Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:11]([C:3]2[C:2]([C:14]([OH:13])=[O:15])=[CH:1][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cc2ccccc2cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 113.8 %

Procedure:
45.0 g (227 mmol) of 2,3-naphthalenedicarboxylic acid anhydride are suspended in 200 ml (2.1 moles) of fluorobenzene. 75.5 g (565 mmol) of powdered aluminium chloride are added in the course of 5 minutes, with vigorous stirring (exothermic reaction up to about 32° C.). The dark red suspension is refluxed and stirred for 6 hours. The solution is then allowed to cool to room temperature and is poured onto about 500 g of ice, and is stirred to bring the hydrolysis to completion. Excess fluorobenzene is evaporated off and the resulting product is suspended in water. The suspension is filtered, the filtrate is rinsed with water and the product is dried. 76 g of crude 2-(4-fluorobenzoyl)-naphthalene-3-carboxylic acid are obtained. The crude product is stirred with 2 liters of 10% sodium carbonate solution, the resulting solution is acidified with hydrochloric acid and the white precipitate is filtered off and dried. 54.2 g (81% of theory) of 2-(4-fluorobenzoyl)-naphthalene-3-carboxylic acid are obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.CN(C)C=O.O=[C:15]1[CH2:20][CH2:19][CH2:18][S:17][CH:16]1[C:21](OCC)=[O:22]>C(O)(=O)C>[CH3:8][S:7][C:4]1[N:3]=[C:2]2[NH:1][C:15]3[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[C:21](=[O:22])[N:6]2[N:5]=1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: CSc1n[nH]c(N)n1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1nc2[nH]c3c(c(=O)n2n1)SCCC3
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To the solution of 6.5 g (0.05 mole) of 5-amino-3-methylthio-1H-1,2,4-triazole, 2.5 ml of acetic acid and 12.5 ml of dimethylformamide 9.4 g (0.05 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added and the reaction mixture is boiled for 60 minutes. The precipitated product is filtered off from the hot solution, then washed with acetic acid and i-propanol and recrystallized from dimethylformamide. Thus 6.5 g (51.1%) of 2-methylthio-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained. M.p.: higher than 350° C.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.Cl.[NH:7]1[CH2:10][CH:9]([OH:11])[CH2:8]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:1]1[CH2:2][CH:3]([N:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH2:4]1
Reactant: O=C1COC1
Reactant: OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: OC1CN(C2COC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of oxetan-3-one (0.5 g, 6.94 mmol), azetidin-3-ol hydrochloride (1.140 g, 10.41 mmol) and 4 A molecular sieves (1.5 g) in dichloromethane (10 mL) was stirred at room temperature for 4 h. sodium triacetoxyborohydride (2.94 g, 13.88 mmol) was added and the reaction mixture was stirred at room temperature overnight. The ppt was filtered through a pad of celite and the filtrate was diluted with ethyl acetate (more ppt appeared) and filtered again. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 3-10% 2N ammonia in methanol/dichloromethane). 1-(oxetan-3-yl)azetidin-3-ol was obtained as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH:12]3[CH:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1.[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18]>CO.C(OC(=O)C)(C)C>[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1
Reactant: c1cncc(N2CC3CNCC32)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: c1cncc(N2C[C@H]3CNC[C@H]32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
The product of Example 40C (65 mg, 0.37 mmol) was treated with fumaric acid (46.4 mg, 0.4 mmol) in methanol/isopropylacetate (1:10 v/v, 20 mL). The mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried under reduced pressure at 40-50° C. to provide the title compound (47 mg, 44% yield). 1H NMR (MeOH-d4, 300 MHz) δ3.18 (dd, J=12.6, 3.4 Hz, 1H), 3.35 (m, 1H), 3.46 (m, 1H), 3.75 (m, 3H), 4.04 (t, J=7.5 Hz, 1H), 4.90 (m, 1H), 6.58 (s, 2H), 7.04 (ddd, J=8.2, 2.7, 1.3 Hz, 1H), 7.27 (dd, J=8.2, 4.8 Hz, 1H), 7.87 (d, 2.7 Hz, 1H), 7.95 (dd, J=4.8, 1.1 Hz, 1H); m/z 176 (M+H)+; Anal. calculated for C10H13N3.1.25C4H4O4.0.6 H2O: C, 54.41; H, 5.84; N, 12.69. Found: C, 54.96; H, 5.50; N, 12.10.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](OC)=[O:26])[CH:7]=[CH:8][CH:9]=1.Cl.[OH-].[NH4+:33]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:26])[NH2:33])[CH:7]=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Yield: 60 %

