Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[O:18]=[C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:22][CH2:21][N:20]1[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][N:40]=1)[C:34](OC)=[O:35]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][N:40]=[C:31]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:19]3=[O:18])[CH:32]=2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Yield: 52 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine to react with methyl 2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinate, the title compound was obtained as a colorless solid in 52% yield: mp 141-142° C.; 1H NMR (300 MHz, CDCl3) δ 8.56-8.53 (m, 2H), 8.35 (d, J=4.8 Hz, 1H), 7.68-6.86 (m, 9H), 4.57-4.54 (m, 4H), 4.06 (t, J=7.9 Hz, 2H), 3.53 (t, J=8.0 Hz, 2H); MS (ES+) m/z 405.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][N:18]([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CS(C)=O.[Cu]I.CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][N:18]([CH3:20])[CH3:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CN(C)Cc1ncc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-n2ccnc2CN(C)C)cc1
Yield: 39.9 %

Procedure:
Part G. 4-Iodo-benzoic acid methyl ester (1.42 g, mmol) and (1H-imidazol-2-ylmethyl)-dimethyl-amine (0.68 g, mmol) were stirred in DMSO (3.5 mL) under N2. K2CO3 (1.52 g, mmol) was added followed by the addition of CuI (0.52 g, mmol) and 1,10-phenanthroline (0.46 g, mmol). The reaction mixture was heated at 120–125° C. for 2 h. After cooling, EtOAc was added. It was washed with dil. NH3H2O, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by FCC (silica gel, CH2Cl2:EtOAc=1:0 to 0:1, then 10% MeOH) to give pure 4-(2-dimethylaminomethyl-imidazol-1-yl)-benzoic acid methyl ester (0.56 g, yield 40%). 1H NMR (CDCl3) δ 7.84 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.87 (d, J=0.9 Hz, 1H), 6.80 (d, J=0.9 Hz, 1H), 3.65 (s, 3H), 3.10 (s, 2H), 1.96 (s, 6H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[N:3]=1.N1C=CC=CC=1C1C=CC(CO)=CC=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:3]=2)=[CH:11][CH:12]=1
Reactant: Clc1cncc(OCc2ccc(-c3ccccn3)cc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: OCc1ccc(-c2ccccn2)cc1
Agent: [K+]
Product: c1ccc(-c2ccc(COc3cncc(N4CCNCC4)n3)cc2)nc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[{4-(2-pyridinyl)benzyl}oxy]pyrazine (2.73 g, 9.16 mmol; obtained according to the procedure of example 50, step 1, starting from 4-(2-pyridinyl)benzyl alcohol*), piperazine (2.41 g, 27.9 mmol) and K2CO3 (1.33 g, 9.62 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 2.06 g (65%) which was obtained as a beige colored oil that solidified when refrigerated. Purity 100% (HPLC). MS m/z 347 (M)+. HRMS m/z calcd for C20H21N5O (M)+ 347.1746, found 347.1749.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][CH:14]([C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1)[C:15]([O:17][CH3:18])=[O:16])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:23]1[S:22][C:21]([CH3:24])=[N:20][C:19]=1[CH:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(OC(C)(C)C)c1csc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1nc(C)sc1Br
Temperature: 70 °C

Procedure:
Under a nitrogen atmosphere, N-bromosuccinimide (39 mg, 0.22 mmol) was added to a solution of methyl 2-(tert-butoxy)-2-(2-methyl-1,3-thiazol-4-yl)acetate (15c) (50 mg, 0.21 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was warmed at 70° C. for 30 minutes then concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with water (2×20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give the desired product as a yellow oil without further purification (70 mg, 0.21 mmol, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].N1C=CC=CC=1>C(O)C>[C:20]([C:19]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=1)=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)#[N:21]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCO
Product: N#CC(=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A 1.5 g sample of p-nitrobenzaldehyde and 1.7 g of p-nitrobenzylcyanide were dissolved in 5 ml of hot ethanol, and 0.05 ml of pyridine was added. The mixture was heated for 10 minutes. After cooling overnight, the precipitated crystals were filtered and recrystallized from a mixture of acetone and ethanol to obtain 1-cyano-1,2-bis(p-nitrophenyl)ethylene having a melting point of 216.5°-217.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][OH:48]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][OH:48])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCCCCCCO
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCCCCO

