Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:28](=[O:30])[NH2:29].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:28](=[O:30])[NH2:29]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A solution of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (47.9 mg, 0.118 mM) and 0.28 mL (0.28 mM) of 1 N NaOH in 10 mL of methanol was sonicated for 6 hours at 50-60° C., then stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to afford 42.8 mg (92%) of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ 7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.5-7.25 (m, 6H), 7.15 (d, 1H, J=8 Hz), 7.05 (dt, 1H, J=1 and 8 Hz), 6.75 (dt, 1H, J=1 and 8 Hz), 6.65 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3428, 3400, 1737, 1635, 1617, 1583, 1572, 1500, 1491, 1453, 1434, 1330, 1248, 1158, 1098, 760, and 714. MS (FD) m/e 392.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:36]1[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([N:36]3[CH2:37][CH2:38][S:39](=[O:42])(=[O:43])[CH2:40][CH2:41]3)(=[O:34])=[O:35])=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: O=S1(=O)CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccccc2S(=O)(=O)N2CCS(=O)(=O)CC2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C21H18FN5O4S2, 487.08; m/z found, 488.1 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.26 (s, 1H), 8.08 (dd, J=8.0, 1.3, 1H), 7.83-7.77 (m, 1H), 7.73-7.68 (m, 1H), 7.68-7.63 (m, 1H), 7.51 (dd, J=7.6, 1.3, 1H), 7.44 (dd, J=10.9, 1.7, 1H), 7.40 (s, 2H), 7.35 (dd, J=7.9, 1.6, 1H), 3.31-3.23 (m, 4H), 3.11-3.04 (m, 4H).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH:6]=1)=[CH2:2].C(O)C>O>[CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)=[CH2:2]
Reactant: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC=C3[C@H]12
Solvent: CCO
Solvent: O
Product: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Reaction time: 0.83 h
Yield: 97.4 %

Procedure:
—Sodium borohydride (1.47 g) was added to a solution of (7α)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (1.50 g) obtained in the previous step in a mixture of tetrahydrofliran (27.8 ml), ethanol (27.8 ml) and water (4.55 ml). The reaction mixture was stirred for 50 min. and then poured into water. The product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated, to afford (7α,17β)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-ol (1.47 g). The product was used in the following step without fiLrther purification.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:15]1=2)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1.C(O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:15]2[N:14]([CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18][S:17][C:16]=2[CH:20]=1
Reactant: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCN1CCSc2cc(N)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of phenyl methyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (100 mg, 0.268 mmol) in tetrahydrofuran (4 mL) and ethanol (4.00 mL) under argon was added 10% Pd—C (28.5 mg, 0.027 mmol). The resulting mixture was stirred at room temperature overnight under an atmosphere of hydrogen (balloon pressure). The mixture was then filtered through a pad of Celite and concentrated, giving the desired product (81 mg, 88%) as a dark oil. MS-EI: (m/z, %) 343 (M+, 64), 179 (100), 151 (45).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])[N:14]=2)[N:11]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>CN(C)C(=O)C>[CH3:19][O:18][CH2:17][C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30]([C:29]4[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=4)=[O:31])[CH:23]=[CH:22][CH:21]=3)=[N:11][N:10]2[CH:12]=1)=[O:20]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: COCC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 63.2 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methoxyacetamide (200 mg, 0.64 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (162 mg, 1.02 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 120, the title compound (176 mg, 64%) was obtained as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])[CH2:3][CH2:2]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])[CH2:3][CH2:2]1)[CH3:21]
Reactant: O=C(c1ccccn1)C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccccn2)CC1
Temperature: 80 °C
Yield: 80.1 %

Procedure:
To a solution of compound piperidin-4-yl-pyridin-2-yl-methanone (170 mg, 0.894 mmol) in 10 mL acetonitrile was added ethyl bromoacetate (0.13 mL, 1.12 mmol) and triethylamine (362 mg, 3.57 mmol). The reaction was heated at 80° C. for 16 hour. The combined organic layers were concentrated under vacuum to afford an orange oily solid. The residue was chromatographed on silica gel (gradient: methanol/dichloromethane; 0:1 to 1:9 over 20 minutes) to afford the title compound as a white solid (198 mg). 1H NMR (400 MHz, CDC3) δ 8.68 (d, J=4.0 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.89 (t, J=9.0 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 4.33-4.27 (m, 2H), 3.92 (s, 2H), 3.70-3.72 (m, 2H), 3.59-3.53 (m, 2H), 2.34-2.28 (m, 4H), 1.34 (t, J=7.1 Hz, 3H). MS m/z ES+=276.8 (M+H), retention time 0.80.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Fuming sulfuric acid (180 mL) is added dropwise to 4-fluoro-2-nitrotoluene (50.21 g) under an argon atmosphere. The internal temperature of the mixture is maintained at 0-5° C. using an ice/sodium chloride bath. A preformed (ice bath) mixture of fuming nitric acid (30 mL) and fuming sulfuric acid (90 mL) is added dropwise to the previous solution over three hours. The reaction is then allowed to warm to room temperature. After stirring at room temperature for 2 hours, the mixture is poured slowly into ice and the products are extracted with methylene chloride (4×500 mL). The combined extracts are dried over magnesium sulfate, filtered and rotary evaporated. The crude mixture is filtered through a short pad of silica gel, using 10% ethyl acetate/hexanes as solvent, then recrystallized from ethyl acetate/hexanes to afford 2,6-dinitro-4-fluorotoluene as a pale yellow solid.
Reaction SMILES: C1(N[C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)CC1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>>[CH:33]1([NH:36][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][NH:13][CH:8]([CH3:9])[CH3:7])=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:35][CH2:34]1
Reactant: CC(C)N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CO)cn2)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CNC(C)C)cn2)cc1

