Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:8])=[O:7].Cl.CN([CH:25]=[C:26]1[C:37]2[C:29](=[CH:30][CH:31]=[C:32]3[C:36]=2[S:35][CH:34]=[N:33]3)[NH:28][C:27]1=[O:38])C>CO.[Pd]>[OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:25]=[C:26]2[C:37]3[C:29](=[CH:30][CH:31]=[C:32]4[C:36]=3[S:35][CH:34]=[N:33]4)[NH:28][C:27]2=[O:38])=[CH:12][CH:11]=1)(=[O:8])=[O:7]
Reactant: CC(C)(CO)CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=C1C(=O)Nc2ccc3ncsc3c21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(CO)CNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Reaction time: 3.5 h
Yield: 70.5 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472–7; Macor, et al., Tetrahedron Letters 1992, 33, 8011–4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI-MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient tempurature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229–230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s, 1H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI-MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: CO[C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[N:4]=1.[NH3:27]>>[NH2:27][C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[N:4]=1
Reactant: N
Reactant: COc1nc2c(=O)[nH]ncc3nn([C@@H]4O[C@H](CO)[C@@H](O)[C@@]4(C)O)cc1c32
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(N)nc3c(=O)[nH]ncc(n1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
The product from Step 6 (20 mg, 0.0551 mmol) was dissolved in liquid ammonia (3 mL) at −78° C. then warmed to ambient temperature in a pressure vessel and stirred for 30 minutes. The reaction was then cooled to −78° C. and opened to allow the ammonia to evaporate. The residue was purified on Phenomenex-C18 reverse phase HPLC with a 0-50% B gradient over 30 min at 10 mL/min (Buffer A=H2O, Buffer B=acetonitrile) to afford 11 mg (57%) of the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3]O.C(=O)([O-])[O-:6].[Ba+2].[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH:25]=[C:26]2[S:30][C:29](=S)[NH:28][C:27]2=[O:32])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:13])[CH3:12]>C(O)C.O>[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH:25]=[C:26]2[S:30][C:29]([NH:3][CH2:2][OH:6])=[N:28][C:27]2=[O:32])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CNO
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Ba+2]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=C2SC(NCO)=NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 104.8 %

Procedure:
A mixture of N-methylhydroxylamine hydrochloride (12.52 g, 0.15 mole), barium carbonate (14.8 g, 0.075 mole), ethanol (50 mL), and water (50 mL) is stirred at room temperature for ten minutes. 5-[(3,5-bis (1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-thioxo-4-thiazolidinone (see Ikuo Katsumi et al Chem. Pharm. Bull., 34(4), 1619-1627 (1986)) (17.5 g, 0.05 mole) and ethanol (600 mL) are added to it and the resulting mixture is stirred and refluxed for 8 hours. The reaction mixture is then cooled, filtered, and the solvent is removed at 45° C. under reduced pressure. The residue is treated with ice-water and the resulting solid is separated by filtration, washed with water and extracted with methylene chloride. The organic layer is dried and concentrated to give 19 g of a residue. The residue is flash chromatographed over silica gel (214 g), eluting first with methylene chloride and then with methylene chloride-methanol (9:1) to give 11.5 g of the pure product. It is recrystallized from methanol-ethyl acetate, to give 8.6 g (48%) of 5-[[2,6-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-(hydroxymethylamino)-4(5H)-thiazolone,(Z)-, mp 199°-200° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21](O)=[O:22].[Cl:24]C1C(Cl)=C2C(CC(C3CCCC3)(C)C2=O)=CC=1CC(O)=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([Cl:24])=[O:22]
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CC1(C2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
The preparation is carried out by following substantially the procedures described in Example 1, Step C except that an equimolar amount of (+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo- 1H-inden-5-yl)oxy]acetic acid is substituted for the (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid used in Example 1, Step C. There is thus obtained first the (+)-enantiomers of the diastereomers of [(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-acetyl chloride and then (+)-enantiomers of the diastereomers of [(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetamide.
Reaction SMILES: CN(C)[CH:3]=[O:4].[CH2:6]([C:9]1[NH:13][C:12](=O)[CH2:11][N:10]=1)[CH2:7][CH3:8].O=P(Cl)(Cl)[Cl:17].[OH-].[Na+]>ClC1C=CC=CC=1>[CH2:6]([C:9]1[NH:13][C:12]([Cl:17])=[C:11]([CH:3]=[O:4])[N:10]=1)[CH2:7][CH3:8]
Reactant: CN(C)C=O
Reactant: CCCC1=NCC(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: CCCc1nc(C=O)c(Cl)[nH]1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
N,N-dimethylformamide (7.04 g, 96.3 mmol) was added to a mixture of 2-n-propyl-3,5-dihydroimidazol-4-one (4.49 g, 35.6 mmol) and POCl3 (14.76 g, 96.3 mmol) in chlorobenzene (40 ml) at 100° C. The mixture was heated for 2 hours at 100° C., cooled and poured on 40 g of ice. The mixture was adjusted to pH 1 by the addition of 30 percent sodium hydroxide solution (22.5 ml) and the phases were separated. The aqueous phase was extracted twice with 40 ml of ethyl acetate each and the combined organic phases were washed with water (20 ml) and filtered on silica gel. After removal of the solvent from the filtrate, 2.79 g of a light brown solid was obtained. Recrystallization from ethyl acetate/petroleum ether yielded the title compound (2.04 g, 33 percent). The product had a melting point of 133.3° to 137.5° C. Other data concerning the product was:
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[SH:50][C@@H:51]1[CH2:55][N:54]([C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=2)=[O:57])[C@H:53]([C:69]([N:71]2[CH2:74][CH:73]([N:75]3[CH:79]=[N:78][CH:77]=[N:76]3)[CH2:72]2)=[O:70])[CH2:52]1>C(#N)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[C:16]([S:50][C@@H:51]3[CH2:55][N:54]([C:56]([O:58][CH2:59][C:60]4[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=4)=[O:57])[C@H:53]([C:69]([N:71]4[CH2:72][CH:73]([N:75]5[CH:79]=[N:78][CH:77]=[N:76]5)[CH2:74]4)=[O:70])[CH2:52]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC(n2cncn2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(n5cncn5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 3 h
Yield: 54 %

