Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1.[NH4+].[Cl-]>CCO.O.C(OCC)(=O)C.[Zn]>[NH2:19][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:22])[O:3][C:2]([CH3:1])([CH3:23])[C:7]=3[CH:8]=2)[NH:16][C:15]=1[C:17]#[N:18]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc([N+](=O)[O-])c(C#N)[nH]3)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(N)c(C#N)[nH]3)cc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 23.6 %

Procedure:
To 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile (0.14 g, 0.45 mmol) in EtOH/H2O (5:1, 20 mL:4 mL) was added Zn powder (0.35 g, 5.3 mmol) and NH4Cl (0.70 g, 13 mmol) and the mixture was heated to 60° C. for 25 minutes. After cooling to room temperature and stirring 24 h, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of celite. The filtrate was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (60% ethyl acetate/hexane) on silica gel gave the product as an orange foam (30 mg, 24%). 1H NMR (500 MHz, d6-DMSO) δ 1.63 (s, 6H), 5.01 (s, 2H), 5.95 (d, 1H, J=2.9 Hz), 6.87 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H, J=2.0, 8.3 Hz), 7.54 (d, 1H, J=2.0 Hz), 10.30 (s, 1H), 11.17 (d, 1H, J=2.5 Hz). MS (ESI) [M−H]− m/z 281.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[O:19][CH2:20][CH2:21][N:10]2[CH2:9][C:8]1=[O:29])(=O)C.[OH-].[Na+].O>CO>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:7]([CH2:6][CH2:5][OH:4])[C:8](=[O:29])[CH2:9][N:10]3[CH2:21][CH2:20][O:19][C:11]3([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:12]=2[CH:17]=1
Reactant: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Reaction time: 3 h

Procedure:
A solution of 0.5g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methanol and water to give 10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo(3,2-d)[ 1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. 141°-146°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12]CC(O)=O)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:30]CC1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][OH:30])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCCn1ccc2ccc(Br)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OCCn1ccc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a 250 mL round bottom flask equipped with a stir bar was added compound (i), above, (3.0 g; 10.6 mmol) and THF (50 mL). The mixture was cooled to 0° C. and diisobutylaluminium hydride (1M in toluene)(42.5 mL; 42.5 mmol) added. The reaction mixture was stirred at room temperature for 2 h, cooled to 0° C. and the quenched with sodium sulfate decahydrate. The resulting thick gel was refluxed for 1 h, after which it was filtered through a pad of celite. Upon removing the solvent in vacuo a yellow oil was isolated, which was subjected to column chromatography on silica gel using hexanes:ethyl acetate (90:10) to yield the title compound as a bright greenish-yellow oil (1.8 g; 71%). 13C NMR (CDCl3): δ136.9, 129.1, 127.5, 122.8, 122.3, 115.3, 122.5, 101.8, 61.7, and 48.7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:42]([NH:45][C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1)([CH3:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:45]([C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]2[CH2:51][CH:50]([OH:52])[CH2:49]2)[CH:42]([CH3:44])[CH3:43])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCC[C@@H](CN1CC(O)C1)NC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](CN1CC(O)C1)N(C(=O)c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a mixture of 4-chlorobenzoic acid (0.067 g, 0.43 mmol) and TBTU (0.137 g, 0.43 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.222 mL, 1.28 mmol). The suspension was stirred at rt for 30 min. A solution of (S)-1-(2-(isopropylamino)pentyl)azetidin-3-ol (Compound O2.1) (0.142 g, 0.43 mmol) in DCM (1 mL) was added and the reaction mixture was stirred at rt overnight. The reaction was washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge. The residue was dissolved in MeOH (2 ml) and 1M NaOH (aq., 0.5 ml) was added. The mixture was stirred at rt for 1.5 h. Acetic acid (110 mg) was added and the mixture was concentrated. The residue was dissolved in DCM (3.5 ml) and washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge and the residue purified by preparative HPLC affording the title compound (20 mg, 14%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.62-0.78, 0.76-0.93, 0.93-1.14, 1.14-1.54, 1.67-1.93, 2.24-2.40, 2.41-2.77, 2.76-2.97, 2.96-3.15, 3.16-3.45, 3.45-3.75, 3.96-4.20, 5.12-5.31, 7.17-7.35, 7.38-7.52. Number of protons: 27. HRMS (M+H)+: calculated 339.1839. found 339.1866
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:25][C@@H:26]1[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:27][C@H:26]([CH3:25])[O:30][C:29]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: C[C@H]1CNC(=O)O1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3)CC2)c(C)c1
Yield: 80.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (435 mg) described in Preparation Example 177 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (330 mg) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][O:4]C(C)(C)C.C(OC([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH:33]([NH:37][C:38](=[O:79])[CH:39]([NH:48][C:49](=[O:78])[CH:50]([S:58]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:34](O)=[O:35])=[CH:24]1)=O)(C)(C)C>>[C:9]([CH:2]([NH:1][C:34]([CH:33]([NH:37][C:38](=[O:79])[CH:39]([NH:48][C:49](=[O:78])[CH:50]([SH:58])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH2:40][C:41]([OH:43])=[O:42])[CH2:32][C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:23][CH:24]=1)=[O:35])[CH2:3][OH:4])([OH:11])=[O:10]
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C(Cc1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC(Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)C(=O)O
Product: O=C(O)CC(NC(=O)C(S)Cc1ccccc1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CO)C(=O)O

