Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]([C@@H:26]([CH3:29])[CH2:27][OH:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:19]([N:18]([C@@H:26]([CH3:29])[CH:27]=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Dry DMSO (0.53 ml, 7.43 mmol) was added to a stirred solution of oxalyl chloride (0.31 ml, 3.6 mmol) in CH2Cl2 (7.5 ml) at −78° C. The solution was allowed to stir 15 minutes followed by the addition of 40 (740 mg, 2.90 mmol) in CH2Cl2 (7.5 ml). After 30 minutes, Et3N (1.0 ml, 7.2 mmol) was added and allowed to warm to room temperature. The solution was extracted with saturated. NaHCO3 (20 ml) and the aqueous layer was extracted with CH2Cl2 (2×15 ml). The organic layer was washed with saturated. NaCl solution, dried with MgSO4 an concentrated in vacuo at room temperature to give 720 mg (98% yield) of a yellow oil which became a solid when cooled to −20° C. The aldehyde was used without further purification: mp 52–54° C., Literature mp 55.5° C. See, Dix et al., Arch Pharm (Weinheim) 1995, 328, 203–205.; [α]26D=−36.0 (c 1, CHCl3) Literature [α]20D=−35.1 (c 1, EtOAc); 1H NMR (400 MHz, CDCl3) d 1.19 (d, 2H, J=7.0 Hz), 3.34 (q, 1H, J=7.0 Hz), 3.58 (δ, 2H, J=13.7 Hz), 3.74 (d, 2H, J=13.7 Hz), 7.26 (m, 2H), 7.33 (m, H), 7.42 (m, 4H), 9.74 (s, 1H); 13C NMR (100 MHz) δ 6.7, 54.9, 62.8, 3.3, 4.4, 4.8, 139.1, 204.6; FABMS m/z 408.2 (M+MB), 254.2 (M+H), 22.2 (M-CHO); HRFABMS calcd for C17H20NO Mr 254.1545 (M+H), found Mr 254.1545.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:19])([O:20][Si:2]([CH3:1])([CH3:8])[CH3:9])[CH3:18])=[CH:15][CH:16]=1
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O[Si](C)(C)C)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
N-trimethylsilylimidazole (80.6 mL, 0.552 mol) was added to a solution of the crude 2-(4-bromo-phenyl)-propan-2-ol in tetrahydrofuran (500 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography (n-hexane:ethyl acetate=40:1) to give the title compound as a colorless oil (125.6 g, 87% in two steps).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 185.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-N,N-diethylacetamide (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (27 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:15])[CH3:14]>C(=S)=S>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([C:13](=[O:15])[CH3:14])=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1ccccc1Cl
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a stirred solution of 2-chlorophenol (10.0 g, 77.8 mmol) in carbon disulfide (20 ml) was added aluminum chloride (21.8 g, 163.4 mmol) at 0° C. under nitrogen. Acetyl chloride (6.72 g, 85.6 mmol) was added, and the mixture was heated at reflux temperature for 6 hours. The mixture was cooled down to room temperature, and poured into ice-water. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized with diethylether-hexane to give the title compound (6.39 g, 48% yield).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C@@H:6]12[C:15](=[O:16])[O:14][C:12](=[O:13])[C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>C.[Cl-].[Cl-]>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]([CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:15]([OH:14])=[O:16])=[O:13])[CH3:2]
Reactant: CCNCC
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: C
Agent: [Cl-]
Product: CCN(CC)C(=O)C1CCCCC1C(=O)O
Reaction time: 2 h