Procedure:
A solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.62 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously for 132 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 150 mg (60%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.15 (m, 5H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), and 5.65 (s, 2H). IR (KBr, cm−1) 3431, 3203, 1629, 1601, 1580, 1548, 1446, 1330, 1261, 1215, and 777. MS (ES) m/e 399, 401.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:8][CH2:9][OH:10].[CH2:11]([O:18][C:19]1[C:20]2[CH2:31][C@:30]3([CH3:44])[C@@H:32]([CH3:43])[CH2:33][CH2:34][C@H:35]4[C:36]([CH3:42])([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH2:39][C@@:29]34[O:28][C:21]=2[C:22]2[CH2:23][NH:24][CH2:25][C:26]=2[CH:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][C:19]1[C:20]2[CH2:31][C@:30]3([CH3:44])[C@@H:32]([CH3:43])[CH2:33][CH2:34][C@H:35]4[C:36]([CH3:42])([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH2:39][C@@:29]34[O:28][C:21]=2[C:22]2[CH2:23][N:24]([CH2:8][CH2:9][OH:10])[CH2:25][C:26]=2[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CNC4
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CN(CCO)C4
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
Under nitrogen, 35 mg (0.25 mmol) of sodium carbonate and 23 μl (0.33 mmol) of 2-chloroethanol were added to a solution of Compound (33a) (40 mg, 0.087 mmol) in dry DMF (0.5 ml). The mixture was stirred for 3 hours at 50° C. and then for 18 hours at 65° C. After cooling, water was added to the reaction, and extracted with ethyl acetate. The extract was washed with water, saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by a silica gel column chromatography (silica gel 1.5 g; chloroform:methanol=19: 1) to give 25 mg (57%) of Compound (33f).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@@H]2C)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@@H]2C)n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
4-Chloro-6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.277 g, 1.07 mmol), hydrazine monohydrate (0.5 mL) and DMSO (2.0 mL) were stirred at room temperature overnight. Then the reaction was heated to 50° C. and stirred for 7 hours. Purified by RP-HPLC to provide 4-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as an orange solid (0.118 g, 43%). LCMS: (M+H)+=255.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[S-:13][C:14]#[N:15].[Na+].BrBr.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]#[N:15])=[CH:11][N:12]=1
Reactant: c1ccc(Nc2nccs2)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CSc1cnc(Nc2ccccn2)s1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(pyridin-2-yl)thiazol-2-amine (4.26 g, 24 mmol) and sodium thiocyanate (3.9 g, 48 mmol, 2 eq) in methanol (100 mL) at 0° C., was slowly added bromine (1.23 mL, 24 mmol, 1 eq) over 2 min, then the temperature was raised to 23° C. and the mixture was stirred for 3 h. The resulting suspension was added to stirring cold water (400 mL) and the resulting precipitate was collected by filtration and vacuum dried (4.5 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00-7.08 (1 H, m), 7.11 (1 H, d, J=8.34 Hz), 7.74-7.84 (1 H, m), 7.89 (1 H, s), 8.39 (1 H, d, J=5.05 Hz), 11.93 (1 H, s). LC/MS (M+H)+: 235.
Reaction SMILES: ClC1C=C(C2SC(C([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=O)=CC=2C2C=C(C#N)C=CC=2)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[C:40]([C:51]([OH:53])=O)[S:41][C:42]=2[C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Cl:50])[CH:44]=2)[CH:34]=[CH:35][C:36]=1[F:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[C:40]([C:51]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:53])[S:41][C:42]=2[C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Cl:50])[CH:44]=2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Reactant: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)sc2-c2cc(F)cc(Cl)c2)c1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)c(-c3cc(F)cc(Cl)c3)s2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 1 starting with 49.1 mg (0.13 mmol) of the compound from Example 20A. 40.9 mg (71% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C:29](=[O:34])C(C)(C)C)=[C:4]([CH:8](O)[CH:9]([CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)C(OC)=O)[CH:5]=[CH:6][CH:7]=1.O.[ClH:36]>CO>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:28][C:29](=[O:34])[C:9]([CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[CH:8]2
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccc(F)c1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reaction time: 2.5 h
Yield: 83 %

