Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:13][CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1.Br.[CH2:16]([N:18]1[C:23]2[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1)[CH3:17].[OH:29]O>O.N.CC(C)=O.C(OCC)(=O)C>[CH2:13]([N:9]([CH:10]([CH3:11])[CH3:12])[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:26]2[C:25](=[O:28])[CH:24]=[C:23]([N:18]([CH2:19][CH2:20][OH:29])[CH2:16][CH3:17])[C:22](=[O:21])[CH:27]=2)=[CH:8][CH:7]=1)[CH3:14]
Reactant: CCN1CCOc2ccc(O)cc21
Reactant: OO
Reactant: CCN(c1ccc(N)cc1)C(C)C
Agent: Br
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCN(CCO)C1=CC(=O)C(Nc2ccc(N(CC)C(C)C)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.10 g (0.005 mol) of N-(4-aminophenyl)-N-ethyl-N-isopropylamine hydrochloride in 5 ml of water and 3 ml of 20% aqueous ammonia is added a solution of 1.30 g (0.005 mol) of 4-ethyl-3,4-dihydro-2H-1,4-benzoxazin-6-ol hydrobromide in 3 ml of water, 1 ml of 20% aqueous ammonia and 15 ml of acetone. 17 ml of aqueous hydrogen peroxide solution are added and the mixture is stirred at room temperature for 3 hours 30 minutes. An oil forms. After 12 hours at 6° C., the oil forms a gum. This gum is taken up in ethyl acetate, dried over disodium sulfate and filtered, and the ethyl acetate is evaporated off. The product is purified on a column of silica (eluent: 80/20 ethyl acetate/heptane). The eluent is evaporated off. After 48 hours at 6° C., the product has crystallized, and is left to dry. 0.52 g of 2-[4-(ethylisopropylamino)phenylamino)-5-[(2-hydroxyethyl)ethylamino][1,4]benzoquinone (compound 11) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=1>>[N:14]1([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:26]([C:23]4[CH:24]=[CH:25][C:20]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:21][CH:22]=4)=[O:27])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: Nc1ccc2c(c1)N(CCN1CCOCC1)CCC2
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccc2c(c1)N(CCN1CCOCC1)CCC2)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 35, the title compound was prepared from 7-amino-1-(2-morpholin-4-ylethyl)-1,2,3,4-tetrahydroquinoline (D17) (0.1 mmol) and 4-biphenylcarboxylic acid (24 mg, 0.12 mmol) as a red gum. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.86 (br, 1H), 7.69 (d, 2H), 7.62 (d, 2H), 7.50 (t, 2H), 7.39 (t, 1H), 7.13 (d, 1H), 6.91 (d, 1H), 6.78 (dd, 1H), 3.75 (m, 4H), 3.46 (m, 2H), 3.33 (m, 2H), 2.80-2.40 (m, 8H), 1.92 (qn, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].C(O)(=O)C.N1CCCCC1>C(O)C>[C:14]([C:16](=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:17]([NH2:19])=[O:18])#[N:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: N#CCC(N)=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(N)=O

Procedure:
A solution containing 1.3 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.73 g of cyanoacetamide and catalytic amount of piperidine acetate in 40 ml of dry ethanol was refluxed over night. The solvent was evaporated in vacuo and the residue was recrystallized water-DMF. Yield 0.84 g (48%), m.p. 296°-298° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)C.C(O)(=O)C.O=[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Fc1ccc2[nH]cc(Cc3ccncc3)c2c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reaction time: 48 h

