Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[C:11]([N+:19]([O-:21])=[O:20])=[CH:12][C:13](O)=[C:14]([CH:17]=1)[CH:15]=[O:16].O>CN(C)C=O>[F:9][C:10]1[C:11]([N+:19]([O-:21])=[O:20])=[CH:12][C:13]([O:4][CH3:1])=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: O=Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(F)cc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a suspension of 0.524 g (3.80 mmole) of potassium carbonate, 0.5 mL of iodomethane and 8 mL of dimethylformamide was added, dropwise, a solution of 0.141 g (0.76 mmole) of 5-fluoro-2-hydroxy-4-nitro-benzaldehyde (IV.46b) in 1 mL of dimethylformamide. The resulting dark red solution was stirred at room temperature for 3 hours. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic layers were washed three times with 25 mL of water, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.143 g of 5-fluoro-2-methoxy-4-nitro-benzaldehyde (IV.46c) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][C:3]=1[Cl:14])=[O:8].[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[Cl:14])=[O:8]
Reactant: O=c1[nH]c2cc(Cl)c(Br)cc2c(=O)o1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c([N+](=O)[O-])c(Cl)c(Br)cc2c(=O)o1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
5.4 g (20 mmol) of 5-bromo-4-chloroisatoic anhydride was suspended in 20 ml of conc. H2SO4 at −10° C. and cooled to −20° C. 2.1 g (21 mmol) of potassium nitrate was dissolved in 6 mL of sulfuric acid and cooled to 0° C., was then added dropwise to the reaction mixture. The reaction mixture was then stirred −10° C. for 15 min and warmed to room temperature overnight. The mixture was poured in to a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to produce 3.2 g (50%) of 5-bromo-4-chloro-3-nitroisatoic anhydride. LCMS: 323 (M+1)+.
Reaction SMILES: NC1C=CC(OC)=CC=1S.FC1C=CC(C(Cl)=O)=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[CH:36]=[C:35]([O:37]C)[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:29][C:30]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc2nc(-c3ccc(F)cc3)sc2c1
Agent: COc1ccc(N)c(S)c1
Agent: O=C(Cl)c1ccc(F)cc1
Product: Oc1ccc2nc(-c3ccc(F)cc3)sc2c1

Procedure:
The procedure set out in Example 7 is repeated using 2-amino-5-methoxybenzenethiol and 4-fluorobenzoyl chloride. The reaction yields a mixture of the title compound and 2-(4-fluorophenyl)-6-methoxybenzothiazole. The mixture is treated with excess boiling 48 percent HBr for one hour to convert the latter product to the title compound. The solution is filtered and the precipitate is recrystallized from ethanol and water. The overall yield is 80.3 percent based on the initial amount of benzenethiol. A recrystallized product melts at about 221° C.-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[SH:29])=[CH:4][CH:3]=1.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:44])([F:43])[F:42])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:42])([F:43])[F:44])[CH:35]=2)=[CH:30][CH:31]=1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(S)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(SCc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-mercapto-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.216 mmol) in DMF (5 mL) was added 1-(bromomethyl)-3-(trifluoromethoxy)benzene (66 mg, 0.259 mmol), followed by potassium carbonate (89 mg, 0.645 mmol). The reaction was stirred at 80° C. for 2 h. The mixture was cooled, diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione (120 mg, 87.3%) as light yellow oil. LCMS retention time 2.106 min; LCMS MH+-THP 555.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9](OC)=[O:10])=[CH:5][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:5][N:6]=1
Reactant: COC(=O)CCc1cnc(C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncc(CCCO)s1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
10.9 g of methyl 2-methyl-5-thiazole-propanoate in 70 ml of tetrahydrofuran was slowly added with stirring at 10°-15° C to a mixture of 125 ml of tetrahydrofuran and 3.42 g of lithium aluminum hydride at 10° C and the mixture was stirred for about 30 minutes. Then, tetrahydrofuran containing 20% water was slowly added and the mixture was filtered. The filter was washed with ethyl acetate and the filtrate was dried over magnesium sulfate and concentrated under reduced pressure to obtain 8.4 g of raw product which was rectified under reduced pressure to obtain 6.4g of 2-methyl-5-thiazole propanol with a boiling point of 106° C under 0.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: Sc1ccccc1Cl
Reactant: ClCCCBr
Product: ClCCCSc1ccccc1Cl