Procedure:
tert-Butyl 4-(1-(3-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate (7.86 g, 16.4 mmol) was dissolved in methanol (20 mL). Water (45 mL) was added to the mixture followed by concentrated hydrochloric acid (15 mL, 183 mmol). The reaction was heated to reflux and held for 2.5 h. The reaction mixture was concentrated in vacuo, redissolved in ethanol (50 mL), and concentrated in vacuo. The residue was crystallized from ethanol. The resulting solids were filtered, washed with cold ethanol, and dried in vacuo. The title compound was obtained as white solid in 83% yield. 1H NMR (500 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.98 (m, 1H), 8.85 (m, 1H), 7.75 (s, 1H), 7.54 (d, J=7.63, 1H), 7.36 (dd, J=0.22, 8.09, 1H), 7.21-7.11 (m, 1H), 3.41-3.29 (m, 2H), 3.14-2.94 (m, 3H), 2.02 (d, J=13.43, 2H), 1.88-1.71 (m, 2H). Mass spec.: 247.2 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:41][C:42]1[N:46]2[C:47](=[O:56])[N:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][C:45]2=[CH:44][N:43]=1>C(#N)C.C(N(CC)CC)C>[CH3:17][O:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:53]1[CH2:52][CH2:51][CH:50]([N:48]2[CH2:49][C:45]3=[CH:44][N:43]=[C:42]([CH3:41])[N:46]3[C:47]2=[O:56])[CH2:55][CH2:54]1)=[O:12]
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Reactant: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 99 %

Procedure:
2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (0.20 g) obtained in Example 73c) was dissolved in acetonitrile (10 ml). HOBt (0.19 g), WSC (0.24 g), triethylamine (0.16 ml) and 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.24 g) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.36 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=1)=[O:8].S(Cl)([Cl:23])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]([Cl:23])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)O)cn1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1

Procedure:
A mixture of 6.2 g of 6-[(5-fluoro-2-methyl-benzoyl)amino]pyridine-3-carboxylic acid and 23 ml of thionyl chloride is refluxed for 1 hour. An additional 12 ml of thionyl chloride is added and the mixture refluxed for 0.5 hour. The mixture is concentrated to dryness under vacuum and 30 ml of toluene added to the residue. The toluene is removed under vacuum and the process (add toluene and remove) is repeated to give 7.7 g of crude product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:35]=[CH:34][C:19]([CH2:20][N:21]5[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:38])[CH:3]=1.[C:39]1([CH2:45][C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CCO.C1(C)C=CC=CC=1>[F:38][C:4]1[CH:3]=[C:2]([NH:1][C:49]([NH:48][C:46](=[O:47])[CH2:45][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[S:50])[CH:37]=[CH:36][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[CH:34][CH:35]=3)[S:15][C:8]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cc4)sc23)c(F)c1
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
Compound 454 (0.3323 g, 0.62 mmol) was suspended in EtOH/toluene (3 mL/3 mL) at RT and stirred for 30 min. 2-Phenylacetyl isothiocyanate (0. 165 g, 0.93 mmol) was added and the reaction mixture was stirred at RT for 1 h, quenched with MeOH (2 mL) and concentrated to dryness. The residue was purified by flash chromatography (eluent 9/1/90 MeOH/NH4OH/DCM) to give compound 450 as a white solid (60 mg, 16% yield). 1H NMR δ(400 MHz, CD3CN): 8.51 (d, J=5.5 Hz, 1H), 7.99 (dd, J=2.5, 12.3 Hz, 1H), 7.84 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.32-7.53 (m, 9H), 6.62 (d, J=4.5 Hz, 1H), 3.81 (s, 2H), 3.54 (s, 2H), 2.30-2.53 (bs, 8H), 2.22 (s, 3H). LCMS: 613 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([CH3:21])[C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:22]1([C:28]2[N:33]=[N:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([C:14]1[N:32]3[N:33]=[C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:29]=[CH:30][C:31]3=[N:34][N:35]=1)[CH3:21])=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(C(C)C(=O)OC(C)(C)C)cc2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cnc2ccc(C(C)c3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate (0.130 g, 0.45 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.17 g, 0.90 mmol), HYDROCHLORIC ACID (0.11 ml, 1.4 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 15 min. at 140° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the solid was collected by filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, DCM:MeOH=97%:3%, Flow=40 mL/min) to afford the desired product as light yellowish solid. MS m/z: 382.3 (M+H). Calc'd. for C23H19N5O—381.43.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.N1C=CN=CC=1>C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:12][CH:11]=1
Reactant: BrC1CCCCC1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: c1cnccn1
Product: COc1ccc(C2CCCCC2)cc1
Yield: 96 %

Procedure:
Bromocyclohexane (81.8 mg, 0.5 mmol) and a THF solution (0.85 mL, 0.88 M, 0.75 mmol) of 4-methoxyphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 4-methoxyphenylmagnesium bromide was added dropwise at 25° C. over 20 minutes. 1H-NMR analysis was conducted using pyrazine (19.0 mg, 0.24 mmol) as an internal standard (yield 96%).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][OH:9].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOCCl
Reactant: OCCc1ccsc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCCc1ccsc1Br
Yield: 91.4 %

