Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CC[C@@H](c2ccccn2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COc2c(N[C@H]3CC[C@@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (180 mg, 0.649 mmol), cis-3-(2-pyridyl)cyclopentylamine (158 mg, 0.973 mmol) and triethylamine (0.200 mL, 0.976 mmol) in anhydrous DMSO (3 mL) was stirred at 80° C. for 8 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/3) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[cis-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (diastereomer mixture, 55.6 mg, 20%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCCCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
To a solution of 4,4,4-trifluorobutan-1-ol (5.0 g, 39.0 mmol) in CH2Cl2 (30 mL) and pyridine (20 mL) was added 4-(dimethylamino)pyridine (0.24 g, 2.0 mmol) followed by p-toluenesulfonyl chloride (7.4 g, 39.0 mmol). The mixture was allowed to stir at ambient temperature for 20 hours then was quenched with 5% aqueous HCl (20 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (5.0 g, 17.7 mmol, 45% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.86-1.98 (m, 2H) 2.06-2.24 (m, 2H) 2.46 (s, 3H) 4.09 (t, J=5.9 Hz, 2H) 7.37 (d, J=7.8 Hz, 2H) 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[S:15][CH2:14][CH2:13][S:12]1.[H-].[Na+].Br[CH2:19][C:20]([NH2:22])=[O:21].O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([NH2:22])=[O:21])[C:6](=[O:11])[C:5]12[S:12][CH2:13][CH2:14][S:15]1
Reactant: NC(=O)CBr
Reactant: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2CC(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 6 (8 g, 33.7 mmol) was dissolved in dry DMF (80 ml) under a nitrogen atmosphere. The solution was cooled at 0° C. and NaH (1.62 g, 37.13 mmol, 60% dispersion) was carefully added portionwise. When the nitrogen evolution ceased, bromoacetamide (5.6 g, 37.13 mmol) was added. After 30 minutes, the mixture was poured into cold water and the solid filtered off, washed with water and hexane. The crude material was directly crystallized in acetonitrile affording 2-[5′-methyl-2′-oxospiro[1,3-dithiolane-2,3′-indol]-1′(2′H)-yl]acetamide 15 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:5]=[CH:4][C:3]=1[OH:14].Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Oc1ccc(Cn2cccn2)cc1Cl
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cn2cccn2)cc1Cl
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 5.0 g of 2-chloro-4-(1-pyrazolyl)methylphenol (produced in Reference Production Example 2), 7.6 g of ethyl chloroacetate, 13.2 g of potassium carbonate and 100 ml of anhydrous dimethylformamide was heated at 50° C. under stirring for 5 hours, and then cooled to room temperature. The reaction mixture was poured into 500 ml of water, which was extracted twice with 50 ml of ethyl acetate. The organic layers were combined, washed with water, saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 2-chloro-4-(1-pyrazolyl)methylphenoxyacetate as an oil.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:7][C:8](=[O:23])[C:9](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:10]([CH3:12])=O)([CH3:6])[CH3:5].C(O)(=O)C.[CH:28]([N:41]1[CH2:44][CH:43]([O:45][C:46](=[O:51])[CH2:47][C:48](=[NH:50])[NH2:49])[CH2:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)(C)C>[CH:4]([O:7][C:8]([C:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:47]([C:46]([O:45][CH:43]2[CH2:42][N:41]([CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:44]2)=[O:51])=[C:48]([NH2:49])[NH:50][C:10]=1[CH3:12])=[O:23])([CH3:6])[CH3:5]
Reactant: N=C(N)CC(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)=C(N)N1
Yield: 88.2 %