Procedure:
The title compound was prepared by condensing H-Ser(But)OBut with the protected dipeptide of Example 88, followed by deprotection and purification by HPLC (40%): (Pos. FAB) ? (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[CH:21]=[C:20]([OH:22])[C:19]2[C:18](=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:24])[C:11](=[O:25])[C:10]=2[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH2:1]([O:5][C:6]([C:8]1[CH:21]=[C:20]([O:22][C:34]([O:36][CH3:37])=[O:35])[C:19]2[C:18](=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:24][C:6]([O:5][CH3:1])=[O:7])[C:11](=[O:25])[C:10]=2[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)Cl
Reactant: CCCCOC(=O)c1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)c1cc(OC(=O)OC)c2c(c1)C(=O)c1cccc(OC(=O)OC)c1C2=O
Reaction time: 3 h

Procedure:
2.7 g (8 mmoles) of the product of Example 15 are dissolved in 100 ml of anhydrous tetrahydrofuran; the resulting solution is added first with 2.42 g (24 mmoles) of anhydrous triethylamine, then, after cooling to 0°-5° C., with 1.6 g (17 mmoles) of methyl chloroformate. The reaction is complete within 3 hours, keeping room temperature. After that, solvent is evaporated off under reduced pressure and the residue is washed with acidulated water, the product is filtered, washed and crystallized from ethyl ether. M.p. 200°-202° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:55][C:56](=[N:68]O)[C:57]1[N:58]=[CH:59][C:60]([C:63]([O:65][CH2:66][CH3:67])=[O:64])=[N:61][CH:62]=1>O1CCOCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:55]=[C:56]([C:57]3[N:58]=[CH:59][C:60]([C:63]([O:65][CH2:66][CH3:67])=[O:64])=[N:61][CH:62]=3)[N:68]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc(C(N)=NO)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(-c2noc(-c3ccc(CC(C)C)cc3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
A mixture of 4-isobutylbenzoic acid (0.28 g, 1.59 mmol), 1-hydroxybenzotriazole (0.042 g, 0.31 mmol), N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.51 g, 1.59 mmol), diisopropylethylamine (1.4 mL, 7.86 mmol) and dioxane (4 mL) was stirred at room temperature for 1 hour. Ethyl 5-[amino(hydroxyimino)methyl]pyrazine-2-carboxylate (0.33 g, 1.57 mmol) was added to the reaction mixture, stirred for 1.5 hours at room temperature and 6 hours at 100° C. The reaction mixture was cooled to room temperature, quenched with H2O (10 mL) and filtered. The precipitate was dissolved in EtOAc (10 mL), washed with 1N NaOH (3×10 mL) and brine (2×10 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (0.15 g, 27%) as a white solid.
Reaction SMILES: O[C:2]1C=C(O)C=C(O)[C:3]=1[CH:10]([C:18](C(C1C(O)=CC(O)=CC=1O)C1C=CC(F)=CC=1)=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.B(F)(F)F.CC[O:43][CH2:44][CH3:45].CS(Cl)(=O)=O.[OH2:51]>CC(N(C)C)=O>[OH:51][C:3]1[C:10]2[C:18](=[O:19])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[C:3]([CH3:2])[O:19][C:18]=2[CH:45]=[C:44]([OH:43])[CH:2]=1
Reactant: O=C(C(c1ccc(F)cc1)c1c(O)cc(O)cc1O)C(c1ccc(F)cc1)c1c(O)cc(O)cc1O
Reactant: O
Reactant: CCOCC
Agent: CS(=O)(=O)Cl
Agent: FB(F)F
Solvent: CC(=O)N(C)C
Product: Cc1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(F)cc1