Procedure:
Using an analogous procedure to that described in Example 27, N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide was oxidised and the resulting aldehyde reacted with isopropylamine to give the title compound; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.68 (m, 2H), 1.00 (d, 6H), 2.25 (s, 3H), 2.70 (m, 1H), 2.86 (m, 1H), 3.71 (s, 2H), 5.76 (s, 2H), 7.14 (d, 2H), 7.33 (d, 1H), 7.49 (d, 1H), 7.64 (m, 1H), 7.80 (m, 2H), 7.99 (d, 2H), 8.40 (d, 1H), 8.55 (s, 1H), 9.87 (s, 1H); Mass Spectrum: M+H+ 473.
Reaction SMILES: OS(O)(=O)=O.[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1N)([CH3:9])([CH3:8])[CH3:7].NC1C=CC=CC=1.N([O-])=[O:28].[Na+].NC(N)=O>O.CCOC(C)=O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[OH:28])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Nc1ccccc1
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C

Procedure:
In a 250 ml round bottom flask, 20 mL concentrated H2SO4 was added to 2-tert-butyl-5-nitro-aniline (7.15 g) by adding 5 mL aliquots of acid and sonicating with occasional heating until all of the starting aniline went into solution. H2O (84 ml) was added with stirring, then the reaction was cooled to 0° C. forming a yellow-orange suspension. A solution of NaNO2 (2.792 g) in H2O (11.2 mL) was added dropwise to the suspension and stirred for 5 min. Excess NaNO2 was neutralized with urea, then the cloudy solution was transferred to 500 ml 3-necked round bottom flask then added 17 mL of 1:2 H2SO4:H2O solution, and heated at reflux. Two additional 5 mL aliquots of 1:2 H2SO4:H2O solution, a 7 mL aliquot of 1:2 H2SO4:H2O solution and another 10 mL of 1:2 H2SO4:H2O were added while heating at reflux. The mixture was cooled to RT forming a black layer floating on top of the aqueous layer. The black layer was diluted with EtOAc (300 mL) and separated. The organic layer was washed with H2O then brine, dried over Na2SO4 and concentrated in vacuo. Crude oil was purified on silica gel column with 8% EtOAc/Hexanes. Upon drying under vacuum, the 2-tert-butyl-5-nitrophenol was isolated as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)cc1
Product: CS(=O)(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(4-methanesulfonyl-phenyl)-1H-imidazole (9.8 g, 25 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 2-(4-Bromo-benzyl)-1-(4-nitro-phenyl)-4-(4-methanesulfonyl-phenyl)-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:19][S:20]([CH3:21])=[O:48])[CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 100 mg (0.24 mmol) of the compound from Example 291 in analogy to the synthesis of the compound from Example 296. 102 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:29]=[C:30]([NH:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[O:45])=[CH:40][CH:39]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[N:29]=[C:30]([NH:37][C:38]4[CH:39]=[CH:40][C:41]([C:44]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[O:45])=[CH:42][CH:43]=4)[C:31]4[N:32]([CH:34]=[CH:35][N:36]=4)[CH:33]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cn3ccnc3c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4cn5ccnc5c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Yield: 16.4 %

Procedure:
A solution of acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzyl ester (320 mg, 0.47 mmol) and K2CO3 (130 mg, 0.95 mmol) in MeOH (15 mL) was stirred at room temperature for 2 hours. The crude reaction mixture was filtered. The filter cake was washed with MeOH (5 mL) and dried to provide the desired product as a yellow solid (50 mg, 16% yield).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]1[CH:7]=[C:8]([F:9])[C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(F)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1Br