Procedure:
According to Japanese Examined Patent Publication (Kokoku) No. Hei 3-31715, sodium methoxide (0.27 g) was added to a solution of 2-(3-nitrobenzylidene)acetoacetic acid isopropyl ester (1.39 g) and amidinoacetic acid (1-benzhydryl-3-azetidinyl) ester acetate (1.62 g) in isopropyl alcohol (80 ml) and the mixture was heated under reflux for 4 hours. After the reaction mixture was cooled, insoluble material was removed and the solvent was evaporated under reduced pressure. The thus obtained residue was dissolved in ethyl acetate and the mixture was washed with water, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (toluene:ethyl acetate=3:1) to obtain pale yellow (±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester (2.17 g, 74%).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C:13]2([F:16])[CH:9]1[CH2:10][N:11]([CH3:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[F:16][C:13]12[CH2:12][N:11]([CH3:17])[CH2:10][CH:9]1[NH:8][CH2:15][CH2:14]2
Reactant: CN1CC2N(Cc3ccccc3)CCC2(F)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CC2NCCC2(F)C1

Procedure:
11 g (43.7 mmol, 93% pure) of 2-benzyl-5-fluoro 7-methyl-2,7-diazabicyclo[3.3.0]octane in 100 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH:25]1[CH:30]=[CH:29][N+:28]([CH2:31][C:32]([NH:34][NH2:35])=[O:33])=[CH:27][CH:26]=1.[Cl-:36].CS(C)=O>C(#N)C>[Cl-:36].[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:35][NH:34][C:32](=[O:33])[CH2:31][N+:28]3[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NNC(=O)C[n+]1ccccc1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NNC(=O)C[n+]1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.172 g (0.9166 mmol) of Girard's reagent P were placed into a 10 ml round bottom flask with 2 ml dimethylsulfoxide and a magnetic stirring bar. The solution was heated to 70° C. with stirring. As the solution began to warm up, the solids began to dissolve and the solution became progressively green in color. After about 30 minutes, the solution was completely homogeneous. The solution was allowed to react at 70° C. for four hours and was allowed to cool to room temperature. 10 ml acetonitrile was added and a white precipitate formed immediately. The solution was filtered and washed with acetonitrile and ether. The solid was allowed to dry but it absorbed H2O from the atmosphere. The hygroscopic effect could either be due to residual dimethylsulfoxide or the product itself.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[CH3:21][S:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](N)=[O:31])[CH:26]=[CH:27][CH:28]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([S:22][CH3:21])[CH:24]=2)=[O:31])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: CSc1cccc(NC(N)=O)c1
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2cccc(SC)c2)cc1C(C)(C)C
Yield: 25 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.2 g (18.5 mmol of 3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy)benzylamine, 4.62 g (25.4 mmol) of N-[3(methylthio) phenyl]urea (prepared substantially in accordance with the procedure described in Example 5), 1.06 ml of acetic acid and 180 ml of toluene. Such reaction provided 2.06 g of N[[3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy)phenyl]methyl]N'-[3-(methylthio)phenyl]urea. The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 444 mg of title compound. m.p. 133°-138° C. (dec).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(OC2CCCC2)c1
Temperature: 25 °C