Procedure:
2,4,6-Trihydroxy-phenyl 4-fluoro-benzyl-ketone (1.31 g, 5 mmole) was dissolved in dimethylacetamide (5.0 ml) and borontrifluoride etherate (2.1 g, 15 mmole) was added cautiously. This solution was then added to a solution of methane-sulphonyl chloride (1.71 g, 15 mmole) in dimethylacetamide (5 ml) and the resulting mixture was heated on the steam batch for 75 minutes. The reaction mixture was poured into cold water (75 ml) and the crystalline diacetate was collected by filtration. The product was hydrolysed by heating in 50% methanolic hydrochloric acid (20 ml, 5N) at reflux for 1 hour, the solution was poured into excess cold water and the crystalline precipitate was collected and dried to give 5,7-dihydroxy-3-p-fluoro-phenyl-2-methyl-4-oxo-4H-benzopyran, m.p. 222°-223°. NMR of the diacetate confirmed that cyclisation had taken place. The product was identical on T.L.C. with a sample prepared via the standard Allen-Robinson synthesis.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccncc5)CC4)c(Cl)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 42.8 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (19 mg, 0.052 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.16 mmol, 0.16 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.058 mmol, 8 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 42%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 2.52-2.55 (m, 2H, piperazine NCH2), 2.63-2.66 (m, 2H, piperazine NCH2), 3.58 (q, J=6.7 Hz, CHCH3), 3.68 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H, methoxyphenyl H-2 & H-6), 7.39 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5), 8.06 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.11 (d, J=8.9 Hz, 2H, methoxyphenyl H-3 & H-5), 8.54 (d, J=6.0 Hz, 2H, pyridine H-2 & H-6), 13.30 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([F:27])[CH:20]=[C:19]([F:28])[C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([C:23]([F:24])([F:26])[F:25])=[C:21]([F:27])[CH:20]=[C:19]([F:28])[C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1c(F)cc(F)c(C(F)(F)F)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)cc(F)c(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.58 g (0.024 mol) of magnesium filings are introduced into 1.3 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 3.4 g (0,019 mol) of diethyl malonate in 2.4 ml of ethanol and 9 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50° and 60° C. Stirring is then continued for one hour at 60° C. A solution of 5.8 g (0,027 mol) of 2,4,6-trifluoro-3-trifluoromethylbenzoylchloride in 2.5 ml of toluene is added dropwise at -10 to -5° C., and stirring is continued for one hour at 0° C. and subsequently while the mixture comes to room temperature. The batch is poured into 10 ml of ice-water, treated with 1.5 ml of concentrated sulphuric acid, and the mixture is extracted using toluene. The toluene phase is washed using saturated sodium chloride solution, and the solvent is removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[C:15]([O:21][C@H:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[C:15]([O:21][C@H:22]([CH3:27])[CH2:23][N+:24]([O-:33])([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2
Reactant: C[C@H](CN(C)C)Oc1nc(Nc2cc3cccc(Cl)c3cn2)cnc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: C[C@H](C[N+](C)(C)[O-])Oc1nc(Nc2cc3cccc(Cl)c3cn2)cnc1C#N
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
(R)-5-(8-Chloroisoquinolin-3-ylamino)-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (30 mg, 0.078 mmol) was dissolved in DCM (1 mL) and cooled to −10° C. 3-Chloroperoxybenzoic acid (77% wt., 12 mg, 0.086 mmol) dissolved in DCM (1 mL) was added dropwise to the solution. The reaction mixture was stirred at −10° C. for 15 minutes, and was then warmed to room temperature. The reaction mixture was diluted with water, the layers partitioned and the aqueous phase extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated to dryness. The residue was dissolved in methanol and absorbed on to an SPE (TsOH) cartridge. The cartridge was washed with methanol and the compound eluted with 2 M and 7 M ammonia in methanol. Preparative HPLC afforded the title compound (23 mg, 0.057 mmol, 73%). 1H NMR (d6-DMSO, 400 MHz) δ 9.25 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.73-7.71 (m, 1H), 7.57-7.56 (m, 1H), 6.10-6.07 (m, 1H), 4.16-4.10 (m, 1H), 3.77 (br d, 1H, J=14 Hz), 3.43 (s, 3H), 3.28 (s, 3H), 1.44 (d, 3H, J=6.6 Hz). LC-MS (2) Rt=2.20 min; m/z (ESI+) 399 & 401 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=[O:8])[CH2:6][CH3:7])[CH3:2].[Br:10]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[C:5](=[O:8])[CH:6]([Br:10])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(=O)CC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)C(C)Br
Reaction time: 18 h

