Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(N)c(Nc2ccccc2)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture of 4-methyl-N2-phenylbenzene-1,2-diamine (600 mg, 3.03 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (861 mg, 4.55 mmol), HOAt (453 mg, 3.33 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (874 mg, 4.55 mmol) and 4-methylmorpholine (0.74 mL, 6.67 mmol) in anhydrous DCM (20 mL) was stirred at RT for 1.5 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 20 h. After cooling to RT, volatiles were removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with a saturated solution of NaHCO3 (2×100 mL). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was absorbed onto HM-N and the solvent was removed in vacuo. The product was purified by column chromatography (Si—PCC, gradient 10-60% EtOAc in cyclohexane) affording [(S)-1-(6-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (969 mg, 92%). LCMS: RT 3.10 min [M+H-tBu]+ 352.1.
Reaction SMILES: [S-:1][CH2:2][CH2:3][CH2:4][CH3:5].[Na+].C(S)CCC.[H-].[Na+].C([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:33]([CH2:34][CH2:35][C@:19]12[CH3:20])[C:32]1[CH:31]=[CH:30][C:29]([O:36]C(=O)C2C=CC=CC=2)=[CH:28][C:27]=1[CH2:26][C@H:25]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]OS(C)(=O)=O)(=O)C>O1CCCC1>[CH2:2]([S:1][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C@@H:25]1[CH2:26][C:27]2[CH:28]=[C:29]([OH:36])[CH:30]=[CH:31][C:32]=2[C@@H:33]2[C@@H:24]1[C@H:21]1[C@@:19]([CH2:35][CH2:34]2)([CH3:20])[C@@H:18]([OH:17])[CH2:23][CH2:22]1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCCCCCCCOS(C)(=O)=O)Cc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@]12C
Reactant: CCCC[S-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCS
Solvent: C1CCOC1
Product: CCCCSCCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 1 h

Procedure:
A solution of sodium thiobutoxide [generated from butanethiol (0.045 g.) and a 60% dispersion of sodium hydride in mineral oil (0.02 g.)] in tetrahydrofuran (2 ml.) was added to a solution of 17β-acetoxy-3-benzoyloxy-7α-(11-methanesulphonyloxyundecyl)oestra-1,3,5(10)-triene (Example 24; 0.078 g.) in tetrahydrofuran (1 ml.) and the mixture was kept for 1 hour at laboratory temperature, neutralised with aqueous N-hydrochloric acid and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (3 ml.), dried and evaporated to dryness, and the residue was dissolved in methanol (3 ml.). Aqueous N-sodium hydroxide solution (1 ml.) was added and the mixture was kept at laboratory temperature for 18 hours, neutralised with aqueous N-hydrochloric acid and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (10 ml.), dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 7α-(11-n-butylthioundecyl)oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCCCl)c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-nitrophenol (15.00 g, 108.0 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (3.42 g of an 80% dispersion in mineral oil, 114.0 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The mixture was cooled to 0-5° C., and 1-chloro-3-iodopropane (26.37 g, 127.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 19.75 g (85.1%) of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]([NH:30][NH2:31])=[O:29])=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:31][NH:30][C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][N:20]=1)=[O:29])=[O:14]
Reactant: NNC(=O)c1n[nH]c2ccccc12
