Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:23]>>[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[C:4]([F:21])[CH:3]=2)=[CH:29][CH:28]=1)(=[O:25])=[O:26])[CH3:23]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Ethylsulfonyl benzene boronic acid. MS (M+H) 445.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:10])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)[C:17](=[O:18])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]([O:18][CH3:17])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC=O)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(OC)cc1
Yield: 91 %

Procedure:
A homogeneous mixture containing 4-methoxycinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLITE® IR 400 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl 4-methoxycinnamate (from formula I where X1═H, X2═H, X3═OCH3, X4═H, X5═H, R═CH3) is isolated in 91% yield. 1H-NMR (CDCl3, 300 MHz) δ7.56 (1H, d, J=16.55 Hz), 7.37 (2H, d), 6.80 (2H, d), 6.22 (1H, d, J=16.55 Hz), 3.73 (3H, s), 3.70 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ167.7, 161.4, 144.5, 129.7, 127.1, 115.2, 114.3, 55.3, 51.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25](=[O:30])[CH:26](Br)[CH2:27][CH3:28])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:26]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:30])[CH2:27][CH3:28])[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C(=O)OC(C)(C)C)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To a chilled solution of 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (50 mg, 0.19 mmol) in dry DMF (1 mL) NaH (60% dispersion mineral oil, 8 mg, 0.20 mmol) was added under N2 atmosphere. The reaction was stirred at room temperature for 15 min. Then, a solution of tert-butyl-2-bromobutyrate (0.054 mL, 0.29 mmol) in DMF (2 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed with water, with a saturated NH4Cl aqueous solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using 15% ethyl acetate in n-heptane as eluent to afford 3-(1-tert-butoxycarbonylpropyl)-5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (55 mg, 72%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Li][CH2:20]CCC.CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:4]([CH3:20])[C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
N-(4-chloro-3-(trifluoromethyl)phenyl)pivalamide (3b) (3 g, 10.7 mmol) was dissolved in dry THF (30 mL), cooled to 0° C., and n-BuLi (15.6 mL, 25.7 mmol) was added. After 3 h, a solution of MeI (0.66 mL, 10.56 mmol) in THF (7 mL) was added to the reaction mixture maintaining the temperature at 0° C. and stirred for further 3 h. and quenched with aqueous NH4Cl solution. The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude material which was purified by column chromatography to afford N-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3c) (2.0 g, 64%) as off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7](Cl)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([CH2:23][OH:24])[CH2:21][NH2:22]>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:22][CH2:21][CH2:20][CH2:23][OH:24])[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1Br
Reactant: NCCCO
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Temperature: 25 °C
Yield: 89.1 %

Procedure:
8-Bromo-4-chloro-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline (7.8 g, 0.0222 mol) is stirred under nitrogen with 3-propanolamine (4.2 mL, 0.0540 mol) in 1,4-dioxane (156 mL) at 95° C. for 2 hours. The reaction mixture is then cooled down to room temperature and concentrated. The residue is partitioned between a saturated ammonium chloride aqueous solution (150 mL) and ethyl acetate (150 mL). The aqueous phase is extracted twice with ethyl acetate (50 mL) and the combined organic phases are dried over sodium sulfate. The organic solution is concentrated to about 100 mL and cyclohexane (300 mL) is added at room temperature. The mixture is filtered at 0-5° C. and the cake is washed three times with cyclohexane (50 mL) and dried under vacuum to afford the title compound as a yellow solid (7.7 g, 88.9%)
Reaction SMILES: Br.NC1C=C(C=C(S(=O)(=O)N)C=1CC1C=CC=CC=1)CBr.C(N)CCC.Br.[NH2:28][C:29]1[C:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:31]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:32]=[C:33]([CH:36]=1)[CH2:34]Br.[CH3:49][NH:50][CH3:51]>>[NH2:28][C:29]1[C:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:31]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:32]=[C:33]([CH:36]=1)[CH2:34][N:50]([CH3:51])[CH3:49]
Reactant: CNC
Reactant: CCCCOc1cc(CBr)cc(N)c1Cc1ccccc1
Agent: Br
Agent: Nc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1
Solvent: CCCCN
Product: CCCCOc1cc(CN(C)C)cc(N)c1Cc1ccccc1