Procedure:
Model compound synthesis and hydrolytic kinetics measurement (Scheme 4—FIG. 4): Briefly, N,N-diethylamine (415 μL, 4 mmol) and 1,2-cis-cyclohexanedicarboxylic anhydride (617 mg, 4 mmol) were dissolved in 10 mL dichloride methane. The reaction was kept at room temperature for 2 h with stirring. The solvent was then removed by rotary evaporation to obtain the raw product. The raw product was purified by recrystallizing from benzene to get 2-[(diethylamino)carbonyl]cyclohexanecarboxylic acid. 1H NMR (400 MHz, CDCl3): δ (ppm): 3.60-3.22 (m), 2.77 (m), 2.51-2.45 (m), 1.87-1.66 (m), 1.58-1.46 (m), 1.49-1.39 (m), 1.28 (q), 1.17 (t). Similarly, 2-[(isopropylamino)carbonyl]cyclohexanecarboxylic acid was synthesized. 1H NMR (400 MHz, CDCl3): δ (ppm): 3.83 (q), 2.73 (q), 2.64 (q), 1.87 (m), 1.79 (m), 1.64 (m), 1.45 (m), 1.33 (m), 1.01 (d).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[OH:19].[CH2:20]=O>C(O)(C)C>[CH2:1]([C:3]1[NH:7][C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[OH:19])=[C:5]([CH3:20])[N:4]=1)[CH3:2]
Reactant: Oc1ccc2ccccc2c1
Reactant: C=O
Reactant: CCc1nc(C)c[nH]1
Solvent: CC(C)O
Product: CCc1nc(C)c(Cc2c(O)ccc3ccccc23)[nH]1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 35% solution of 2-ethyl-4-methylimidazole (110g, 1 mole) and 2-naphthol (144 g, 1 mole) in isopropanol, formaline (37% aqueous solution, 1 mole of CH2O) is added over a period of 15 minutes at room temperature, followed by three hours of refluxing at 82°-84° C. The product (a white powder) is obtained in a yield of 85%, with a melting point of 166° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:3]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,3′]bipyridinyl (example E.24) (0.15 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.093 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 22%). MS (ISP) 408.3 [(M+H)+]; mp 248-252° C.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:8]=1[C:9](O)=[CH:10][C:11]([CH3:19])=[N:12]2.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:3][C:9]1[C:8]2[C:13](=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:7]=2[F:6])[N:12]=[C:11]([CH3:19])[CH:10]=1
Reactant: COc1ccc(F)c2c(O)cc(C)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(F)c2c(Cl)cc(C)nc12
Temperature: 118 °C

Procedure:
POCl3 (3.4 mL, 36 mmol) was added dropwise to 5-fluoro-8-methoxy-2-methyl-quinolin-4-ol (0.56 g, 2.7 mmol) at 0° C. The reaction vessel was equipped with a drying tube containing P4O10 and heated to 118° C. for 2 h. The reaction mixture was concentrated in vacuo and partitioned between DCM (30 mL), water (2 mL), and concentrated aqueous NH3 (2 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with EA/DCM 1:15) to give the title compound. MS (m/z): 226.5 [M+H+]
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].C(=O)(O)[O-].[Na+].Cl/[C:13](=[N:19]\[OH:20])/[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOC(C)=O>[F:1][C:2]([F:6])([F:5])[CH:3]1[O:20][N:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C=CC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NOC(C(F)(F)F)C1
Temperature: 22 °C
Reaction time: 60 h
Yield: 84.2 %

Procedure:
To a suspension of 3,3,3-trifluoroprop-1-ene (ca. 4.3 g, 45 mmol) in AcOEt (30 ml) and sodium bicarbonate (6.3 g, 75.0 mmol) was added at −78° C. a solution of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (2.81 g, 18.0 mmol) in AcOEt (6 ml), the suspension was allowed to warm to 22° C. and stirring was continued for 60 h. The suspension was filtered, the filtrate was evaporated and the residue purified by chromatography on silica gel using heptane/AcOEt (10:1) to give ethyl 5-(trifluoromethyl)-4,5-dihydroisoxazole-3-carboxylate (3.2 g) as a colorless oil. MS: m/z=211 [M]+.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)(=O)C>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=CC=Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=CC=Cc2ccccc2)N1