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NNC(=O)c1n[nH]c2ccccc12)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N′-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-1H-indazole-3-carbohydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.47 mmol of 1H-indazole-3-carboxylic acid hydrazide. LC/MS [9.14 min; 517 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[C@H:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:45]([O:49][NH2:50])([CH3:48])([CH3:47])[CH3:46].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(OCC)(=O)C>[C:45]([O:49][NH:50][C:14](=[O:15])[C@H:13]([N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:24])[CH2:19][CH2:18]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)O)C2CCN(C(=O)OCCc3cccc4ccccc34)CC2)cc1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NOC(C)(C)C)C2CCN(C(=O)OCCc3cccc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
To a solution of the crude 2-(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-[(N-(2-(1-naphthyl)-ethoxycarbonyl))-4-piperidinyl] acetic acid (6.02 mmol) in methylene chloride (150 ml) is added O-t-butylhydroxylamine (2.27 g, 18.06 mmol), N-methylmorpholine (3.65 g, 36.12 mmol), 1-hydroxy-7-azabenzotriazole (819 mg, 6.02 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g, 7.83 mmol). The reaction mixture is stirred at room temperature for 1.5 hours, diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product is purified by silica gel chromatography (2% methanol in methylene chloride) to provide N-(t-butyloxy)-2-(R)-[(4-methoxybenzenesulfonyl) (4-picolyl)amino]-2-[(N-(2-(1-naphthyl)-ethoxycarbonyl))-4-piperidinyl]acetamide (3 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH:7](P(C1C=CC=CC=1)(C1C=CC=CC=1)=O)[O:8][CH2:9][CH3:10])[CH3:4].[C:26]([O:30][C:31](=[O:50])[N:32]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH2:3]([O:5][C:6](=[O:25])[C:7]([O:8][CH2:9][CH3:10])=[CH:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:32]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:43][CH:44]=1)[CH3:4]
Reactant: CCOC(=O)C(OCC)P(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCN(CCc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(C=C(OCC)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 43.8 %

Procedure:
To a suspension of 60% by weight sodium hydride oil dispersion (6.97 mmol, 277 mg) in anhydrous tetrahydrofuran (20 mL) cooled to 0° C. was added 2-diphenylphosphinoyl-2-ethoxyacetic acid ethyl ester (3.80 mmol, 1.26 g) followed by [2-(4-formyl-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester (3.46 mmol, 1.2 g) dissolved in anhydrous tetrahydrofuran (15 mL). The resulting heterogeneous solution was heated to reflux for one hour. The mixture was cooled to room temperature, quenched by the addition of ethanol (2 mL) and diluted with water (20 mL). The aqueous layer was isolated and extracted with diethyl ether (3×). The organic layers were combined, washed with saturated NaHCO3 (2×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to a crude yellow oil. The crude oil was chromatographed on silica gel (20% ethyl acetate/hexanes) to give 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-ethoxy-acrylic acid ethyl ester as a clear oil (700 mg, 44%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH:25]C(=O)OCCCC)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].O1CCC(=O)CC1.C1(=O)CCCCC1.Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCCCOC(=O)NC1(Cn2c(COCC)nc3cnc4ccccc4c32)CCOCC1
Agent: Cl
Agent: O=C1CCOCC1
Solvent: O=C1CCCCC1
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCOCC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of tent-Butyl {4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}carbamate (3.0 g, prepared according to the general methods of Parts A through F of Example 54 using tetrahydro-4H-pyran-4-one in lieu of cyclohexanone in Part A), hydrochloric acid (12.2 mL of 2.8 M in ethanol), and ethanol (18 mL) was heated at reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature and was then concentrated under reduced pressure. The residue was combined with isopropanol (100 mL). A solid was isolated by filtration to provide 2.56 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-amine as a tan solid.