Procedure:
By replacing in Example 110 3-amino-4-benzyl-5-sulfamylbenzylbromide hydrobromide and n-butylamine with 5-amino-4-benzyl-3-n-butoxybenzyl bromide hydrobromide and dimethylamine (40% in water) respectively, and following the procedure described, (5-amino-4-benzyl-3-n-butoxybenzyl)dimethylamine is obtained as a semi-solid material.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])(=[O:13])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2ccccc21

Procedure:
1,3-Dihydro-2H-indol-2-one (35.6 g, 0.268 mol) suspended in acetic anhydride (30 mls) and mixture refluxed for 20 hours. Filtered and washed with diethyl ether (50 mls) dried in vacuo at 80 deg C. to give a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])=[C:6]([CH:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+].O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:17]([S:15]([C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[CH:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])(=[O:24])=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCS(=O)c1ccc(Cl)cc1C1NC(=O)NC1=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCS(=O)(=O)c1ccccc1C1NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.1 %

Procedure:
To a solution of 5-(5-chloro-2-hexylsulfinylphenyl)hydantoin (4.8 g, 0.014 mol) in glacial acetic acid (50 ml) was added potassium permanganate (2.2 g, 0.014 mol) and water (5 ml). The mixture was stirred at room temperature for 45 minutes then poured into 10% sodium bisulfite solution (50 ml). The resulting solution was extracted with ether, the ethereal extract then dried (MgSO4) and evaporated under reduced pressure. The brown oily residue was chromatographed on silica gel and the product eluted with ethyl acetate:hexane (40:60). Evaporation of the eluate under reduced pressure afforded 1.32 g of product as a white solid (26% yield). M.P. 188°-189° C.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[CH2:44][CH2:43][CH2:42]4)[CH:32]=2)[O:11][C@@H:10]1[CH2:48][O:49]CC1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.[Pd]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:48][OH:49])[O:11]2)=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][CH2:42]2
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)CCC4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-((2,3-dihydro-1H-inden-5-yl)methyl)phenyl)-tetrahydro-2H-pyran (122) (425 mg, 0.56 mmol) in THF:MeOH(v/v=1:1)(8 mL) at room temperature was added Pd/C. The mixture was stirred under H2 for 2 h, Pd/C was removed by filtration and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to furnish the title compound (42 mg, 0.10 mmol, 18%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN1C(=O)CCC1>CCOC(C)=O>[F:11][C:12]1([F:18])[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1nc(Cl)ncc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nc(N2CCC(F)(F)CC2)ncc1F
Temperature: 120 °C

Procedure:
A 5 mL microwave vial was charged with 2-chloro-5-fluoro-4-methylpyrimidine (JOC 2004, 69, 3943-3949) (0.19 g, 1.3 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.5 mmol) and NMP (2.6 mL). The mixture was heated in a microwave oven at 120° C. for 24 hours then cooled to ambient temperature. The mixture was then diluted with EtOAc, washed with water (3×), and brine. The organic extract was concentrated and purified by chromatography (silica gel, 0-5% EtOAc/hexanes gradient) to afford the title compound. MS (ESI) m/z: 232.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[C:3]1=[O:28].CCN(CC)CC.[C:36](Cl)(=[O:40])[CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[C:36]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:13][N:4]3[C:5](=[O:12])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]([CH3:1])[C:3]3=[O:28])[CH2:15][CH2:16]2)=[O:21])[CH2:23][CH2:24]1)(=[O:40])[CH2:37][CH2:38][CH3:39]
Reactant: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)N3CCNCC3)CC2)c(=O)c2ccccc21
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)c4ccccc4n(C)c3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.26 mmol) of 1-Methyl-3-[trans-4-(piperazine-1-carbonyl)-cyclohexylmethyl]-1H-quinazoline-2,4-dione was dissolved in DCM (3 ml). 75 μL (0.52 mmol) of Et3N and then 41 μL (0.39 mmol) of butyryl chloride were added and the mixture was stirred at room temperature overnight. The solution was washed with a 0.4 M solution of Na2CO3, the organic phase was separated and dried over Na2SO4. The solvent was removed under reduced pressure and the crude material purified by column chromatography using acetone as eluent. In total 28 mg (yield 24%) of the titled compound were isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1)CCC>>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:23]=[CH:22][N:21]2[C:17]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=3)=[CH:18][N:19]=[C:20]2[N:25]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 14 %

