Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[C:25]([CH3:28])[C:26]=3[CH3:27])=[O:21])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:36]C(OC(C)(C)C)=O)=O)(C)(C)C.[I-:44].[Na+].C(O)(C(F)(F)F)=O>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[F:17][C:13]1[C:12]([C:18]([I:44])=[CH:19][C:20](=[O:21])[C:22]2[NH:23][CH:24]=[C:25]([CH3:28])[C:26]=2[CH3:27])=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:36])[CH2:10]2
Reactant: [I-]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c(C(=O)C#Cc2c(F)ccc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c(C(=O)C=C(I)c2c(F)ccc3c2CC(=O)N3)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-3,4-dimethyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 47 above) (0.79 g, 1.33 mmol) and sodium iodide (Aldrich, 0.50 g, 3.33 mmol) was slowly added TFA (Aldrich, 15 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, and then diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. After separation, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate, filtered, and dried to give 5-fluoro-4-[1-iodo-3-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one as a brown solid which was used in the next step without further purification. (Yield 0.40 g, 71.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (64) (45 mg, 0.23 mmol) using Method C to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:14][C:13]=2[CH:21]=1.C(=O)(O)[O-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:6]([O:5][C:3]([CH2:2][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:14][C:13]=2[CH:21]=1)=[O:4])[CH3:7]
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 36 h
Yield: 38.1 %

Procedure:
To a solution of ethyl bromoacetate (1.2 ml, 11 mmol) and 6-hydroxy-2-sulfamoylbenzo[b]thiophene (2.29 g, 10 mmol) in DMSO (10 ml) was added dropwise a solution of potassium bicarbonate (1.0 g, 10 mmol) and potassium carbonate (0.13 g, 1 mmol) in water (7 ml). The mixture was stirred for 1-2 days, then diluted with water. The precipitated product was collected dissolved in ethyl acetate, dried (Na2SO4) and evaporated to dryness. The residue was recrystallized from hot ethyl acetate, boiling off solvent until crystallization began, to give 1.2 g of product, m.p. 182°-184° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].CO>C(Cl)Cl>[Br:12][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 106.1 %

Procedure:
To a stirred suspension of methyl 4-hydroxybenzoate (180 g, 1183 mmol) in DCM (3 L) was added dropwise bromine (64 mL, 1242 mmol) under nitrogen and at 0° C. and the reaction mixture was left to stir at room temperature for 36 h. A solution of sodium thiosulfate (500 mL of a 10% solution) was then added while keeping the temperature around 15° C. followed by addition of MeOH (250 mL). The organic layer was washed with water, then brine, dried over MgSO4, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (290 g) as a white solid. Mass Spectrum: m/z [M−H]−=229.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc(F)c(F)c1O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(F)c(F)c1O

Procedure:
A solution of 3,4-difluoro-2-hydroxybenzoic acid (6.45 g, 37.05 mmol) and sulfuric acid (6 ml, 113 mmol) in MeOH (25 ml) was heated at reflux overnight. The mixture was diluted with water and extracted with ether. The ether was washed with aqueous NaHCO3, water and brine. The combined aqueous layers were twice more extracted with ether, which was washed with NaHCO3, water, and brine. The combined ether extracts were dried (MgSO4) and concentrated to give 6.4 g of product as a white solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][CH3:18])[CH2:22][CH2:23]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: CCCC1CCNCC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC1CCN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 4-N-propylpiperidine (18 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. LC/MS showed the presence of the target compound and no starting material after 24 h. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a white solid. This solid was triturated in acetone, filtered, washed with acetone and diethyl ether to give the title compound (15 mg, 38%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].C([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=O)C.[OH-].[K+].O>C(O)C>[NH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:13][C:12]([C:3]2[C:4]([O:10][CH3:11])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[OH:1])=[O:14])=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(O)c(C(=O)C=Cc2ccc(N)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
A mixture of 98 mg of 2'-hydroxy-4',6'-dimethoxyacetophenone, 85 mg of 4-acetamidobenzaldehyde and 1 g of potassium hydroxide in 4 ml of 50% aqueous ethanol was stirred at room temperature for 3 days. The mixture was poured into 30 ml of cold water and then extracted with three 30 ml portions of ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography using a silica gel plate (Kiesel gel 60 F254, Merck Co.) and cyclohexane/ethyl acetate (1:1, v/v) as the developing solvent, whereby 12 mg of 4-amino-2'-hydroxy-4',6'-dimethoxychalcone as a yellow powder were obtained: Rf value 0.22; 1H-nmr spectrum (in CDCl3): δ3.6(2H), 3.72(3H), 3.82(3H), 5.90(1H), 6.06(1H), 6.56(1H), 6.70(1H), 7.50(1H), 7.62(1H) and 14.4 ppm (1H).
Reaction SMILES: Cl[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C[Si]([C:21]#[N:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CCCCCCC>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]#[N:22])[CH:8]=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1cccc(C(Cl)c2ccccc2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1cccc(C(C#N)c2ccccc2)c1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
A solution of 1-(chlorophenylmethyl)-3-methoxybenzene (5.5 g, 24 mmol) in DCM (100 mL) was cooled to 0° C. Trimethylsilyl cyanide (3.5 mL, 26 mmol) was added to the stirred solution. 1.0 M of tin tetrachloride in heptane (0.75 mL, 0.75 mmol) was then added. The solution was stirred for 2 hours, then quenched with MeOH (50 mL). The solvent was removed under reduced pressure. The crude material was then purified via silica gel chromatography to obtain the title compound (2.2 g, 10 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O.CN(C)CCN>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:25][CH2:26][CH2:27][N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: ClCCl
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stream of nitrogen was bubbled through a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.50 g, 0.0157 mole), 1,1'-carbonyldiimidazole (2.54 g, 0.0157 mole) and anhydrous methylene chloride (100 ml) for 2 hrs at room temperature. A solution of N,N-dimethylethylenediamine (1.50 g, 0.0170 mole) in 10 ml of methylene chloride was added dropwise and the reaction mixture was stirred overnight at room temperature. The methylene chloride was washed with water (2×30 ml), 5% sodium hydroxide (2×30 ml), water (30 ml), dried over sodium sulfate and concentrated. The residue (4.5 g) was recrystallized from isopropyl alcohol to give 3.5 g (62%) of white flakes, mp 195°-196.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1.[N:33]1C=CC=C[CH:34]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH:33][CH3:34])=[O:25])[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: c1ccncc1
Reactant: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)noc1-c1nc2cc(OCC3CC3)ccc2o1
Product: CNC(=O)N[C@@H](C)COc1noc(-c2nc3cc(OCC4CC4)ccc3o2)c1C