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 6-amino-1-hexanol (34 mg) according to Method A to give the title compound (64 mg). 1H-NMR (400 MHz, CD3OD) d 7.79 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27-7.18 (m, 5H), 7.02 (dd, J=7.0 Hz, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.57 (m, 1H), 4.25 (dd, J=4.8 Hz, J=9.5 Hz, 1H), 3.77 (m, 1H), 2.74 (dd, J=10.2 Hz, J=13.2 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3291, 2932, 1691, 1647 cm−1; HRMS m/z 629.2948 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCCCC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and bromocyclohexane (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:27]=[C:26]3[C:20]([N:21]([CH3:34])[C:22](=[O:33])[CH2:23][CH2:24][N:25]3[CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:19][N:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:27]=[C:26]3[C:20]([N:21]([CH3:34])[C:22](=[O:33])[CH2:23][CH2:24][N:25]3[CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:19][N:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC(C)(C)C)cc3Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3Cl)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
tert-butyl 5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoate (Intermediate 220; 220 mg, 0.45 mmol) was dissolved in DCM (7.5 mL) and trifluoroacetic acid (2.5 mL) added. The mixture was stirred at room temperature for 2 hours. The refraction mixture was evaporated, the residue dissolved in methanol/DCM and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated to yield the title compound as a white solid (195 mg, 100%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[OH:4].[CH3:14][C:15]([CH3:17])=O>>[F:13][CH2:12][C@@H:2]1[C@@H:3]([C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=2)[O:4][C:15]([CH3:17])([CH3:14])[NH:1]1
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Reactant: CC(C)=O
Product: CC1(C)N[C@H](CF)[C@@H](c2ccc(I)cc2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol (6.0 g, 20.0 mmol) is dissolved in acetone (150 mL) and the mixture stirred at room temperature for 16 hours. The solvent is removed under reduced pressure to give the title compound (7.0 g). m/z (Cl) M+H 295.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: Oc1cccc(-c2nnco2)c1
Product: Fc1ccc(N2CCN(CCCOc3cccc(-c4nnco4)c3)CC2)cc1
Yield: 68 %