Procedure:
2-Chloro-6-trifluoromethylpyridine (385 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 7-trifluoromethyl-3-(6-trifluoromethyl-pyridin-2-yl)imidazo[1,2-α]pyrimidine (65 mg) as a white solid: δH (360 MHz, DMSO) 7.89 (2H, d, J 7.4), 8.27 (1H, t, J 7.9), 8.46 (1H, d, J 7.4), 9.01 (1H, s), 10.26 (1H, d, J 7.4); m/z (ES+) 333 (M++H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].O1CCOCC1>[Cu]Br>[CH2:18]([O:17][C:11]([CH:12]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:13](=[O:14])[CH3:15])=[O:16])[CH3:19]
Reactant: O=C(O)c1ccccc1Br
Reactant: CCOC(=O)CC(C)=O
Agent: [Cu]Br
Solvent: C1COCCO1
Product: CCOC(=O)C(C(C)=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold (ice/water bath) stirred mixture of 2-bromobenzoic acid (20.1 g, 0.1 mol) and ethyl acetoacetate (13.01 g, 0.1 mol) in 1,4-dioxane (200 ml) sodium hydride (8 g, 0.2 mol, 60% dispersion in mineral oil) was added in small portions. After addition the cold bath was removed and the reaction mixture was allowed to stir at ambient temperature for 10 min. Copper (I) bromide (15.2 g, 0.106 mol) was added in portions and the obtained mixture was heated at reflux for 1 h. It was allowed to cool and stirred overnight at ambient temperature. The obtained green suspension was quenched with ethyl acetate (200 ml) and ice (300 g) and acidified with concentrated HCl (50 ml). The organic phase was washed with aq. 2 M HCl (2×100 ml) and brine, dried (Na2SO4) and evaporated in vacuo. The remaining mineral oil was removed by decantation after shaking with heptane (3×100 ml) and evaporation. Yield ca. 20 g, pale-yellow oil. The crude product was used in the next step without further purification. LC-MS (m/z) 205 ([M−CO2]+); tR=0.91. 1H NMR (500 MHz, DMSO-d6): mixture of at least 3 tautomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[Br:13]Br>ClCCl>[Br:13][C:3]1[C:2]([F:1])=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: O=C1COc2ccc(F)cc2N1
Reactant: BrBr
Solvent: ClCCl
Product: O=C1COc2cc(Br)c(F)cc2N1
Temperature: 30 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
30.0 g of 6-fluoro-4H-benz[1,4]oxazin-3-one are initially charged in 300 ml of dichloromethane, and 37.4 g of bromine are then slowly added dropwise at room temperature. The mixture is heated at 30° C. with stirring for 15 h. The reaction solution is cooled to room temperature and poured onto ice. The aqueous phase is extracted repeatedly with dichloromethane. The combined organic phases are washed with saturated sodium thiosulphate solution, dried over magnesium sulphate and concentrated. This give 44.1 g (yield 99.5% of theory) of 7-bromo-6-fluoro-4H-benz[1,4]oxazin-3-one of melting point 244° C.
Reaction SMILES: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl.ClOC(N(C)C)=[N+](C)C.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:36])[C:23]=1[S:24][C:25]1[S:29][C:28]([C:30]([OH:32])=O)=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34].[CH:37]([NH2:40])([CH3:39])[CH3:38].C(N(CC)CC)C>ClCCl>[Cl:36][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:17])[C:23]=1[S:24][C:25]1[S:29][C:28]([C:30]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:32])=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)N
Agent: CN(C)C(OCl)=[N+](C)C
Agent: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
Chloro-1,1,3,3-tetramethyluronium hexachloroantimonate (47 mg, 0.1 mmol) was added to a suspension of 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (39 mg, 0.11 mmol) in dichloromethane (1 mL) and the mixture was stirred at ambient temperature for 10 min. A solution of isopropylamine (9 mg, 0.12 mmol) and triethylamine (12 mg, 0.12 mmol) in dichloromethane (0.5 mL) was added to the above mixture and was stirred at ambient temperature for over night. After passing through a ISOLUTE™ PE-AX cartridge to remove excess amines, the resulting mixture was concentrated and the residue was purified by reverse-phase HPLC to afford the title product as a white solid (25 mg, 49% yield). 1H NMR (300 MHz, d6-DMSO) δ: 9.0 (2H, s), 8.65 (1H, d), 8.50 (1H, s), 4.0 (1H, m), 1.25 (6H, d). MS m/z: 391.70, 393.80 [M+H]+.
Reaction SMILES: C([NH:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12])(=O)C.Cl.O.[OH-].[Na+]>CO>[NH2:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12]
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=NNC(=O)N(N)C1
Temperature: 5 °C