Procedure:
To a mixture of 4-bromo-2,5-difluoroaniline (8 g, 39 mmol) and potassium carbonate (16 g, 116 mmol) in acetonitrile (200 mL) was added (bromomethyl)benzene (14.5 g, 85 mmol). After refluxing for 20 hours, the mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 388 (M+H+).
Reaction SMILES: [OH-].[K+].[CH2:3]1COC[CH2:4]1.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11](B(O)O)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(OC(=O)C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.ClCCl>[CH:3]([C:11]1[C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[C:16]=2[CH:8]=[CH:9][CH:10]=1)=[CH2:4]
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=Cc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
16.09 g (0.259 mol) of Potassium hydroxide (86%) are placed in a 500 ml three necked round bottomed flask equipped with a magnetic stirrer and a reflux condenser. 200 ml of THF and 6.5 ml of Dichloromethane are added. The mixture is refluxed. After 1 hour the mixture is cooled to room temperature. A solution of 8 g (37.74 mmol) dibenzofuran-4-boronic acid, 0.8 g (3.02 mmol) of Triphenylphosphine, 339 mg (0.7 mmol) of Palladium (II) acetate and 200 ml of Methanol are added. The reaction mixture is heated to 60° C. internal temperature. After 2 hours the reaction is complete and cooled down to room temperature. The mixture is diluted with H2O and Ethylacetate. The organic phase is extracted twice with water and once with brine. The organic phase is dried over Sodiumsulfate and the solvent evaporated. The crude product is purified by column chromatography (Heptane). 4-Vinyl-dibenzofuran is isolated in 42% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A stirred solution of 4-methyl-2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.48 g, 10.8 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise slowly with 1M borane-tetrahydrofuran complex in tetrahydrofuran (32.4 ml, 32.4 mmol) under an argon atmosphere. Upon Completion of the addition, the mixture was stirred for 1 hour at room temperature and heated to reflux for another 5 hours. The resulting mixture was added with cold water (5 ml) and 1N hydrochloric acid (15 ml) dropwise, adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[2-(2-morpholin-4-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.08 g) as a red oil which was used as such.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([F:39])[C:25]=1[OH:40]>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:27]=[C:26]([F:39])[C:25]=1[OH:40]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1NC1CCN(C)CC1
Yield: 46.6 %

Procedure:
Following general procedure II, 1-{6-chloro-4-[(1-methylpiperidin-4-yl)amino]-1,5-naphthyridin-3-yl}ethanone (69 mg, 0.22 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (88 mg, 0.32 mmol) to afford the desired product (44 mg, 47%) as a yellow solid: 1H NMR (500 MHz, CD3OD+D2O) δ 8.94 (s, 1H), 8.15 (s, 2H), 7.92 (s, 1H), 7.74 (dd, J=12.0, 2.2 Hz, 1H), 5.70-5.62 (m, 1H), 3.17-3.12 (m, 2H), 2.71 (s, 3H), 2.69-2.64 (m, 2H), 2.53 (s, 3H), 2.37-2.35 (m, 2H), 1.85-1.82 (m, 2H); ESI MS m/z 429 [M+H]+; HPLC>99% (AUC), tR=8.80 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:24])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.[Cl:25][C:26]([Cl:30])=[CH:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:28][CH:27]=[C:26]([Cl:30])[Cl:25])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=1
Reactant: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(Cl)c1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 0.5 g of 3,5-dichloro-4-[3-(5-trifluoromethylpyridin-2-yloxy)-propyloxy]phenol, 0.25 g of 1,1,3-trichloropropene, 0.2 g of potassium carbonate and 3 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was subjected to silica gel chromatography, which afforded 0.3 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-[3-(5-trifluoromethylpyridin-2-yloxy)propyloxy]benzene (47% yield), nD20.5 1.5377.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.BrBr>O1CCOCC1.Cl>[N:11]1([C:3]2[NH:4][C:5]3[C:10]([C:2]=2[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: Cc1c[nH]c2ccccc12
Agent: BrBr
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-n2ccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methylindole (7.87 g) and imidazole (20.42 g) in dioxane (350 ml) stirring at 10° is added a solution of bromine (3.1 ml) in dioxane (125 ml) dropwise over a period of 25 hrs. Upon complete addition, the cooling bath is removed and the resulting yellow suspension is allowed to warm to room temperature while stirring overnight. The solid which had formed is removed by vacuum filtration. The filtrate is concentrated in vacuo to give an amber oil. This oil is suspended in 2 N HCl (100 ml) and washed with ether (3×100 ml). The acidic layer is made basic to pH 10 with 3 N NaOH and extracted with ether (6×100 ml). The ether extract is dried (MgSO4), filtered and concentrated in vacuo to give a partially crystalline residue. This residue is triturated with petroleum ether/ether and the solid which resulted is collected and recrystallized from acetonitrile (30 ml) to give 2-(1-imidazolyl)-3-methylindole, m.p. 156°-158°.
Reaction SMILES: [C:1]([N:11](C)[CH:12]([CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1)(OCC1C=CC=CC=1)=O.[ClH:23]>>[ClH:23].[ClH:23].[CH3:1][NH:11][CH:12]([CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1
Reactant: CC(Cc1ccc(O)cn1)N(C)C(=O)OCc1ccccc1
Agent: Cl
Product: CNC(C)Cc1ccc(O)cn1

Procedure:
The mixture of 0.08 g of 2-(N-carbobenzyloxy-2-methylaminopropyl)-5-pyridinol and 2.5 ml of 5 N hydrochloric acid is refluxed for 23 hours, cooled and extracted with diethyl ether. The extract is dryed and evaporated, to yield the 2-(2-methylaminopropyl)-5-pyridinol dihydrochloride, which is identical with that obtained according to Example 15.