Procedure:
886 mg of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) was dissolved in 10 ml of dry acetonitrile, and 0.26 ml of diisopropylethylamine and 873 mg of (2S,4S)-4-mercapto-2-[3-(1-1,2,4-triazolyl)-1-azetidinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 120) dissolved in 5 ml of acetonitrile were added dropwise at the same time to the resulting solution, whilst ice-cooling. The mixture was then stirred at the same temperature for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was diluted with ethyl acetate. The resulting mixture was washed with water, with an aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride. The aqueous layer was dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using a gradient solution method, with mixtures of ethyl acetate and methanol ranging from 6:1 to 4:1 by volume as the eluent, to obtain 661 mg of the title compound, as a powder.
Reaction SMILES: [Na].C([C:4](CC)([C:8]([O-:10])=O)[C:5]([O-:7])=[O:6])C.[C:13]1(=[C:19]([C:23]#[N:24])[C:20]([NH2:22])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[CH2:26](O)[CH3:27]>>[C:23]([CH:19]1[C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:4]([C:5]([O:7][CH2:26][CH3:27])=[O:6])[C:8](=[O:10])[NH:22][C:20]1=[O:21])#[N:24]
Reactant: CCO
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: N#CC(C(N)=O)=C1CCCCC1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C1C(=O)NC(=O)C(C#N)C12CCCCC2
Reaction time: 1 h

Procedure:
0.69 g of sodium metal are suspended in 30 ml of anhydrous ethanol in a 100 ml flask equipped with a magnetic stirrer, thermometer and condenser, in a nitrogen atmosphere. When the sodium has dissolved, 4.8 g of diethylmalonate are added followed, after 15 minutes, by 4.92 g of cyclohexylidenecyanoacetamide. The mixture is left for 1 hour under agitation at 25° C. and then acidified with 36% HCl. The solid obtained is filtered off and dried under vacuum. 6.84 g of ethyl 5-cyano-2,4-dioxo-3-azaspiro[5,5]undecane-1-carboxylate are obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])=[C:15]([CH2:18][O:19][C:20]([O:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(C)C)(C)C>ClCCl.FC(F)(F)C(O)=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([OH:34])=[O:33])=[C:15]([CH2:18][O:19][C:20]([O:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)Oc3ccc([N+](=O)[O-])cc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)Oc3ccc([N+](=O)[O-])cc3)CS[C@H]12
Reaction time: 0.83 h