Procedure:
Potassium carbonate (400 mg, 2.8 mmol) was added to 3-Bromophenol (500 mg, 2.8 mmol) dissolved in acetonitrile and the mixture was refluxed for 1 h and cooled to RT. cyclopentyl bromide (430 mg, 2.8 mmol) was added and the mixture refluxed again overnight. Work up (H2O/EtOAc) and purification afforded the title compound as a pale-yellow liquid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.11 (t, J 8.3, 1H), 7.05-7.00 (m, 2H), 6.82-6.76 (m, 1H), 4.76-4.68 (m, 1H), 1.94-1.73 (m, 6H), 1.65-1.54 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>C(#N)C>[C:1]([CH:3]([C:19](=[O:22])[CH2:20][CH3:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C#N)C(=O)CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A solution of ethyl cyanoacetate (17.0 g, 150 mmol), magnesium chloride (14.4 g, 151 mmol) and triethylamine (42 mL, 301 mmol) in acetonitrile (150 mL) was stirred at 0° C. for 15 minutes. To the solution, propionyl chloride (13.8 g, 150 mmol) was added dropwise over 15 minutes at the same temperature, and subsequently the solution was allowed to warm to room temperature and stirred for 24 hours. After addition of 30% hydrochloric acid (100 mL), the organic matter was extracted with diethylether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude ethyl 2-cyano-3-oxopentanoate (24.6 g, 97% yield). The compound (25.4 g, 150 mmol) was dissolved in a mixed solvent of dimethylsulfoxide (50 mL) and water (5 mL), and the solution was stirred at 120° C. for 1.5 hours. The solution was allowed to cool to room temperature and poured into saturated brine, and the organic matter was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure to give the title compound (14.6 g, quantitative).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH2:34]O)=[CH:17][CH:16]=1.S(Cl)(Cl)=O.[C:40]([O:43][CH2:44][CH3:45])(=[O:42])[CH3:41]>>[CH2:44]([O:43][C:40]([CH:41]([CH2:34][C:24]1[N:25]=[C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:27][C:23]=1[CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:20][CH:19]=1)[C:40]([O:43][CH2:44][CH3:45])=[O:42])=[O:42])[CH3:45]
Reactant: CCOC(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCc2oc(-c3ccccc3)nc2CO)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(Cc1nc(-c2ccccc2)oc1CCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A mixture of (5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-2-phenyl-1,3-oxazol-4-yl)methanol (0.78 g) and thionyl chloride (2 mL) was stirred at 0° C. for 30 min. After concentration of the reaction mixture, ethyl acetate was poured into the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a solution of the obtained residue in tetrahydrofuran (10 mL) was added a mixture of diethyl malonate (1.36 g), sodium hydride (60% in oil, 0.33 g) and tetrahydrofuran (30 mL) at 0° C. After stirring at room temperature for 15 hr, the mixture was refluxed for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 2-ethoxycarbonyl-3-(5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-2-phenyl-1,3-oxazol-4-yl)propionate (0.55 g, yield 53%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[CH:4].[O:13]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=2)[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[C:4][C:23]1[N:22]=[C:21]([CH:20]2[O:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:26]=[CH:25][CH:24]=1
Reactant: C#CC(O)CCCCCCCC
Reactant: OCCCCC1OC1c1cccc(Br)n1
Product: CCCCCCCCC(O)C#Cc1cccc(C2OC2CCCCO)n1
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
3-Hydroxy-undec-1-yne (33 mg, 0.194 mmole) and 5,6-epoxy-6[6-bromopyridine-2yl]hexane-1-ol (44 mg, 0.162 mmole) are combined in 1 ml degassed triethylamine in a 25 ml one-neck round bottom flask under argon. The solution is treated with (bis)triphenylphosphine palladium dichloride (3 mg, 0.004 mmole), warmed to 55° C., and is treated with cuprous iodide (1 mg, 0.005 mmole). The reaction mixture is stirred 1.5 hours at 55° C., cooled to room temperature, and the volatiles are removed in vacuo. The residue is partitioned between 1×10 ml diethyl ether and 1×10 ml saturated sodium chloride/ammonium chloride (1:1). The aqueous layer is further extracted with 3×10 ml diethyl ether. The combined organics are dried over magnesium sulfate and concentrated in vacuo to a pale oil.
Reaction SMILES: [CH2:1]1[O:16][C:4]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[NH:6][CH2:5]2)[O:3][CH2:2]1.[H-].[Na+].Cl[CH2:20][CH:21]([OH:29])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>COCCOC>[CH2:1]1[O:16][C:4]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[N:6]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:5]2)[O:3][CH2:2]1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Reactant: OC(CCl)CN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S1(=O)c2ccccc2C2(CN1CC(O)CN1CCOCC1)OCCO2
Yield: 70.2 %

