Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: c1ccc(-c2nccs2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
A solution of 2-bromothiazole (1.0 g, 6.1 mmol, Aldrich) in dioxane (25 mL) was treated with phenylboronic acid (0.82 g, 6.4 mmol), Pd(PtBu3)2 (0.16 g, 0.3 mmol, Strem) and Cs2CO3 (3.97 g, 12.2 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure, and purified by column chromatography (SiO2, 1:1 hexanes/ethyl acetate) to give provide the title compound (0.69 g, 4.3 mmol, 70%). 1H NMR (CDCl3, 300 MHz) 7.33 (m, 1H), 7.41-7.48 (m, 3H), 7.87 (d, 1H, J=3.4 Hz), 7.95-8.00 (m, 2H); MS (DCl/NH3) m/z 162 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:17]3[N:16]([C:17]4[CH2:18][CH2:19][CH2:20][N:16]=4)[CH2:20][CH2:19][CH:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: Clc1cccc2c1Sc1ccccc1N2
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc2c1Sc1ccccc1N2C1=CCCN1C1=NCCC1
Yield: 17.1 %

Procedure:
A solution of 4-chlorophenothiazine (32.3 g., 0.134 mole) and 2-pyrrolidinone (23 g., 0.27 mole) in 125 ml. of 1,2-dichloroethane is added dropwise to a solution of phosphorus oxychloride (20.5 g., 0.134 mole) in 50 ml. of 1,2-dichloroethane in about 35 min. Isolation of the product from the reaction mixture according to the procedure of Example 1 provides 7.5 g., (17.1% yield) of 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN- 2-YL]PHENOTHIAZINE free base, m.p. 195°-197° C. Analytically pure 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE HYDROCHLORIDE obtained by crystallization from ethanol-ether has a melting point of 232°-234° C. (corr.).
Reaction SMILES: CI.[Cl:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([O:11][CH3:12])=[CH:6][N:5]=1.[C:13]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:3][C:4]1[N:9]([CH3:13])[C:8](=[O:10])[C:7]([O:11][CH3:12])=[CH:6][N:5]=1
Reactant: COc1cnc(Cl)[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cnc(Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
128 g (0.9 mol) of MeI was added dropwise to the suspension of 2-chloro-5-methoxypyrimidin-4(3H)-one (74 g, crude, about 0.3 mol) and Cs2CO3(195 g, 0.6 mol) in 600 mL of DMF at 0° C. and the reaction mixture was stirred at this temperature for 1 h, then warmed to r.t., and stirred another 1 h. The mixture was poured into water and extracted with EtOAc several times. The extract was washed with water, brine and dried over Na2SO4 before being filtered and concentrated to give a crude product, which was purified by silica gel chromatography to give 31.2 g (71.2%) of 2-chloro-5-methoxy-3-methylpyrimidin -4(3H)-one. 1H-NMR (CDC3, 400 MHz) δ 7.37 (s, 1H), 3.80 (s, 3H), 3.61 (s, 3H). MS (ESI) m/z (M+H)+ 175.0/176.0.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[Cl:9][C:10]1[S:14][C:13]([C:15](=[O:45])[CH2:16][N:17]2[C:22](=[O:23])[C:21]3[CH:24]=[C:25]([CH2:27][CH3:28])[S:26][C:20]=3[N:19]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)[C:18]2=[O:44])=[CH:12][CH:11]=1.[N:46]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[Cl:9][C:10]1[S:14][C:13]([C:15](=[O:45])[CH2:16][N:17]2[C:22](=[O:23])[C:21]3[CH:24]=[C:25]([CH2:27][CH3:28])[S:26][C:20]=3[N:19]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:46][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)[C:18]2=[O:44])=[CH:12][CH:11]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(Cl)s3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(Cl)s3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A mixture of hydroxylammonium chloride (1.21 g), sodium hydrogencarbonate (1.83 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(5-chloro-2-thienyl)-2-oxoethyl]-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue were added 20% sulfuric acid (10 mL) and ethanol (50 ml). The mixture was stirred at 100° C. for 1 hr, and extracted with chloroform and water. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.32 g, 36%).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:7])=[O:6].[CH3:36][N:37]([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[S:12]([O-:14])(=[O:13])(=[O:11])[CH3:15].[CH:30]1([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH:3]([O:2][CH3:1])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][N+:37]([CH3:39])([CH3:38])[CH3:36])(=[O:7])=[O:6])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(COCCCCCCCCCCCCC1CCCCC1)CS(=O)(=O)CCCOS(C)(=O)=O
Reactant: CN(C)C
Solvent: Cc1ccccc1
Product: COC(COCCCCCCCCCCCCC1CCCCC1)CS(=O)(=O)CCC[N+](C)(C)C
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
In 50 ml of toluene containing 10 g of trimethylamine is dissolved 5.4 g of 3-mesyloxypropyl 2-methoxy-3-(12-cyclohexyldodecyloxy)propyl sulfone, and the mixture is stirred at room temperature for 5 days. The reaction mixture is then concentrated to dryness and the residue is purified by silica gel column chromatography to obtain 3.17 g of the captioned compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([N:40]5[CH2:44][CH2:43][CH2:42][C:41]5=[O:45])[CH:35]=4)=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>CO.O1CCOCC1>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:19]=[C:18]3[NH:29][N:30]=[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[C:36]([N:40]5[CH2:44][CH2:43][CH2:42][C:41]5=[O:45])[CH:37]=[CH:38][CH:39]=4)[C:17]3=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH:21]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2cccc(N4CCCC4=O)c2)nn3C2CCCCO2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1cc(-c2ccc(O)cc2)nc2[nH]nc(/C=C/c3cccc(N4CCCC4=O)c3)c12)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.8 %