Procedure:
To a solution of benzhydryl 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate (6.79 g, 0.01 mol) in dichloromethane (14 ml), trifluoroacetic acid (17 ml) was added dropwise under ice cooling, followed by stirring for 50 minutes. The reaction mixture was poured into diisopropyl ether. The precipitate thus obtained was collected by filtration, washed with diisopropyl ether and dried in air, whereby 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid was obtained (yield: 4.50 g; 87.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([OH:20])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CN1CCCC1=O>[Cl:1][C:2]1[C:3](=[O:21])[N:4]([O:20][CH3:22])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:17])[F:18])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2c(F)cc(Cl)c(=O)n2O)c(Cl)c1OC(F)F
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: COn1c(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc(Cl)c1=O
Yield: 62.5 %

Procedure:
0.20 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-5-fluoro-1-hydroxy-[1H]-pyridin-2-one (Example P32) is introduced into 2 ml of N-methylpyrrolidone (NMP) at 22° C. and 0.16 g of anhydrous potassium carbonate is added. With stirring, 0.10 g of methyl iodide in 0.5 ml of NMP is then added dropwise. The reaction mixture is stirred for 2 hours at 22° C. and then partitioned between 20 ml of water and diethyl ether. The separated ethereal phase is washed with brine, dried over sodium sulfate, filtered and concentrated to dryness by evaporation in vacuo. 0.13 g of the desired crude product is obtained in the form of a yellow oil which, after purification by means of flash chromatography (silica gel; eluant: n-hexane/ethyl acetate 1/1 (v/v)), yields 0.08 g of pure product in the form of a colourless oil.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N:16]3[C:24](=[O:25])[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[C:17]3=[O:26])[C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:27])(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N:16]3[C:17](=[O:26])[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[C:24]3=[O:25])[C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:27])#[N:2]
Reactant: NC(=O)CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 78.8 %

Procedure:
N,N-dimethylformamide (3 drops) was added to a mixture consisting of 2-[4-carbamoylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.2 g), toluene (30 ml) and thionyl chloride (0.2 g), and then the mixture was refluxed under heating for 3 hours. After the solvent was concentrated, toluene (50 ml) was added and fully mixed therewith, and then toluene was distilled off. The resulting solid was recrystalled from ethanol to give the desired 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.15 g). mp. 225°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[F:11].[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][NH:15][CH2:14][CH2:12][OH:13])=[CH:4][C:3]=1[F:11]
Reactant: NCCO
Reactant: Fc1cc([C@@H]2CO2)ccc1Cl
Product: OCCNC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.6 %

Procedure:
(R)-2-(4-chloro-3-fluorophenyl)oxirane (1.66 g, 9.62 mmol) was added dropwise to ethanolamine (3.5 mL, 53.9 mmol). The (R)-2-(4-chloro-3-fluorophenyl)oxirane residue was rinsed with 4 mL of THF and this was added to the reaction mixture. The clear solution was stirred at room temperature for 48 h. TLC indicated complete consumption of the starting material. The mixture was treated with water (30 mL) under ice bath and then extracted with ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic phase was washed with water and brine, dried and concentrated in vacuo to afford (R)-1-(4-chloro-3-fluorophenyl)-2-(2-hydroxyethylamino)ethanol (2.06 g) as a colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54 (br. s., 3H) 2.64-2.77 (m, 1H) 2.84 (td, J=5.00, 3.59 Hz, 2H) 2.93 (dd, J=12.27, 3.59 Hz, 1H) 3.72 (t, J=5.10 Hz, 2H) 4.72 (dd, J=8.88, 3.59 Hz, 1H) 7.08 (dd, J=8.31, 1.89 Hz, 1H) 7.20 (dd, J=9.82, 1.89 Hz, 1H) 7.31-7.43 (m, 1H).
Reaction SMILES: [Na].[F:2][C:3]([F:9])([CH:6]([F:8])[F:7])[CH2:4][OH:5].[NH2:10][C:11]1[N+:16]([O-:17])=[C:15]([NH2:18])[CH:14]=[C:13](Cl)[N:12]=1>>[NH2:10][C:11]1[N+:16]([O-:17])=[C:15]([NH2:18])[CH:14]=[C:13]([O:5][CH2:4][C:3]([F:9])([F:2])[CH:6]([F:8])[F:7])[N:12]=1
Reactant: OCC(F)(F)C(F)F
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Agent: [Na]
Product: Nc1cc(OCC(F)(F)C(F)F)nc(N)[n+]1[O-]
Temperature: 90 °C