Procedure:
A solution of hydantoin (40 g), freshly distilled cinnamaldehyde (50 g), and fused sodium acetate (80 g) in acetic acid (160 ml) was heated to reflux for 11/2 hours. The solution was poured into cold water (1.5 l) to precipitate the orange product, which was removed by filtration. This product was washed with water until neutral and then with cold ethanol to give 69 g (85% theoretical yield) of virtually pure product. Before use, the product was recrystallised from ethanol to give yellow crystals of 5-cinnamylidenehydantoin, m.p. 268°-270° (decomp.), the infra-red spectrum of which showed the expected main peaks at 1750, 1700, 1640, 1390, 1350, 1020, 970, 895, 825, 750, 690, and 655 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=N[CH:7]=1.[CH:12]([Mg]Br)(C)C.[O:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH2:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([C:20]2([OH:27])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:26]3[O:17][CH2:18][CH2:19]2)=[CH:7][CH:12]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: O=C1CCOc2cccnc21
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCOc2cccnc21
Reaction time: 1 h

Procedure:
To a 0° C. solution of 5-bromo-2-(trifluoromethyl)pyridine (0.604 g, 2.68 mmol) in THF (10 mL) was added isopropyl magnesium bromide (1 mL, 2.68 mmol) in a drop-wise fashion. The reaction mixture was stirred in a cooling bath for 1 h and was then treated with 2H-pyrano[3,2-b]pyridin-4(3H)-one (200 mg, 1.34 mmol) in THF (5 mL). After stirring for 1 h, saturated NH4Cl (50 mL) was added to the reaction mixture, and the aqueous solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the desired alcohol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][CH:64]([CH3:68])[C:65](O)=[O:66]>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:38])=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:65](=[O:66])[CH:64]([CH3:68])[CH3:63])[N:8]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:29]
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 55 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
To suspension of N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) in dichloromethane (1.778 ml) was added HATU (0.084 g, 0.222 mmol) and 2-methylpropanoic acid (0.047 g, 0.533 mmol). The reaction mixture was stirred and heated at 55° C. After 16 h, the reaction mixture was quenched with water, extracted with DCM (2×), dried over MgSO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with DCM with 10% MeOH in DCM (5% to 40%) and collected fractions to obtain the title compound as a solid (48 mg, 42% yield). MS (ESI): 633 [M+H]+.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl[CH2:48][C:49](Cl)=[O:50].C(N(CC)C(C)C)(C)C.[CH3:61][N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>O1CCCC1.O>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:49](=[O:50])[CH2:48][N:65]3[CH2:66][CH2:67][N:62]([CH3:61])[CH2:63][CH2:64]3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CC(=O)Nc2cccc(-c3n[nH]c4ccc(-c5nc[nH]n5)cc34)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.400 g, 0.66 mmol) in tetrahydrofuran (4 mL) was added 2-chloroacetyl chloride (0.083 mL, 1.0 mmol) followed by N,N-diisopropylethylamine (0.116 mL, 0.66 mmol). The reaction was stirred at room temperature for 4 h. Water (20 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in N,N-dimethylformamide (5 mL) and N-methylpiperazine (0.320 mL, 3.3 mmol) was added. The mixture was stirred at room temperature for 14 h. Water (30 mL) was added and the mixture extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. Dioxane was removed with a rotary evaporator and the residue was purified by preparative HPLC. The desired fractions were neutralized with ammonium hydroxide, extracted with butanol and evaporated to give the title compound (0.150 g, 54% yield): 1H NMR (DMSO-d6) δ 13.45 (br s, 1H), 10.04 (s, 1H), 8.73 (s, 1H), 8.34 (d, 2H), 8.10 (d, 1H), 7.75 (d, 1H), 7.69 (d, 2H), 7.48 (t, 1H), 2.15 (s, 3H), 1.80 (m, 8H), 1.33 (s, 3H). ES-MS (m/z) 417 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCO.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>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5-chloro-2-nitroanisole (0.094 g, 0.50 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (0.19 g, 0.60 mmol), Na2CO3 (0.16 g, 1.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.019 g, 0.030 mmol) in dioxane (3 mL) and H2O (1.5 mL) was degassed for 30 min. The mixture was heated at 120° C. for 20 min in the microwave. Upon completion by TLC, the reaction was placed under H2 (1 atm.). The mixture was transferred to a separate flask and diluted with EtOH and subsequently stirred under H2 (1 atm.) overnight. Upon completion by TLC, the reaction was filtered through Celite®, washed with EtOAc, dried (MgSO4), concentrated and purified by flash chromatography to provide the title compound of step A (0.12 g, 0.40 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.52-1.64 (m, 2H), 1.79 (d, J=12.8 Hz, 2H), 2.54 (tt, J=12.1, 3.5 Hz, 1H), 2.77 (t, J=11.9 Hz, 2H), 3.65 (d, J=2.6 Hz, 1H), 3.70 (d, J=6.2 Hz, 1H), 3.83 (s, 3H), 4.22 (br. s., 2H), 6.60-6.66 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(#N)C>[CH2:3]([CH:2]([NH:1][C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:5][CH3:6])[CH3:4]
Reactant: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Reactant: CCC(N)CC
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1NC(CC)CC