Procedure:
The preparation is carried out as described in Example 1, using 3-(1,3,4-oxadiazol-2-yl)-phenol and 1-(3-chloropropyl)-4-(4-fluorophenyl)-piperazine. The crude product is recrystallized from toluene/petroleum ether, and a product of melting point 105°-106° C. is obtained (yield: 68%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]1[C:19]2[NH:20]C(=O)O[C:23](=[O:24])[C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C.O>[NH2:20][C:19]1[C:14]([F:13])=[CH:15][CH:16]=[CH:17][C:18]=1[C:23]([N:3]([O:4][CH3:5])[CH3:2])=[O:24]
Reactant: CNOC
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON(C)C(=O)c1cccc(F)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a suspension of N,O-dimethylhydroxylamine hydrochloride (703 mg, 7.21 mmol) in ethanol (5.4 ml) and water (0.6 ml) was added triethylamine (729 mg, 1.00 ml, 7.21 mmol) and the mixture was stirred for 10 min at room temperature. Then 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (870 mg, 4.8 mmol) and additional ethanol (2 ml) were added and the reaction mixture was heated to reflux for 3.5 h. After cooling to room temperature, the mixture was poured onto ice/saturated NaHCO3-solution, extracted with EtOAc and the combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 80:20-70:30) to afford the title compound (765 mg, 80%) as light brown oil. MS (ESI): 199.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3O[CH:23]=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.N[CH:27]([C:29]1N=NC(NC2C=CC(OC)=CC=2)=NC=1)[CH3:28].C1(CC(Cl)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=[O:20])[CH2:21][C:25]3[CH:24]=[CH:23][CH:29]=[CH:27][CH:28]=3)[CH3:17])=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: O=C(Cl)Cc1ccccc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)Cc3ccccc3)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and phenylacetyl chloride (0.059 mL, 0.45 mmol) to afford N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-phenylacetamide (50 mg) as a yellow solid. MS m/z 364 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[NH2:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].O.ClCCl>CN(C)C=O>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][C@@H:7]2[CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:8]2)=[CH:11]1
Reactant: N[C@@H](CNC(=O)CBr)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CN[C@H](Cc2c[nH]c3ccccc23)CN1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a solution of (1R)-N2 -(bromoacetyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (3.30 g) in dimethylformamide (70 ml) was added potassium carbonate (3.30 g) at room temperature. The reaction mixture was stirred at 110° C. for 1 hour and 20 minutes. After cooling to room temperature, water and dichloromethane were added into the mixture, and the organic layer was separated. The aqueous layer was extracted successively with dichloromethane several times and a mixed solvent of ethyl acetate and methanol (10:1). The extracts were combined and dried over magnesium sulfate, and concentrated under reduced pressure to give (5R)-5-(1H-indol-3-ylmethyl)piperazin-2-one (2.47 g) as an oil.
Reaction SMILES: [CH:1](=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:2][CH:1]=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=C1c2ccccc2C=Cc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 5-ethylidene-5H-dibenzo[a,d]cycloheptene (10.9 g., 0.05 mole), N-bromosuccinimide (8.9 g., 0.05 mole), benzoyl peroxide (15 mg.) and 150 ml. of carbon tetrachloride is stirred and heated to refluxing on the steam-bath for 4 hours. After cooling, the succinimide is separated by filtration and washed with carbon tetrachloride. The combined filtrate and washings are evaporated to dryness under reduced pressure. Crystallization of the residual solid from petroleum ether gave 5-(2-bromoethylidene)-5H-dibenzo[a,d]cycloheptene in a yield of 10.65 g. (72%), m.p. 87.5°-89.5°C. An analytical sample, after recrystallization from petroleum ether, melted at 89°-90°C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]#[N:24]>CN(C=O)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:22][C:23]#[N:24])=[CH:3][CH:2]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
A mixture of 9H-carbazol-4-ol (2.543 g, 0.014 mol), potassium carbonate (0.2.386 g, 0.017 mol), bromoacetonitrile (2.5 mL, 0.036 mol) and DMF (42 mL) is stirred at room temperature for 4 h. The mixture is then partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to a residue. The resulting residue is chromatographed on silica gel (200 mL) using ethyl acetate/hexane (20/80) to give 0.703 g (23%) of the title compound; mp 120-120.5° C.; MS (ESI−) for C14H10N2O m/z 221.0 (M−H)−; IR (drift) 3399, 1605, 1585, 1508, 1452, 1346, 1336, 1269, 1242, 1212, 1106, 785, 757, 750, 723 cm−1; 1H NMR (CDCl3) δ5.07, 6.76, 7.21, 7.29, 7.38-7.47, 8.18, 8.28. Anal. Calcd for C14H10N2O: C, 75.66; H, 4.53; N, 12.60. Found: C, 75.41; H, 4.52; N, 12.48.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38](B(O)O)[CH:39]=2)[CH:34]=[CH:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:39]=2)[CH:34]=[CH:33]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2cc[nH]c2c1
Yield: 82.6 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 1H-indol-6-ylboronic acid (0.201 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.165 g (83%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[Br:25][C:12]1[S:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[N:14][C:13]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1nc(-c2ccc(C(F)(F)F)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-((tert-butyldimethylsilyloxy)methyl)-4-(4-(trifluoromethyl)phenyl)thiazole (500 mg) in ethyl acetate (10 mL) was added bromine (428 mg), and the mixture was stirred at room temperature 12 hr, and further at 60° C. for 2 hr. To the reaction mixture was added aqueous sodium thiosulfate solution, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([N:10]([C:19]([O:21]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[N:5]2.[C:27]1([C:33]2[N:37]=[C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[S:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([NH:10][C:19]([N:41]1[CH2:42][CH2:43][N:38]([C:36]3[S:35][N:34]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:37]=3)[CH2:39][CH2:40]1)=[O:21])=[N:5]2
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1ccc2nccn2n1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc2nccn2n1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A mixture of bis(2,2,2-trichloroethyl) imidazo[1,2-b]pyridazin-6-ylimidodicarbonate (295 mg, 0.609 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.106 ml, 0.609 mmol) in dimethylsulfoxide (2.0 ml) was stirred at 70° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 212 mg (85.7%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH3:19].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:13][CH:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2cc(-c3ccc(O)cc3)sc2c1F
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1F
Temperature: 25 °C

Procedure:
A solution of 7-fluoro-2-[4-hydroxyphenyl]-6-methoxybenzo[b]thiophene (Part C; 550 mg, 2.0 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (375 mg, 2.2 mmol) and Cs2CO3 (1.65 g, 5.0 mmol) in 20 mL of DMF was heated at 80° C. for 5 h. The reaction mixture was cooled to ambient temperature and poured into saturated aqueous NaHCO3 solution (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with H2O (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by radial chromatography (SiO2; 2% MeOH in CHCl3, saturated with NH4OH) afforded 598 mg (1.61 mmol; 80%) of the title compound as a yellow oil.