Procedure:
A solution of 2-bromo-3-(2-hydroxyethyl)thiophene (40.0 g, 0.193 mol) in methylene chloride (200 ml) was cooled in ice and methoxyethoxymethyl chloride (41.9 g, 0.336 mol) was added with stirring. After several minutes N,N-diisopropylethylamine (44.3 g, 0.336 mol) was added and the solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in ether (150 ml) and water (75 ml). The ether layer was separated and was washed with saturated NaHCO3 solution and with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature to give 52.1 g of an amber liquid. TLC indicated that the product was pure and NMR confirmed the structure. Field desorption mass spectral analysis gave a molecular ion of M/Z 294. The yield was 91%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[CH:6][C:7]=1[C:8]#[N:9].O.[NH2:19][NH2:20]>C(O)C>[F:17][C:11]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=1[C:5]1[CH:6]=[C:7]2[C:8]([NH2:9])=[N:4][NH:3][C:2]2=[N:19][N:20]=1
Reactant: NN
Reactant: N#Cc1cc(-c2cccc(F)c2F)nnc1Cl
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2nnc(-c3cccc(F)c3F)cc12

Procedure:
3-Chloro-6-(2,3-difluorophenyl)pyridazine-4-carbonitrile (2.82 g, 11.2 mmol) and hydrazine hydrate (1.25 mL, 25.8 mmol) were stirred at reflux in ethanol (50 mL) for 1 hour. The mixture was cooled and evaporated to dryness. The residue was triturated with water, and the solid was filtered off and dried, giving the title compound as a solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=CC=CC=3)C=CC=1.CI.[Mg].C1[C:31]2[C:22](=C[C:24]3[C:29]([CH:30]=2)=CC=CC=3)C=CC=1.[Mg].[CH3:33]C1CC=CC=1.[Co+3:39].C/C(/[O-])=C/C(C)=O>C1COCC1>[CH3:5][C:14]1[CH2:13][CH:12]=[CH:7][CH:1]=1.[CH3:33][Co:39][CH:24]1[CH:29]=[CH:30][CH:31]=[CH:22]1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: [Co+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC1=CC=CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: C[Co]C1C=CC=C1
Temperature: 25 °C

Procedure:
1.1 g (6.2 mMoles) of anthracene, 300 ml of THF and 0.1 ml of methyliodide are added in an inert gas atmosphere to 7.2 g (300 mMoles) of magnesium powder (particle size <0.15 mm). A yellow-green solution is formed while stirring at room temperature, orange colored magnesium anthracene precipitating therefrom after about 2 hours. The reaction mixture is treated for about 3 hours in an ultrasonic bath (as in Example 1) and then heated while stirring to 60° C. After the addition of 32.0 g (400 mMoles) of monomeric methyl cyclopentadiene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III)-acetylacetonate are added over a period of 30 minutes, the reaction mixture changing color to deep red-brown with a reflux-producing heat effect (65° C.). After cooling to 23° C., the reaction mixture is filtered off from any undissolved fractions through a G-3-glass frit and the deep red-brown filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr). The residue is taken up in 500 ml of pentane and any undissolved fractions are eliminated by filtration. The clear, deep red filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr) and the residue distilled at 10-3Torr (bath temperature 80°-140° C.). 13.6 g (62.4 mMoles=62.4% of the theoretical) of η5 -methylcyclopentadienyl cobalt methylcyclopentadiene are obtained in the form of a dark red oil which solidifies at around -5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[NH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])=[CH:5][C:4]=1[Cl:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)c(N)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(NC(=O)C(Cl)(Cl)Cl)cc1Cl
Temperature: 5 °C
Yield: 113.6 %

Procedure:
2,6-Dichloro-1,4-benzenediamine (225 g., 1.27 mol) is suspended in methylene chloride (1.3 liters) containing triethylamine (245 mL, 1.7 mol). After the mixture is cooled to 5° C., trichloroacetylchloride (169 mL, 1.5 mol, Aldrich Chemical Co.) is added dropwise with stirring at a rate to maintain 5° C. Upon complete addition, the stirred reaction is allowed to reach room temperature. After 24 hours the mixture is filtered and the collected solid is washed with methylene chloride (700 mL). The filtrate is evaporated to a small volume. A solid is collected and washed with methylene chloride (250 mL) to yield 465 grams of N-(4-amino-3,5-dichlorophenyl)-trichloroacetamide. The product exhibits a mass spectral analysis of m/e+· 320 for C8H5Cl5N2O.