Procedure:
3-Aminopentane (5 mL) was added to a solution of ethyl 7-chloro-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-carboxylate (1.94 g, 5.22 mmol) in acetonitrile (20 mL), followed by heating under reflux for eight hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (1.70 g).
Reaction SMILES: [H-].[Na+].CN([CH:6]=[O:7])C.CO.[Cl:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3>O>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH3:6])[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3
Reactant: CN(C)C=O
Reactant: Cn1c(=O)c(-c2ccc(F)cc2Cl)cc2c3ccccc3n(C)c21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc3c4ccccc4n(C)c3n(C)c2=O)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
3.25 g (81.1 mmol) of 60% NaH are added to 300 ml of DMF and 9.6 ml of MeOH. The mixture is left to stir for 5 minutes, and then 9.22 g (27.0 mmol) of compound A 3-(2-chloro-4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are added. The mixture is stirred at ambient temperature and then, as soon as no more gas is being given off, is heated at 80° C. for 16 h. The reaction medium is left to cool and poured into H2O, the yellow precipitate is filtered off and washed with H2O, the residue is taken up in MeOH and the product is concentrated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][C:14]([O:17]C)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.B(Br)(Br)Br.C(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(O)cc12
Reaction time: 2.5 h
Yield: 57 %

Procedure:
To a solution of the methyl ether from Step 1 (0.35 g, 1.03 mmol) in CH2Cl2 (5 mL) at 0° C. was added 1M BBr3/CH2Cl2 (5.2 mL, 5.2 mmol) over a period of 55 minutes. The dark gummy suspension was then brought to RT for 2.5 hours. MeOH (≈5 mL) was then added at −78° C. followed by saturated NaHCO3 solution. The cold bath was removed and the mixture was stirred for 30 minutes. The product was then extracted with CH2Cl2 and the organic phase was washed with H2O. After drying (MgSO4), filtering, and evaporating, the residue was purified by flash chromatography (1:2, 1:1 EtOAc:hexane) to give a light brown solid (0.19 g).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])[CH2:16]1
Reactant: CCNC(=O)C1CCCC(c2ccc(OCOC)cc2OCOC)C1
Solvent: CO
Product: CCNC(=O)C1CCCC(c2ccc(O)cc2O)C1
Yield: 10.7 %

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-N-ethylcyclohexanecarboxamide (25 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated to reflux for 4 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a solid (2 mg, 12%). δH (CD3OD) 1.80 (3H, t), 1.30-1.60 (4H, m), 1.74-1.94 (4H, m), 2.26-2.36 (1H, m), 2.82-2.92 (1H, m), 3.16 (2H, q), 6.21-6.26 (2H, m), 6.88 (1H, d); m/z (ES+) 264 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1([F:23])[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:14]=2[O:13]1.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:21]([C:19]4[CH:18]=[CH:17][C:15]5[O:16][C:12]([F:23])([F:11])[O:13][C:14]=5[CH:20]=4)[CH2:31][NH:30][C:35]3=[O:36])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc3c(c2)OC(F)(F)O3)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde (0.744 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.81 mL, 5.81 mmol), di-(imidazol-1-yl)methanone (0.514 g, 3.17 mmol) as described in method 2. The product was purified by means of FPLC.