Procedure:
85 g of 4-acetylamino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine in 250 ml of methanol are stirred together with 63 ml of hydrochloric acid(37%) for 4 hours at 50° C. After cooling to 5° C., 250 ml ofice cold water and 125 ml of sodium hydroxide solution (50%) are added. Thesolvent is removed by evaporation in vacuo. The residue is taken up in 100 ml of ethanol, and the solvent is removed again in vacuo. The residue is taken up in 1200 ml of acetonitrile, undissolved salt precipitates are removed by filtration, the filtrate is concentrated to a small volume, theresidue is caused to crystallise by adding 100 ml of acetic acid ethyl ester at 0° C., and the colourless crystals are filtered off and dried yielding 60.4 g (92% of the theoretical amount) of the title compound having a melting point of 118°-120° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[NH:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:31]1[C:32]([CH2:34][C:35]([NH:1][CH:2]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:36])=[CH:33][N:29]=[CH:30]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
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(Cc1cnc[nH]1)NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A flask was charged with 2-amino-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (150 mg, 0.42 mmoles), prepared as in Reference 5, 1H-imidazol-4-ylacetic acid hydrochloride (81 mg, 0.50 mmoles), HATU (188 mg, 0.50 moles) and DMF (1 mL). DIEA (370 μL, 2.1 mmoles) was added and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized H2O. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL) and then deionized water (2×5 mL) and concentrated in vacuo. Product was purified from the residue by preparative HPLC (ammonium acetate/acetonitrile). The purified product was taken up into methanol and the solution was neutralized with basic resin, filtered and concentrated in vacuo to give Compound 142, 2-(2-(1H-imidazol-5-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (118 mg, 60% yield), as a white solid. 1H-NMR (400 MHz, CDCl3): 9.23 (s, 1H), 7.53-7.40 (m, 4H), 7.35-7.27 (m, 6H), 7.08 (t, 1H), 7.00-6.92 (m, 3H), 6.87 (s, 1H), 4.77 (m, 1H), 4.55 (dd, 2H), 4.18 (dd, 1H), 3.70-3.58 (m, 3H). MS (EI) for C27H26N4O4. found 471.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([CH2:32][OH:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34]>CN(C)C=O.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([CH:32]=[O:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34]
Reactant: Cc1cc(CO)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-hydroxymethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (15 mg) in N,N-dimethylformamide (1 mL) was added manganese(IV) oxide (0.3 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give the title compound (12 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[S:9](Cl)([Cl:12])(=[O:11])=[O:10]>CC#N>[Cl:12][S:9]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:11])=[O:10]
Reactant: CCOC(=O)CN
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)CNS(=O)(=O)Cl

Procedure:
To glycine ethylester hydrochloride (5.00 g, 35.8 mmol) in CH3CN (200 mL), was added sulfuryl chloride (29.00 g, 214.8 mmol), refluxed for 12 hr, and concentrated under reduced pressure. To the reaction mixture, was diethyl ether (100 mL), concentrated under reduced pressure (2×), and dried under vacuum. The resultant was used without further purification.