Reaction SMILES: [CH2:1]1COCC1.C[O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl>[CH3:1][N:9]1[CH:10]=[CH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:18][CH:19]=2)=[CH:13][C:8]1=[O:7]
Reactant: COc1cc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)ccn1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1
Temperature: 85 °C
Yield: 69 %

Procedure:
To a stirred anhydrous THF (10 mL) mixture of N-({(5S)-3-[4-(2-methoxypyridin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.667 g, 1.95 mmol) in a sealed tube, is added potassium carbonate (0.807 g, 6.0 mmol) and methyl iodide (1 mL, 17 mmol). The mixture is heated to 85° C. for 16 hours. The reaction is cooled to RT and diluted to 300 mL with CH2Cl2. The K2CO3 is filtered. The solution is concentrated to dryness, dissolved in MeOH (20 mL) and treated with saturated Na2S2O3. The solution is concentrated to dryness on silica. The residue is loaded onto a SIM and purified on a Biotage 12M column with 2–4% MeOH in CH2Cl2 to yield the desired compound (0.460 g, 69%). 1H-NMR (DMSO) δ: 8.26, 7.77, 7.64, 6.68, 6.60, 4.74, 4.17, 3.78, 3.43, 1.83
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10]([C:24]1[CH:29]=[C:28]([N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:31])[N:27]=[CH:26][N:25]=1)[C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([N:10]([C:11]1[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:24]1[N:25]=[CH:26][N:27]=[C:28]([N:30]([CH3:31])[C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])[CH:29]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(N(C(=O)OC(C)(C)C)c2ccc(CO)cc2[N+](=O)[O-])ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Lithium borohydride (0.157 g, 7.14 mmol) was added to a solution of methyl 4-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)(methyl)amino)pyrimidin-4-yl)amino)-3-nitrobenzoate (1.8 g, 3.57 mmol) in THF (20 mL) under an argon atmosphere at 0° C. The resulting mixture was then allowed to warm to rt and stirred for 12 h. The reaction mixture was then quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to get a crude residue. The residue was purified by silica gel column chromatography to afford desired intermediate-6 (1.2 g, 75%) as a solid. MS (ESI): 476.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)[CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH2:41][CH2:42][CH2:43][OH:44]>CN1C(=O)CCC1>[OH:44][CH2:43][CH2:42][NH:41][C:25](=[O:26])[NH:24][C:20]1[CH:19]=[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:34])[N:3]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[N:16][CH:15]=2)[CH:23]=[CH:22][N:21]=1
Reactant: NCCO
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)NCCO)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 97.7 %

Procedure:
A mixture of phenyl (4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.1 g, 0.187 mmol), NMP (10 mL) and 2-aminoethanol (14.0 mg, 0.224 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and then diluted with EtOAc (20 mL). The precipitate was collected by filtration and washed with EtOAc (3 mL) to give the title compound as a white solid (92 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10](C3C=C(C=C(F)C=3)C(NCC3CCN(C)CC3)=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C.CC(N(C)C)=O>ClCCl>[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[N:11]=2)[CH2:37]1
Reactant: CN1CCC(CNC(=O)c2cc(F)cc(-c3ccc4ncnc(N)c4n3)c2)CC1
Reactant: c1c[nH]c(C2CCCNC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2ccc(N3CCCC(c4ncc[nH]4)C3)nc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To an 8 mL screw-cap vial was added 6-chloropyrido[3,2-d]pyrimidin-4-amine 10 (1 equiv., 0.68 mmol, 123 mg), 3-(1H-imidazol-2-yl)piperidine hydrochloride (1 equiv., 0.68 mmol, 128 mg), triethylamine (3 equiv., 2.05 mmol, 0.287 mL) and DMA (2 mL). The reaction was capped and shaken at 100° C. overnight. The reaction was then cooled to room temperature, diluted with dichloromethane, and washed with water. The organic was then concentrated, then purified by reverse phase HPLC, yielding 16 mg of product. 1H NMR (400 MHz, DMSO) δ 8.20-8.14 (m, 3H), 7.82-7.77 (m, 1H), 7.54-7.49 (d, J=9.4 Hz, 1H), 7.38-7.28 (d, J=8.1 Hz, 2H), 6.96-6.94 (s, 2H), 4.79-4.71 (d, J=12.7 Hz, 1H), 4.53-4.46 (d, J=17.4 Hz, 1H), 3.17-3.07 (m, 1H), 3.07-2.96 (m, 1H), 2.96-2.84 (m, 1H), 2.18-2.08 (m, 1H), 1.91-1.77 (m, 2H), 1.66-1.51 (m, 1H). LCMS M/Z (M+H)=296.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:24][C:23]1[C:22]([CH3:25])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=3)[N:1]=2)=[CH:17][C:16]=1[CH3:15]