Procedure:
Prepared by Procedure R and Scheme Z using 2-chlorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][NH:12][C:11](=[O:18])[CH:10]=2)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[F:19][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:22])[C:11](=[O:18])[CH:10]=1
Reactant: O=c1cc(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(Br)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To the yellow solution of 4-(4-bromo-2-fluorophenylamino)-5-nitropyridin-2(1H)-one (1.235 g, 3.78 mmol) dissolved in dry DMF (15 mL) at −5−>0° C., was added NaH (182 mg, 4.55 mmol) (60% in oil). The color of solution turned into dark brown in 20 min at 0° C. The stirring was continued at r.t. for 40 minutes, followed by the addition of MeI (283 uL, 4.54 mmol) through a syringe at 5° C. The resulted solution was stirred at r.t. for 36 hours. The desired compound started to precipitate out of solution after 20 min of MeI addition. Water was added, and the precipitate was vacuum filtered, washed with water, and dried at 40° C. under a high vacuum for 2.5 hours. The product was used for the next reaction without further purification. (1.12 gram, 87% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)[CH2:4][NH2:5].CS[C:38](SC)=[N:39][C:40]#[N:41]>C(Cl)Cl>[C:40]([N:39]=[C:38]1[NH:1][CH2:2][CH:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=3)=[O:14])=[C:8]([C:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=3)[CH:7]=2)[CH2:4][NH:5]1)#[N:41]
Reactant: CSC(=NC#N)SC
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=NC#N)NC2)cc1C1=CCCCC1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in the previous step, 15 mg, 0.030 mmol) in DCM (10 mL), dimethyl N-cyanodithioiminocarbonate (4.2 mg, 0.28 mmol) was added. The resulting solution was heated at reflux for 4 h. The reaction mixture was allowed to cool to RT and was concentrated in vacuo. The residue obtained was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (11 mg, 62%): Mass spectrum (ESI, m/z): Calcd. for C28H36N8O2Si, 545.3 (M+H), found 545.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[CH3:9])[N:3]=1
Reactant: CC1CCCCN1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1CCCCN1c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.49 g), 2-methylpiperidine (1.76 mL), potassium carbonate (2.07 g) and DMA (10 mL) was stirred at 80° C. for 22 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.85 g, 87%) as a pale-yellow oil.
Reaction SMILES: CC([O:5][C:6](=[O:40])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:28])=[O:12])(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:22]1([C:27]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:20][S:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([OH:40])=[O:5])=[O:12]
Reactant: CC(C)(C)OC(=O)CCCNC(=O)c1ccccc1SSc1ccccc1C(=O)NCCCC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCNC(=O)c1ccccc1SSc1ccccc1C(=O)NCCCC(=O)O
Yield: 139.9 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using 4,4'-[dithiobis(2,1-phenylenecarbonylimino)]bis butanoic acid bis (1,1-dimethylethyl) ester (0.5 g, 0.9 mmol) from Example 43, 10 mL dichloromethane, 10 mL trifluoroacetic acid, and 1 mL anisole. The crude product was recrystallized from methanol/dimethylformamide/water to afford 0.6 g of the title compound, mp 165°-166° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O>C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)cc(OC)c1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1
Yield: 53 %

Procedure:
86.3 mg (0.50 mmol) of 1-chloro-3,5-dimethoxybenzene (36), 45 μL (2.5 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 30 minutes at 1,100 rpm. After the lapse of 30 minutes, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 36.6 mg (0.265 mmol) of 1,3-dimethoxybenzene (37). The yield was 53%. The reaction is expressed by the following scheme.
Reaction SMILES: CS(C)=O.C1C=CC=CC=1.[F-:11].[K+].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>O>[F:11][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1F
Temperature: 140 °C
Yield: 22.1 %