Procedure:
A mixture of 5-fluoro-3-(4-pyridinylmethyl)-1H-indole (4.50 g, 20 mmol) and PtO2 (0.50 g, 2.2 mmol) in ethanol and acetic acid is hydrogenated under 45 psi at room temperature for 48 hr. After filtration of the catalyst and concentration of the filtrate, the residue is taken up with water, basified to pH 11 with 1N NaOH and extracted with CH2Cl2/iPrOH (3/1). The combined extracts are dried over Na2SO4 and concentrated in vacuo to give a pink solid. The solid is crystallized from EtOAc to afford the title compound as a white solid, 4.0 g (86%) mp 155-157° C. (Lit. mp 163° C., Malleron et al, J. Med. Chem. 1193,36,1194).
Reaction SMILES: [CH3:1][C@@H:2]([OH:20])[C@H:3]1[C:9](=[O:10])[N:8]2[C@@H:4]1[CH2:5][C:6]([S:14][CH2:15][CH2:16][NH:17][CH:18]=[NH:19])=[C:7]2[C:11]([OH:13])=[O:12]>ClCCl>[CH3:1][C@@H:2]([OH:20])[C@H:3]1[C:9](=[O:10])[N:8]2[C@@H:4]1[CH2:5][C:6]([S:14][CH2:15][CH2:16][N:17]=[CH:18][NH2:19])=[C:7]2[C:11]([OH:13])=[O:12].[OH2:10]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCCNC=N)C[C@H]12
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCCN=CN)C[C@H]12
Product: O
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
The reaction mixture containing imipenem obtained at step (d) Example 1 was stirred with dichloromethane (900 ml) maintaining pH between 7.0 to 8.0 and the aqueous layer separated. The aqueous portion was degassed to remove dichloromethane and given activated carbon treatment. The filtered aqueous solution was mixed with isopropanol (400 ml) and stirred at 5-10° C. for 3 hours. The crystalline product so obtained was filtered, washed with isopropropanol followed by acetone and dried at 35-40° C. for 1 hour to obtain crystalline imipenem monohydrate (9.0 g, purity 99% by HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[CH:26]=[CH:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:17][C:16]2=[O:18]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Product: CCCOc1ccc(C=CC(=O)OC(C)(C)C)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
The title compound was prepared from 2-(5-bromo-2-n-propoxyphenyl)-8-methylquinazolin-4(3H)-one (Preparation 11) and t-butyl acrylate following the procedure of Example 9 and was obtained as colorless crystals (18%), m.p. 196-197° C.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:28]([OH:29])=[CH:27][C:20]4[N:21]([CH3:26])[C:22](=[O:25])C[O:24][C:19]=4[CH:18]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCI>O1CCCC1>[C:1]1([CH:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:28]([OH:29])=[CH:27][C:20]4[N:21]([CH3:26])[C:22](=[O:25])[O:24][C:19]=4[CH:18]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C(=O)COc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Agent: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cn1c(=O)oc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 7-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one (3.4 g, 7.1 mmol) in anhydrous tetrahydrofuran (30 mL) was deoxygenated for 1 h with dry argon. Cesium carbonate (8.1 g, 25 mmol) and chloroiodomethane (1.5 mL, 21 mmol) were added and the heterogeneous reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (50 mL). The filtrate was concentrated in vacuo and the crude product was purified by column chromatography with ethyl acetate in hexanes (10% to 70% gradient) to afford 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one. To a solution containing 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one (1.0 g, 20 mmol), in trifluoroacetic acid (10 mL) was added triethylsilane (1.6 mL, 10 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography with ethyl acetate in hexanes (10% to 60% gradient) to afford 4-methyl-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione (0.52 g, 78%) as an off-white solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.63 (s, 1H), 7.28-7.23 (m, 1H), 7.10 (d, J=7.1 Hz, 1H), 6.99-6.90 (m, 2H), 6.87 (s, 1H), 6.36 (s, 1H), 4.81 (d, J=9.3 Hz, 1H), 4.70 (d, J=9.3 Hz, 1H), 4.51 (s, 2H), 3.26 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ178.0, 164.4, 156.0, 141.7, 139.2, 132.2, 130.7, 128.8, 123.7, 123.0, 122.2, 110.8, 109.8, 97.8, 79.7, 67.0, 57.6, 28.1; MS (ES−) m/z 321.2 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].C(=O)(O)[O-].[Na+].[Cl:15][CH2:16][C:17](=[O:22])[C:18](Cl)=[N:19][OH:20]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][C:17]([C:18]1[CH2:5][CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[O:20][N:19]=1)=[O:22]
Reactant: C=Cc1ccccc1F
Reactant: O=C(CCl)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CCl)C1=NOC(c2ccccc2F)C1
Temperature: 55 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a suspension of 2-fluorostyrene (2.78 g, 22.8 mmol) and sodium bicarbonate (2.88 g, 34.2 mmol) in anhydrous toluene (15 mL) heated at 55° C. was added 3-chloro-N-hydroxy-2-oxo-propanimidoyl chloride (1.78 g, 11.4 mmol). After 2 h at 55° C., the reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using 10% ethyl acetate in hexanes as eluant to provide the title compound as a yellow solid (2.35 g) melting at 42-44° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH3:12].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19](C#N)=[CH:18][CH:17]=1.P(Cl)(Cl)([Cl:28])=O>>[ClH:28].[ClH:28].[Cl:28][C:3]1[C:4]2[C:5](=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[CH:12]=[C:1]([C:19]2[CH:22]=[CH:23][C:16]([C:15]([F:25])([F:24])[F:14])=[CH:17][CH:18]=2)[N:2]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CNC(=O)c1ccc(OC)cc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(C(F)(F)F)cc3)cc2c1
Product: Cl