Procedure:
To a solution of 4-[6-(4-Hydroxy-phenyl)-3-{(E)-2-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-vinyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.246 g, 0.36 mmol) in methanol (5 ml) was added 4N HCl in dioxane (0.9 ml). The reaction mixture was stirred at room temperature for 18 hours, diethyl ether was then added, the resulting precipitated was filtered and washed once with diethyl ether to afford the hydrochloride salt of the title compound (0.19 g, 93%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][O:14][C:15](=[O:22])[C:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17]>>[CH3:13][O:14][C:15](=[O:22])[C:16]([CH3:18])([CH3:17])[NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)C(C)(C)N=C=O
Product: COC(=O)C(C)(C)NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
9.75 g. of 5-amino-2-chlorobenzotrifluoride and 7.15 g. of 2-isocyanato-2-methylpropionic acid methyl ester are melted a 80° and the melt is kept at this temperature for 30 minutes. The product which has crystallized out during this process is recrystallized from isopropanol/methylene chloride and dried under greatly reduced pressure at 50° for 20 hours. N-[(3-trifluoromethyl-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, which melts at 141°-142° is obtained.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)c1

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 381 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:11]([O:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)C1C=CC=CC=1.[CH2:40]([OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[H-].[Na+]>C1COCC1>[CH2:40]([O:47][C:2]1[C:7]([C:8](=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:11]([O:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[C:6]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:5]=[CH:4][N:3]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: CCOc1c(S(C)(=O)=O)ccc(C(=O)c2c(Cl)ccnc2Cl)c1C
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1c(S(C)(=O)=O)ccc(C(=O)c2c(OCc3ccccc3)ccnc2OCc2ccccc2)c1C
Temperature: 25 °C

Procedure:
To a solution of the product of step (b) (0.49 g, 1.26 mmol) in 5 ml THF at -20° C. under nitrogen was added a slurry of benzyl oxide (73.78 mmol) generated from benzyl alcohol and oil free sodium hydride in 2 ml THF. The reaction mixture was allowed to warm to room temperature and stirred for several hours, then partitioned between ether and water. The organic layers were dried and evaporated to yield 0.5 g of a crude product. This was purified via chromatography on silica gel using 25% ethyl acetate in hexanes as the eluant to give 0.177 g of 2,4-dibenzyloxy-3-(3-ethoxy-2-methyl-4-methylsulfonylbenzoyl)pyridine, a viscous yellow oil.
Reaction SMILES: CC(C)=O.C1(C([NH:24][CH:25]2[C:38](=[O:39])[N:27]3[CH:28]([C:33]4[NH:37][N:36]=[N:35][N:34]=4)[C:29]([CH3:32])([CH3:31])[S:30][C@H:26]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[NH2:24][CH:25]1[C:38](=[O:39])[N:27]2[CH:28]([C:33]3[NH:34][N:35]=[N:36][N:37]=3)[C:29]([CH3:31])([CH3:32])[S:30][C@H:26]12
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.17 h