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2cc1OC
Temperature: 150 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of 2-amino-4,5-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethylacetamide (5 mL) were added 3,5-dimethyl-4-hydroxybenzaldehyde (0.120 g, 0.8 mmol), sodium hydrogen sulphite (58.5%, 0.156 g, 0.88 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h. The reaction mixture was cooled to room temperature and water (40 mL) was added. A white precipitate was formed and filtered off, washed with water and a small amount of methanol and dried under vacuum to give 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (0.230 g, 88% yield) as an off-white solid. Selected data: MS (ES) m/z: 327.12; MP>300° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[ClH:5].[F:6][C:7]([F:18])([F:17])[CH2:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].[OH-].[Na+]>O.Cl.C(OCC)(=O)C.CCOCC>[ClH:5].[F:6][C:7]([F:17])([F:18])[CH2:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][NH2:1]
Reactant: Nc1ccccc1OCC(F)(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NNc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Sodium nitrite (11.7 g, 0.17 mol) in 25 mL water was added dropwise to a cold stirred mixture of 2-(2,2,2-trifluoroethoxy)aniline hydrochloride (33.7 g, 0.15 mol), concentrated HCl (53 mL) and water (25 mL) so that the temperature remained at -5° to -3° C. After the additio was complete, a solution of stannous chloride dihydrate (71.7 g, 0.32 mol) in 122 mL 6N HCl was added over a 1 hour period. After 0.5 hour at 0° C. the reaction was allowed to warm to room temperature. Stirring was continued for 24 hours, the reaction diluted with water, ethyl acetate (400 mL) added, cooled and made alkaline using 50% NaOH. The phases were separated and the organic phase washed with water, dried (MgSO4), filtered and concentrated to give an oil. The oil was dissolved in ether and treated with ethereal HCl. The resulting precipitated solid was collected and dried to give 26.4 g (73%) of 2-(2,2,2-trifluoroethoxy)phenylhydrazine hydrochloride, m.p. 168°-170° C.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(O)C>[C:1]([NH:3][C:4](=[N:13][CH2:12][CH2:11][N:10]([CH3:14])[CH3:9])[S:5][CH3:6])#[N:2]
Reactant: CSC(=NC#N)SC
Reactant: CN(C)CCN
Solvent: CCO
Product: CSC(=NCCN(C)C)NC#N
Reaction time: 3 h

Procedure:
A stirred solution of N-cyano-bis(methylthio)methanimine (30 g) in warm ethanol (150 ml) was treated dropwise with 2-dimethylaminoethylamine (24 ml) during 1 hour and stirring was continued for a further period of 3 hours. The resulting white precipitate was recrystallised from ethanol, to give N-cyano-N'-(2-dimethylaminoethyl)-S-methylisothiourea (13.4 g), m.p. 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2cc(-c3ccccc3Cl)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc2cc(-c3ccccc3Cl)sc2c(Cl)c1Cl
Yield: 72.4 %

Procedure:
A mixture of 26.8 g of 6,7-dichloro-2-(2'-chlorophenyl)-5-methoxybenzo[b]thiophene and 260 g of pyridine hydrochloride is heated at 190°-200° for 4.5 hrs. To the cooled mixture is addded 800 ml of water and the aqueous mixture is extracted with three 400-ml portions of ethyl ether. The organic layers are collected, washed with 400 ml of 2N hydrochloric acid and with 200 ml of water. The organic layer is dried over anhydrous magnesium sulfate, decolorized (charcoal) overnight and the solvent is removed. Recrystallization from acetone-hexane gives 18.6 g of 6,7-dichloro-2-(2'-chlorophenyl)-5-hydroxybenzo[b]thiophene, mp 174°-175°.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Yield: 91.7 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-butylpropionate (450 mg), which is the product of Example 21, was reacted with aqueous sodium hydroxide solution (1N, 3.00 ml) and the reaction mixture was treated to give the title compound (388 mg) as a white powder.