Procedure:
A mixture of 120 ml of dimethylsulfoxide, 80 ml of benzene, 35 g of potassium fluoride and 50 g of 2,5-dichloronitrobenzene was heated with stirring to 140° C. and was then heated at 180°-185° C. for three hours and then cooled. The water vapor was entrained and the distillate was extracted with isopropyl ether. The combined organic phases were dried and distilled at 40° C. under reduced pressure and were rectified at 14 mm Hg to obtain 10.1 g of 2-fluoro-5-chloro-nitrobenzene with a refractive index of nD20 =1.5558.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCNC1)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(+)-(E)-3-[1′-Tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (710 mg, 1.77 mmol) was dissolved in DCM (50 ml). 4 M HCl in dioxane (2 ml) was added and the mixture was stirred at RT for 3 h. The precipitate was filtered, washed with DCM and dried to give (−)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (516 mg)
Reaction SMILES: [F:1][C:2]1([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][CH2:3]1.[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.O>[N:21]([CH:7]1[CH2:8][CH2:9][C:2]([F:1])([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][CH:5]1[OH:6])=[N+:22]=[N-:23]
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC2OC2CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(N=[N+]=[N-])CC1
Temperature: 100 °C

Procedure:
A solution of 5-(4-fluoro-8-oxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-1H-pyrazole (2.75 g, 10.8 mmol, Intermediate 155) in DMF/water (35 mL/10 mL) was treated with ammonium chloride (1.43 g, 27.0 mmol) and sodium azide (3.5 g, 53.9 mmol) and the mixture was heated at 100° C. behind a blast shield for 18 hr. The reaction mixture was extracted with EtOAc (200 mL) and the organic layer was washed with water (8×30 mL), washed with brine (30 mL), separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (30-40% EtOAc/isohexane) gave 2-azido-5-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)cycloheptanol as the second eluting isomer as a white solid (2.16 g, 67%). 1H NMR (400 MHz, CDCl3) δ 8.06 and 8.05 (2s, 1H), 4.08 and 4.06 (2s, 3H), 3.88-3.78 (m, 1H), 3.65-3.58 (m, 1H), 2.87-2.55 (m, 2H), 2.31-2.21 (m, 2H), 2.18-2.00 (m, 3H), 1.98-1.85 (m, 2H).
Reaction SMILES: BrC1C(F)=CC2OCCN3C(C(O)C4C=CC=C(C(F)(F)F)C=4)=C(C(O)=O)N=C3C=2C=1.[Br:32][C:33]1[C:34]([F:61])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([C:52]4[CH:57]=[C:56]([F:58])[CH:55]=[C:54]([F:59])[CH:53]=4)[OH:51])=[C:44]([C:46]([O:48]C)=[O:47])[N:45]=[C:38]3[C:37]=2[CH:60]=1.[OH-].[Li+]>>[Br:32][C:33]1[C:34]([F:61])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([C:52]4[CH:57]=[C:56]([F:58])[CH:55]=[C:54]([F:59])[CH:53]=4)[OH:51])=[C:44]([C:46]([OH:48])=[O:47])[N:45]=[C:38]3[C:37]=2[CH:60]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Agent: O=C(O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was prepared similarly according to the procedure for the synthesis of 10-bromo-9-fluoro-3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid. Methyl 10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with lithium hydroxide to the crude title compound which was carried forward without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][NH2:13])=[O:11])=[CH:5][CH:4]=1.[N:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[C:17]=S.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.Cl>O1CCCC1.C(OCC)(=O)C>[S:30]1[CH:31]=[CH:32][N:33]=[C:29]1[NH:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:16][C:17]2[O:11][C:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=3)=[N:12][N:13]=2)=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(N=C=S)cc1
Reactant: NNC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nnc(Cc3ccc(C(F)(F)F)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
A mixture of (4-trifluoromethyl-phenyl)-acetic acid hydrazide (200 mg, 0.9 mmol, 1.0 equiv) and 4-isothiocyanato-N-thiazol-2-yl-benzenesulfonamide (273 mg, 0.9 mmol, 1.0 equiv) in 3 mL of anhydrous tetrahydrofuran was stirred at ambient temperature. After 18 h, p-toluenesulfonyl chloride (210 mg, 1.1 mmol, 1.2 equiv) and pyridine (156 mL, 1.93 mmol, 2.10 equiv) were added, and the reaction mixture was heated at reflux. After 4 h, the reaction mixture was cooled to ambient temperature. Ethyl acetate (3 mL) and 1 N hydrochloric acid (3 mL) were added. After stirring vigorously for 5 min, the layers were separated. The aqueous layer was extracted with ethyl acetate (3 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with hot acetonitrile to afford the product as a light yellow solid (295 mg, 60%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][Si](C)(C)C.C(OCC)(=O)C.Cl>CO.CCCCCC>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccccc1Cl
Temperature: 0 °C
Yield: 65.6 %

