 hours. The reaction mixture was filtered and concentrated to give the active ester of 16-azidohexadecanoic acid. To the active ester dissolved in DMF were further added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (310 mg) and triethylamine (1 ml), and the mixture was stirred for 24 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (6:1) to give SPK226 in the yield of 92 mg.