Procedure:
2 g of sodium are introduced into 100 g of 2,2,3,3-tetrafluoropropanol at 40° C. After the addition of 10 g of 2,4-diamino-6-chloropyrimidine 3-oxide, the reaction mixture is maintained for 32 hours at 90° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH3:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH2:9]([N:16]1[C:20]([Br:1])=[CH:19][N:18]=[C:17]1[CH3:21])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ncc(Br)n1Cc1ccccc1
Reaction time: 6 h
Yield: 84.2 %

Procedure:
Add N-bromosuccinimide (7.85 g, 44 mmol) to a solution of 1-benzyl-2-methyl-1H-imidazole (8.0 g, 46 mmol) in chloroform (200 mL) and stir for 6 h. Wash with saturated aqueous sodium hydrogen carbonate and saturated aqueous NaCl, dry over MgSO4, and filter through a pad of silica gel. Concentrate filtrate and suspend the residue in diethyl ether (600 mL), heat to reflux, and filter hot. Concentrate ether filtrate to give the title compound as a tan solid (9.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-])=O.[NH2:15][C@@H:16]([C:20]([NH2:22])=[O:21])[CH:17]([CH3:19])[CH3:18].Cl.CO.C(N(CC)CC)C>>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:15]([C@H:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH2:22])=[O:21])[C:9]2=[O:14]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (2 g, 0.01 mol) and H-D-Val-NH2HCl (1.9 g, 0.012 mol) were refluxed in methanol (40 mL, 1 mol) with triethylamine (5 g, 0.05 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g of silica gel, 0-30% EtOAc/Hexane) to give a yellow solid. MS m/z 290.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([Br:18])=[N:13][N:12]([CH:19]([CH3:21])[CH3:20])[C:11]2=[O:22])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH2:28]OC.O.[CH3:32][N:33](C=O)[CH3:34]>>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([Br:18])=[N:13][N:12]([CH:19]([CH3:20])[CH3:21])[C:11]2=[O:22])[CH2:27][CH2:28][N:33]([CH3:34])[CH3:32])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)n1nc(Br)c2ccc(NC(=O)OC(C)(C)C)cc2c1=O
Reactant: CN(C)C=O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)n1nc(Br)c2ccc(N(CCN(C)C)C(=O)OC(C)(C)C)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
(1-Bromo-3-isopropyl-4-oxo-3,4-dihydro-phthalazin-6-yl)-carbamic acid tert-butyl ester (0.75 g, 1.96 mmol) was dissolved in DMF (10 ml). To this was added NaH (60%, 0.2 g, 4.9 mmol) as a suspension in DMF (5 ml). The mixture was stirred at RT for 30 min then 1-bromo-2-methoxyethane (0.4 g, 2.9 mmol) was added in one portion as a solution in DMF (5 ml) and the reaction mixture was stirred at RT for 3 hours. After this time, the reaction mixture was cooled to RT and water (20 ml) was added cautiously, the mixture was extracted with EtOAc (3×50 ml), the organic layers were combined, dried (MgSO4), filtered, concentrated under vacuum and the residue subjected to flash column chromatography (elution: 60% heptane, 40% EtOAc) to afford (1-bromo-3-isopropyl-4-oxo-3,4-dihydro-phthalazin-6-yl)-(2-dimethylamino-ethyl)-carbamic acid tert-butyl ester (0.2 g, 23% yield) as a white solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])[CH:9]=[C:10]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20]CC)=O)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)([CH3:5])([CH3:4])[CH3:3].[NH3:35]>CO>[C:18]([CH2:17][N:14]1[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11][C:10](=[CH:9][C:8]2[CH:27]=[C:28]([C:31]([CH3:33])([CH3:32])[CH3:34])[C:29]([OH:30])=[C:6]([C:2]([CH3:3])([CH3:5])[CH3:4])[CH:7]=2)[C:15]1=[O:16])(=[O:20])[NH2:35]
Reactant: CCOC(=O)CN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)Sc2ccccc21
Reactant: N
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3N(CC(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 96 h
Yield: 37.3 %

Procedure:
0.1N hydrochloric acid in methanol (3 ml) was added to a solution of 2-(3,5-di-tert.-butyl-4-hydroxybenzylidene)-3,4-dihydro-4-ethoxycarbonylmethyl-3-oxo-2H-1,4-benzothiazine (Compound No. 1-1, 0.4 g) in 17.85 N ammonia in methanol (15 ml). After the addition, the mixture was stirred for 4 days at 80° C. in a sealed tube and followed by concentration in vacuo. To the residue, dilute hydrochloric acid was added and the whole was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.14 g (37.3%) of the titled compound.