Procedure:
Potassium hydroxide (77.5 g, 1.38 mol) was added in 4 portions to a stirred solution of (2-chlorophenylethynyl)-trimethylsilane (95.0 g, 0.46 mol) in methanol (250 ml) at 0° C. The mixture was stirred at 0° C. until the reaction was complete (by tlc 1:1 ethyl acetate:hexane). The mixture was neutralised by the addition of 10% hydrochloric acid and the product was extracted into dichloromethane (2×150 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo. The residual oil was purified by short path distillation (Kugelrohr) to give 1-chloro-2-ethynylbenzene (41.23 g) as a clear oil. B.pt. 38° C./10 mBar. 250 MHz 1H-NMR (CDCl3) δ (ppm): 3.25 (s, 1H)(CH), 7.1-7.5 (m, 4H) (ArH); GC purity 89%, GC retention time 2.67 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[C:23]([C:28](=[O:37])[NH:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]4[CH3:36])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:36][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[NH:29][C:28]([C:23]1[C:22]2[C:27](=[C:18]([S:15](=[O:17])(=[O:16])[NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:20][CH:21]=2)[CH:26]=[CH:25][CH:24]=1)=[O:37]
Reactant: CC1CCCCC1NC(=O)c1cccc2c(S(=O)(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)cccc12
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCCCC1NC(=O)c1cccc2c(S(=O)(=O)NC3CCNCC3)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.1 %

Procedure:
4-[5-(2-Methyl-cyclohexylcarbamoyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid tert-butyl ester 47 (380 mg) was dissolved in 4N HCl/dioxane (10 mL) and stirred for 3 hours at room temperature. Concentration in vacuo afforded 48 (370 mg) as its hydrochloride salt that was used without further purification. LC/MS m/z 430 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])[CH:10]=[CH:11][C:4]=2[NH:3]1.[OH-].[Na+].CC(O)=O>CCO.O>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])[CH:10]=[CH:11][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)OCC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)OCC(=O)N2
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of Ethyl 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl)propanoate (80 mg, 0.321 mmol) in 90% aq. EtOH (5 mL) was added NaOH (64 mg, 1.60 mmol) at room temperature. The reaction mixture was stirred for 12 hrs at 50° C. then cooled to room temperature. The mixture was diluted with H2O (20 mL) and acidified with AcOH then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: CN(C)C[CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.NCC[N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C1(N2CCNCC2)C=CC=CC=1>O1CCCC1>[C:15]1([N:12]2[CH2:11][CH2:10][N:9]([C:7]([NH:6][CH2:5][CH2:4][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:8])[CH2:14][CH2:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)CCCNC(=O)N1CCN(c2ccccc2)CC1
Reactant: NCCN1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: O=C(NCCN1CCCC1)N1CCN(c2ccccc2)CC1
Yield: 59 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 5. A mixture of 5.7 g (0.035 mole) of 1,1'-carbonyldiimidazole, 3.9 g (0.034 mole) of N-(2-aminoethyl)pyrrolidine, and 4.9 g (0.03 mole) of 1-phenylpiperazine in a total of 200 ml of tetrahydrofuran gave 5.4 g (59%) of the title compound as a white powder, m.p. 81.5°-84° C., after recrystallizing from diisopropyl ether.