Procedure:
6-Methoxy-3-(4-trifluoromethylphenyl)isoquinolin-1-one obtained by reacting N-methyl-4-methoxy-2-methylbenzamide (1.0 g) and 4-trifluoromethylbenzonitrile (0.96 g) according to Example 10-1 was reacted with phosphorus oxychloride (10 ml) according to Example 10-2, to give 1-chloro-6-methoxy-3-(4-trifluoromethylphenyl)isoquinoline dihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][C:19]=3[S:20][C:21]=2N(C)C)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[F-].[CH2:38]([N+](CCCC)(CCCC)CCCC)[CH2:39]CC.[CH2:55]1[CH2:59][O:58][CH2:57][CH2:56]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:25][C:19]=3[S:20][C:21]=2[C:59]2[CH:55]=[CH:56][C:57]([OH:58])=[CH:39][CH:38]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: C1CCOC1
Reactant: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Magnesium turnings (0.24 g) were placed in a two-neck 100 mL round-bottom flask fitted with a reflux condenser and a magnetic stir bar. The whole apparatus was flame-dried and allowed to cool to ambient temperature. Dry THF (17 mL) and a small crystal of iodine were then introduced followed by slow addition of 4-bromophenyl triisopropylsilyl ether (3.5 g) while stirring at ambient temperature. The reaction mixture was warmed to a gentle reflux for 1 h or until the magnesium turnings were completely consumed to give a 0.5 M solution of the Grignard reagent. This freshly prepared Grignard solution (15 mL) was added slowly to a stirring solution of 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methoxy-4-[(1-pyrrolidinyl)methyl]phenyl ketone (2.5 g, 5.0 mmol) in THF (15.0 mL) at 0° C. under argon. The mixture was stirred at 0° C. for 2 h before quenching with saturated aqueous NH4Cl solution (50 mL) and extraction with CH2Cl2 (50 mL×3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with EtOAc afforded a oily brown material as the major fraction. This material was dissolved in THF (25 mL), treated with a solution of tetrabutylammonium fluoride (1.0 M in THF, 6 mL) at ambient temperature for 1 h, and then concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) afforded the title compound as a yellow foam (2.75 g, 100%).
Reaction SMILES: ClCCl.[Sn](Cl)(Cl)(Cl)Cl.[CH3:9][C:10]([CH3:14])([OH:13])[C:11]#[N:12].[Br:15][CH2:16][CH2:17]O>O>[Br:15][CH2:16][CH2:17][O:13][C:10]([CH3:14])([CH3:9])[C:11]#[N:12]
Reactant: CC(C)(O)C#N
Reactant: OCCBr
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)OCCBr
Temperature: 2.5 °C
Reaction time: 22 h
Yield: 31.6 %

Procedure:
Dichloromethane (42 mL) and tin tetrachloride (64.9 g, 249 mmol) were added to a 250 mL round bottom flask equipped with a magnetic stirrer, temperature probe, condenser and Argon inlet-outlet. The mixture was cooled to 0-5° C. Acetone cyanohydrin (21.2 g, 249 mmol) was added over 15 min, followed by slow addition of 2-bromoethanol (46.69 g, 373.6 mmol). The reaction mixture was stirred at 20-25° C. for 22 h. The mixture was cooled to 0-5° C., diluted with water (148 mL), and extracted with dichloromethane (3×64 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered and concentrated under vacuum to afford the crude product as a yellow liquid. The material was purified by vacuum distillation (10 mm Hg) using a Vigreux column. The fraction boiling between 75-85° C. was collected to afford 2-(2-Bromoethoxy)-2-methylpropanenitrile as a colorless oil (15.09 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23](B(O)O)=[CH2:24].C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.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>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:23]=[CH2:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB(O)O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 100 °C
Yield: 37 %

Procedure:
A suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (6.8 g, 20 mmol), vinyl boronic acid [CAS-No. 4363-34-2] {Bull. Soc. Chim. Fr. 1966, (8), 2557-64} (4.312 g, 60 mmol) and K2CO3 (8.29 g, 60 mmol) in water (10 mL) and dioxane (50 mL) was purged by Ar-stream at 23° C. for 10 min, then tetrakis(triphenylphosphine)palladium(0) (693 mg, 0.6 mmol) was added and the mixture was heated to 100° C. for 20 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield a light yellow solid (2.476 g, 37%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:38][C:39]1[CH:54]=[CH:53][C:42]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][C@H:46]([C@@H:50]([OH:52])[CH3:51])[CH2:45]2)=[CH:41][CH:40]=1>C1COCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:6](/[CH:12]=[CH:13]/[C:14]([N:47]2[CH2:48][CH2:49][N:44]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([F:38])=[CH:54][CH:53]=3)[CH2:45][C@H:46]2[C@@H:50]([OH:52])[CH3:51])=[O:16])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Reactant: C[C@H](O)[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1[C@H](C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.8 %