Procedure:
To a slurry of dry acetone (5 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazolyl)penam (483 mg., 1.0 mmole) at room temperature is added p-toluenesulfonic acid monohydrate (209 mg., 1.1 mmole). The resulting solution is stirred for 10 minutes, and then ether (30 ml.) is added over a five minute period. The mixture is stirred for 10 minutes after which the solvent is decanted from the residue. The residue is dissolved in tetrahydrofuran (30 ml.) and placed on a column (300 × 6 mm.) packed with 10 g. of Florisil (synthetic magnesium silicate). The column is eluted with tetrahydrofuran until a total of 125 ml. is collected. The eluate is concentrated to dryness under reduced pressure at 40° C. to give 210 mg. of solid. The solid is slurried in ether (30 ml.), filtered, washed with ether and air-dried. Yield = 121 mg. (50%). NMR (DMSO-d6): 5.88 (s, 3H), 5.10 (s, 3H) 5.52 (d, 1H), 4.60 (d, 2H), 1.59 (s, 3H) and 1.08 ppm (s, 3H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.Br[C:21]1[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][CH:26]=1.C([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=C.CCCCCCCCCCCCCCCC>C(OCC)C.C1(=O)OC(C)CO1>[F:28][C:27]([F:30])([F:29])[C:23]1[CH2:22][C:21]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH:26]=[CH:25][CH:24]=1)[CH:1]=[CH2:2]
Reactant: C=COCCCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)(F)c1cccc(Br)c1
Solvent: CCCCCCCCCCCCCCCC
Solvent: CCOCC
Solvent: CC1COC(=O)O1
Product: C=CC1(OCCCC)C=CC=C(C(F)(F)F)C1
Temperature: 120 °C

Procedure:
26 mg (0.025 mmol) bis-(dibenzalacetone)-chloroform-palladium and different amounts of triphenyl phosphine are placed in a Schlenk-tube under argon. 4 ml propylene carbonate, 1.12 g (5 mmol) 3-bromo-benzotrifluoride 0.76 g (7.5 mmol) triethyl amine and 0.75 g (7.5 mmol) butyl vinyl ether are added. The reaction mixture is heated to 120° C. for 20 hours. It is cooled to room temperature and 200 mg hexadecane (internal standard) and 15 ml diethyl ether are added. The mixture is analysed by GC.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[Cl:19][C:20]1[C:26]([OH:27])=[CH:25][C:23]([NH2:24])=[C:22]([F:28])[CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[C:26]([OH:27])=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[C:22]([F:28])[CH:21]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Temperature: 140 °C

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.1 g, 0.74 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-2-fluoro-5-hydroxyaniline (432 mg, 0.82 mmol), (prepared as described in EP 061741 A2), in DMF (2.5 ml) was heated at 140° C. for 45 minutes. The work up procedure was as described in Example 6 and gave 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid, 157 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: COC(=O)CNc1cccc(C(N)=O)c1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
To a mixture of 6.8 g of 3-aminobenzamide, 5.5 g of methyl monochloroacetate and 10.0 g of calcium carbonate was added 30 ml of dimethylformamide and the mixture was stirred at 110° to 120° C. for 2 hours. The inorganic salt precipitated was filtered off and the filtrate was concentrated under reduced pressure. 50 ml of water was added to the resulting residue and the mixture was stirred to precipitate crystals. The crystals were collected by filtration, dried and recrystallized from a mixture of methanol and diethyl ether to obtain 5.7 g of N-(3-carbamoylphenyl)glycine methyl ester as colorless needles having a melting point of 146°-147° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[Li]CCCC.[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>C1COCC1.CCCCCC>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]
Reactant: OCC1CCOCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1c(OCC2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of tetrahydropyran-4-methanol (782 mg, 6.73 mmol) in THF (25 mL), was added slowly 1.38M nBuLi (4.13 mL, 5.70 mmol) in hexane at −78° C. under nitrogen. At one hour a solution of 2,6-dinitrobenzonitrile (1.00 g, 5.18 mmol) in THF (25 mL) was added. The reaction was stirred under N2 overnight at rt, then was quenched with water (100 mL). The precipitate was collected by filtration to provide 2-nitro-6-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile (1.13 g, 83%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 1.68 (m, 2H), 2.06 (br, 1H), 3.33 (m, 2H), 3.88 (m, 2H), 4.11 (d, J=6.0 Hz, 2H), 7.72 (d, J=6.0 Hz, 1H), 7.89-7.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([NH:16][C:11]([C:8]1[S:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: O=C(O)c1cc2cccc(Br)c2s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CN2CCC1CC2)c1cc2cccc(Br)c2s1