Procedure:
Using tert-butyl [(1S)-2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-4-methylisoxazol-3-yl}oxy)-1-methylethyl]carbamate, and in the same manner as in Example 16 (using pyridine instead of triethylamine), the title compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>C1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCOCC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1onc(-c2nonc2NCc2ccc(CN3CCOCC3)cc2)n1-c1ccc(F)c(Br)c1

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-(morpholin-4-ylmethyl)benzamide trifluoroacetate (60 mg, 91 μmol) in benzene (1.8 mL) was treated with phosphorus pentachloride (76 mg, 0.36 mmol) and stirred at reflux for 2.5 h. The reaction mixture was concentrated to a residue which was diluted with ethanol (1.4 mL), treated with sodium cyanoborohydride (17 mg, 0.27 mmol), and stirred for 2 h. The reaction mixture was quenched with acetic acid (50 μL) and purified by preparative LCMS to give the intermediate, 4-(3-bromo-4-fluorophenyl)-3-(4-{[4-(morpholin-4-ylmethyl)benzyl]amino}-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.2 mL, 4 mmol), and stirred for 45 min. The reaction mixture was purified by preparative LCMS to give the desired product (15 mg, 27%). LCMS for C21H23BrFN6O3 (M+H)+: m/z=505.0, 507.0.
Reaction SMILES: Cl.[NH2:2][NH2:3].CCO/[CH:7]=[CH:8]/[C:9]([C:11]([F:14])([F:13])[F:12])=O.FC(F)(F)C(Cl)=O.C(OCC)=C>CO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][NH:3][N:2]=1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Reactant: NN
Agent: C=COCC
Agent: Cl
Agent: O=C(Cl)C(F)(F)F
Solvent: CO
Product: FC(F)(F)c1cc[nH]n1