Procedure:
The 2-oxo-butyric acid ethyl ester prepared above was dissolved in chloroform (100 mL) and bromine (20.964 g, 131.19 mmol) was added dropwise at room temperature. The reaction mixture was allowed to stir for 18 h. Concentration of the reaction mixture under reduced pressure provided 12.0 g of the title compound as an orange oil. 1H NMR (CDCl3) δ 4.39 (q, 2H), 4.32 (q, 1H), 1.88 (d, 3H), 1.39 (t, 3H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].CCOCC>C(Cl)(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CCC(CO)CC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in CHCl3 (30 mL) was added tosyl chloride (3.26 g, 17.1 mmol) and pyidine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at 25° C. for 14 hours after which time the reaction was concentrated in vacuo to yield a wet white solid. To this solid was added ether (50 mL) and the solid was filtered and subsequently washed with additional ether (2×50 mL) The ether layers were pooled, concentrated in vacuo to yield a clear oil which was purified by flash chromatography, on a silica gel column, eluting with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83%) as a white solid. 1H NMR (CDCl3) δ 7.78 (d, J=7.7, 2H), 7.33 (d, J=7.7 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.37 (d, J=6.2, 2H), 2.44 (s, 3H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H), 1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7, 38.0, 29.1, 26.5, 22.1, 18.9, −4.9; APCI m/z (rel intensity) 413 (MH+, 100).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][C@H:23]1[CH2:34][OH:35])=[O:21])([CH3:18])([CH3:17])[CH3:16].O[C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][C@H:23]1[CH2:34][O:35][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Yield: 149 %

Procedure:
DIAD (0.64 ml, 3.25 mmol) was added dropwise while stirring a mixture of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (1.16 g, 3.25 mmol), methyl 4-hydoxybenzoate (494 mg, 3.25 mmol) and triphenylphosphine (852 mg, 3.25 mmol) in THF (30 ml) at room temperature in a nitrogen gas stream. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 20 minutes and at 80° C. for 8 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (silica gel: 200 g), whereby from chloroform/acetone (20/1) eluate fractions, the title compound (2.07 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](S(O)(=O)=O)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[S:18]([Cl:21])(Cl)=[O:19].CN(C=[O:26])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:18]([Cl:21])(=[O:19])=[O:26])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(O)c1cc(Br)ccc1-c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A 500 mL round-bottom-flask equipped with an addition funnel, stirring bar, and gas inlet was charged with the 4-bromo-biphenyl sulfonic acid, DMF (200 mL) then purged with nitrogen. The flask was chilled in an ice-bath and thionyl chloride (45 mL, 0.62 mol) was added dropwise to the solution from the addition funnel. The flask was allowed to warm to room temperature and stirred for 3 hours. The solution was poured into 2 L ice water to precipitate the product, which was collected by vacuum filtration. The solids were dissolved in ether and the solution was dried with magnesium sulfate, filtered, and evaporated on a rotary evaporator. The resulting solids were dried under vacuum to give 59.66 g (84% yield) and recrystallized from hot toluene (100 mL) by adding cyclohexane (250 mL). The crystals were collected, washed with cyclohexane, and dried under vacuum to give 55.20 g of 4′-bromo-biphenyl-4-sulfonyl chloride (78% yield).