Procedure:
903.8 mg (3.52 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid (Example 7A), 700 mg (3.52 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1604.0 mg (4.22 mmol) of HATU, 1635.7 mg (12.66 mmol) of N,N-diisopropylethylamine and 7.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1N hydrochloric acid and then concentrated and dried under high vacuum. 1087 mg (77% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([N:19]([CH2:25][C:26]3[CH:31]=CC=C[CH:27]=3)[C@H](C)C(O)=O)(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)CCCC.C(Cl)(=O)[C:33]([Cl:35])=[O:34].CN(C=O)C>ClCCl>[CH3:31][CH:26]([CH3:27])[C@@H:25]([NH:19][S:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([S:6][CH3:1])[S:8][C:9]=2[CH:15]=1)(=[O:17])=[O:18])[C:33]([Cl:35])=[O:34]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@H](C)C(=O)O)cc2s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)Cl)C(C)C)cc2s1
Temperature: 0 °C

Procedure:
(2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl) benzylamino]propionic acid (157 mg, 0.328 mmol) prepared in Example 33 was dissolved in dichloromethane (2 mL) and cooled down to 0° C. Oxalylchloride (0.114 mL, 10 equi.) and DMF of catalytic amount were added and the reaction solution was refluxed for 3 hours at RT. After reaction, the solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure to give (2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic chloride. The compound was then dissolved in THF (1 mL) to obtain acid chloride THF solution. Hydroxyamine hydrochloride salt (0.23 g, 10 equi.) and NaHCO3 (0.33 g, 12 equi.) were dissolved in THF/H2O (3 mL/3 mL) and cooled down to 0° C. to give a hydroxyamine solution. The above acid chloride THF solution was slowly added to the hydroxyamine solution at 0° C. After 1 hour, the solvent was removed from the reaction solution. Then, the product was extracted with ethylacetate 10 mL), washed with H2O and 0.1N HCl, dried over MgSO4, distilled under reduced pressure and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)benzylamino]propionamide (163 mg, 100%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=2)[CH:20]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:20]=[C:21]2[C:26]([CH:25]=[CH:24][C:23]([C:12]3[C:11]4[C:6]([C:5]5[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=5[CH:13]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:22]2)=[CH:27][CH:28]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: Brc1ccc2ccc(-c3cc4ccccc4c4ccccc34)cc2c1
Temperature: 85 °C
Reaction time: 7 h
Yield: 38.7 %

Procedure:
In argon atmosphere, a mixture of 18.64 g (83.9 mmol) of 9-phenanthreneboronic acid, 30.00 g (104.9 mmol) of 2,7-dibromonaphthalene, 4.85 g (4.2 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of dimethoxyethane, 200 ml of toluene, and 106 ml of a 2 M sodium carbonate was stirred at a bath temperature of 85° C. for 7 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. Then, the toluene was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain 12.46 g (yield: 31.0%) of 7-bromo-2-(9-phenanthrenyl)naphthalene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)[S:8][C:6]=2[N:7]=1
Reactant: OCCN1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OCCN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.1 g, 3.9 mmol) in 1,2-dichloroethane (20 mL) was added 1-(2-hydroxyethyl)piperazine (0.7 mL, 5.4 mmol), and AcOH (3.9 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (4.6 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. 2-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)ethanol was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 2-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)ethanol (0.8 g). MS (Q1) 398 (M)+