Procedure:
(E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid (2.1 g, 8.8 mmol), EDCI (3.4 g, 17.6 mmol); HOBT (2.4 g, 17.6 mmol) and 2.1 g (8.8 mmol) (S)-1-[(S)-4-(4-Fluorobenzyl)-piperazin-2-yl]-ethanol were dissolved in 180 ml THF and stirred for 20 hours at room temperature. This mixture was then extracted 3 times with water and once with saturated sodium chloride solution. The title compound was purified by chromatography (SiO2, ethyl acetate/MeOH/NH3conc. 90/10/1) and was isolated as a pale solid (2.5 g, 62%)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17]C)=[O:16])=[CH:5][C:4]=2[NH:3]1.[Li+].[OH-].C1COCC1.[OH-].[Na+]>O.CO>[O:1]=[C:2]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ncsc12
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1ncsc12
Yield: 2.7 %

Procedure:
Methyl 4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylate (35 mg, 0.12 mmol) and LiOH (60 mg, 0.83 mmol) were stirred in a (1:1:1, v:v:v) mixture of THF, MeOH and water (0.6 ml) for 2 hours. 6N aqueous NaOH was added and the solution filtered through celite. The solution was acidified and the resulting solid filtered. Preparative HPLC purification and genevac evaporation provided 4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylic acid as a white solid (0.8 mg). LCMS (ES): 95% pure, m/z 247 [M+1]+.
Reaction SMILES: C[OH:2].O.[Si]([O:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([F:52])=[C:17]([CH:23]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:50]=[C:49]([CH3:51])[O:48][N:47]=3)=[CH:42][CH:41]=2)[C:24]2[NH:25][C:26](=[O:38])[N:27]([C:29]3[C:34]([N+:35]([O-])=O)=[CH:33][CH:32]=[CH:31][N:30]=3)[N:28]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)(C(C)(C)C)(C)C>[Fe].C(O)(=O)C>[C:49]([OH:2])(=[O:48])[CH3:51].[NH2:35][C:34]1[C:29]([N:27]2[C:26](=[O:38])[NH:25][C:24]([CH:23]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]([NH2:50])=[NH:47])=[CH:44][CH:45]=3)[C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH2:13][CH2:12][OH:11])[C:16]=3[F:52])=[N:28]2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)c1
Reactant: CO
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 55 mg of 5-{{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one. The mixture was stirred at 65° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (21 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccnn1C
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccnn1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(2-methyl-2H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]-ethylamine, (0.093 g, 0.36 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.119 g, 0.50 mmol) and DIPEA (0.12 mL, 0.65 mmol) in IPA (2 mL) was stirred at 80° C. in a sealed tube for 16 h. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-8% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (4 mL) and treated with HCl/dioxane (4M, 0.6 mL, 2.4 mmol) then stirred for 30 minutes. The resulting mixture was concentrated in vacuo and residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3/MeOH then concentrated in vacuo to give 417 as a white solid (0.078 g, 58%). LCMS (Method K): RT 2.79, 2.95 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.91-12.00 (1H, m), 8.30-7.81 (3H, m), 7.78-7.71 (1H, m), 7.50 (1H, s), 7.23-7.03 (1H, m), 7.03-6.92 (1H, m), 6.69-6.51 (1H, m), 5.60-5.22 (1H, m), 3.62-3.55 (3H, m), 1.65-1.54 (3H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[O-:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>O1CCCC1>[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CC(C)NCC(Cl)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: [O-]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)NC(Cc1ccc(O)c(NS(C)(=O)=O)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 3.25 g sample of 2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride is slowly added to 45 g of sodium phenoxide in 150 ml of dry tetrahydrofuran at 0° to 5° C. under N2 atmosphere. The mixture is stirred for 24 hours at ambient temperature and then poured on ice whereafter the crude product compound is separated.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[SH:19][CH2:20][C:21](O)=[O:22].N1CCCCC1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[C:21](=[O:22])[CH2:20][S:19][CH:11]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(O)CS
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1CSC(c2ccccc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.133 g, 1.0 mmol), benzaldehyde (0.306 mL, 3.0 mmol), mercapto acetic acid (0.276 g, 2.0 mmol), piperidine, according to method 9 step A. yield: 118 mg (40%), MS m/z: 296.3 (M+H)+, HPLC [A]): rt 5.72 min (96%)