Procedure:
To a solution of 4.4 moles hydrazine.hydrochloride in 2.2 L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel an equimolar amount of ETFBO which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether was added dropwise over about 4 hours under N2 atmosphere. The temperature of the reaction mixture was kept below 15° C. After 12 h of reflux, the reaction batch was filtered in a 2-L flask and concentrated under vacuum (an identical batch was made under the same conditions, yield of both crude products was ca. 95%). Subsequently, the combined crude product was purified by shortpass-vacuum distillation at 27 mbar. The yield was 1105 g, which corresponded to 92% of the theoretical yield.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:19]([OH:22])(=[O:21])=[O:20]>ClCCl>[C:1]([O:9][C:10]1[CH:15]=[C:14]([S:19]([OH:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1OC(=O)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)O)cc1OC(=O)c1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
A stirred solution of 2-methoxyphenyl benzoate (10 g) in dichloromethane (100 mL) from 0-5° C. is treated dropwise with chlorosulfonic acid (2.9 mL) and the solution is then stirred for 3 hours from 0-5° C. The precipitate which forms is filtered off, washed with cold dichloromethane, and dried in vacuo, to give 3-benzoyloxy-4-methoxybenzenesulfonic acid (11.45 g), in the form of a white solid, m.p. 139-140° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(CNC(=O)Nc3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.47 g, 1.4 mmol) and triethylamine (0.27 mL, 2.0 mmol) in THF (8 mL) at 5-10° C., was added 4-chlorophenyl isocyanate (0.28 g, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (400 mg, 63% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.18 min (98.9%); mp, 225-227° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH), 4.41 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=6 Hz, 1H, CH2NH), 7.23-7.95 (m, 7H, Ar), 8.80 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.93, 23.38, 30.61, 42.33, 56.54, 119.23, 120.01, 123.67, 124.57, 126.53, 128.42, 133.95, 139.05, 139.37, 145.74, 154.53, 155.09, 160.46, 169.47, 172.60. LCMS MH=454, 456; Anal Calcd For C22H20N5O4Cl+0.8H2O: C, 56.43; H, 4.65; N, 14.95; Cl, 7.57. Found: C, 56.45; H, 4.56; N, 14.87; Cl, 7.69.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:12].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:25](=[O:27])[CH3:26])=[O:12]
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCCC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1sc2c(c1C(=O)c1ccco1)CCCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
To a stirred solution of (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-furan-2-yl-methanone (Example 4, 200 mg, 0.8 mmol) in dichloromethane (5 mL), cooled to 4° C. with an ice-water bath, was added triethylamine (0.12 mL, 0.88 mmol), followed by acetyl chloride (0.062 mL, 0.88 mmol). The mixture was warmed to room temperature, stirred for 12 hours, diluted with dichloromethane (5 mL), and washed with 5% aqueous HCl (5 mL), followed by saturated aqueous NaHCO3 (5 mL). The organic phase was dried (Na2SO4), filtered, and evaporated, and the residue precipitated with ethyl acetate and petroleum ether. Yield: 69%; IR (KBr) cm−1: 3448, 3118, 2931, 1677, 1606, 1529, 1466, 1432, 1267, 1063, 774; 1H NMR (CDCl3): 61.67 (m, 2H), 1.86 (m, 2H), 2.26 (s, 3H), 2.38 (t, 2H, J=6.0 Hz), 2.72 (t, 2H, J=7.4 Hz), 6.58 (m, 1H), 7.12 (d, 1H, J=3.4 Hz), 7.63 (s, 1H), 10.7 (s, 1H); yellow solid, mp: 126-127° C. (petroleum ether).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:25][CH2:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([CH:1]3[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]3)[S:9][C:10]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(Cc3ccccc3)sc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2nc(C3CCCCC3)sc2c1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
Combine 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.42 mmol), NBS (0.5 g, 2.54 mmol), AIBN (40 mg, 0.24 mmol), carbon tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the organic extracts over anhydrous Na2SO4, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white solid (0.4 g, 53%). MS (ES+) m/z: 311 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:23]3[C:19](=[CH:20][CH:21]=[N:22]3)[N:18]=[C:17]3[C:13]=2[CH2:14][O:15][CH2:16]3)=[CH:8][CH:7]=1.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:23]3[C:19](=[CH:20][CH:21]=[N:22]3)[N:18]=[C:17]3[C:13]=2[CH2:14][O:15][CH2:16]3)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)COC3)cc1
Reactant: CC1CCCN1
Product: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)COC3)cc1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[t]indene, the reaction of 8-[4-(3-Chloro-propoxy)-phenyl]-5H,7H-6-oxa-1,4,8a-triaza-s-indacene and 2-methyl-pyrrolidine provided compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.0500 g, 0.129 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0198 g, 0.136 mmol) and piperidine (0.0877 g, 0.103 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperazine-1-carboxylate (0.0625 g, 94%).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[C:27]3[N:36](C(OC(C)(C)C)=O)[C:37]4[CH:38]=[CH:39][C:40]([Br:43])=[CH:41][C:42]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:51])[CH:22]=2)(OC(C)(C)C)=O.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[Br:43][C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:27]1[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Br:51])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCCBr)c21
Reactant: C1COCCN1
Agent: c1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(OCCCCN4CCOCC4)c4[nH]c5ccc(Br)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the starting indole is 5,7-diBOC-2,10-dibromo-6-(4-bromobutoxy)indolo[2,3-b]carbazole and the reagent is morpholine. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.22 (s, 2 H), 8.64 (s, 1 H), 8.25 (d, J=1.6 Hz, 2H), 7.44 (dd, J=8.4, 2.0 Hz, 2 H), 7.41 (d, J=8.4 Hz, 2 H), 4.26 (t, J=6.8 Hz, 2 H), 3.57-3.40 (m, 6 H), 2.32-2.18 (m, 4 H), 1.92-1.80 (m, 2 H), 1.65-1.50 (m, 2 H); MS (ESI) m/z 570.0 (M−H)−