Procedure:
A suspension of 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (0.48 g, 2 mmol) and 60% sodium hydride (0.08 g, 2 mmol.) in 1,2-dimethoxyethane (20 mL) was heated for one hour under refluxing. The resulting reaction liquid was further heated for 16 hours under refluxing, after addition of 1-chloro-3-morpholino-2-propanol (0.36 g, 2 mmol.). The reaction liquid was placed under reduced pressure to distill the solvent off. The residue was treated with 1N hydrochloric acid and ethyl acetate, and the aqueous layer was taken out. The aquous solution was made basic by addition of potassium carbonate, and the precipitated oil was extracted with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried solution was placed under reduced pressure to distill the solvent off. The resulting residue was treated by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the desired compound (0.54 g, yield 70%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)N(C)C)cc1
Agent: BrB(Br)Br
Product: CN(C)S(=O)(=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 28.1 %

Procedure:
Following General Procedure F, the crude material from Example 74, 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-N,N-dimethylbenzenesulfonamide (33 mg, 0.080 mmol), was reacted with tribromoborane (0.2 mL) to afford the desired product (9 mg, 7% over 2 steps) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.44 (s, 1H), 7.88 (dd, J=6.8, 1.6 Hz, 2H), 7.79 (d, J=5.4 Hz, 1H), 7.57 (dd, J=6.6, 1.7 Hz, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 5.69 (d, J=5.4 Hz, 1H), 2.71 (s, 6H); ESI MS m/z 401 [C19H6N2O4S2+H]+; HPLC 94.5% (AUC), tR=14.84 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(O)C.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:22][CH:19]3[CH2:21][CH2:20]3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Reactant: NC1CC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(NC3CC3)ncc2Cl)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
4-(2,5-Dichloropyrimidin-4-yl)-benzoic acid methyl ester (85 mg, 0.30 mmol) was dissolved in ethanol with 0.2 mL cyclopropylamine and the reaction mixture heated to 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 4-(5-chloro-2-cyclopropylaminopyrimidin-4-yl)-benzoic acid methyl ester as a solid, 90 mg, 0.30 mmol, 100% yield. LCMS: ES+=304.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32](OC)=[O:33])(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:42]([OH:45])([CH3:44])[CH3:43]>C1COCC1>[C:1]([NH:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([O:45][CH:42]([CH3:44])[CH3:43])=[O:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C(=O)OC(C)C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 50 °C
Reaction time: 14 h

Procedure:
To the product of EXAMPLE 91 (10 mg) in isopropanol (4 mL) and THF (1 mL) was added Cs2CO3 (10 mg). The reaction stirred for about 14 hours at 50° C. LC/MS indicated incomplete reaction and the solution was then heated to 90° C. in a pressure tube for three hours. The reaction was concentrated and then diluted with EtOAc. After washing with saturated aqueous NaHCO3 the solution was dried (Na2SO4). The concentrated residue was purified by preparative TLC on silica gel eluted with 5% methanol in CH2Cl2 affording the title compound. HPLC/MS: 558.0 (M+1), 560.0 (M+3); Rt=4.93 min.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[ClH:1].[ClH:1].[CH3:13][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)[CH2:9][CH2:8]1
Reactant: Cc1ccc(OCCBr)cc1
Reactant: CN(C)CCC1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(OCCN2CCC(CCN(C)C)CC2)cc1
Temperature: 0 °C

Procedure:
A mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (7.0 g), 2-bromoethyl 4-methylphenyl ether (6.6 g), triethylamine (12.75 ml) and DMF (50 ml) was heated on a steam bath for 16 hours. The mixture was poured into ice/water (500 ml), basified with 2M sodium hydroxide solution and extracted with dichloromethane. The combined organic extracts were washed with water and then extracted with 2M hydrochloric acid. The combined acidic layers were basified with 2M sodium hydroxide solution and then extracted with dichloromethane to give an oil. The oil was distilled at 120° C. at 0.05 mbar and the distillate was dissolved in ether, acidified with ethereal hydrogen chloride solution and filtered. The solid obtained was washed with ether and recrystallised from absolute ethanol to give 4-(2-dimethylaminoethyl)-1-[2-(4-methylphenoxy)ethyl]piperidine dihydrochloride m.p. 281°-283° C.