Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C:11]4([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCCOC3)Oc3ccc(-c4cc(F)cc(F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 30.1 %

Procedure:
In a 10 mL flask, 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (30 mg, 0.08 mmol), Pd(PPh3)2Cl2 (15 mg), 3,5-difluorophenylboronic acid (25 mg, 0.16 mg) were dissolved in 1,4-dioxane (4.0 mL), followed by addition of Cs2CO3 (2 N, 1 mL). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 6-(3,5-difluorophenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (10 mg, 30%). 1H-NMR (MeOD): 1.62 (m, 2H), 1.96 (m, 3H), 2.70 (m, 1H), 3.30 (s, 3H), 3.38 (m, 4H), 3.83 (m, 2H), 4.12 (m, 2H), 6.84 (m, 1H), 6.96 (m, 1H), 7.18 (m, 2H), 7.64 (m, 1H), 7.86 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([CH:38]=[CH:39][CH:40]=4)[O:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:41])=[N:7]1>Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:40]=[CH:39][CH:38]=[C:23]([O:24][CH:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:41])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(OC4CCN(C(=O)OC(C)(C)C)CC4)c3)cc12
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(OC4CCNCC4)c3)cc12
Yield: 49.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)piperidine-1-carboxylate (80 mg, 0.134 mmol) was deprotected in HCl in methanol (5 ml). This afforded 33 mg (40.2% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.75-8.60 (bs, 1H), 8.37 (s, 1H), 7.66 (s, 1H), 7.48-7.44 (t, 1H), 7.42-7.37 (q, 1H), 7.33-7.29 (m, 2H), 7.11-7.04 (m, 3H), 6.93-6.91 (d, 1H), 5.41 (s, 2H), 4.85-4.82 (m, 1H), 3.48-3.41 (m, 2H), 3.28-3.23 (m, 2H), 2.25-2.28 (m, 8H), 2.12-2.06 (m, 2H). MS: m/z=496.3 (M+1), HPLC: 96.84% in method A.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=3)[N:10]=2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:32])C=CN=C1.C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[O:32])[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3c(O)cccc3F)nc2c1
Reactant: O=C(OCc1ccncc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)OCc4ccncc4)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg, 0.15 mmol), (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (53 mg, 0.26 mmol) and triethylamine (30.4 mg, 0.3 mmol) were added into a tube, followed by the addition of DMSO (1 mL). The mixture was stirred at room temperature for 18 h and then filtered, and purified via preparative reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) giving (pyridin-4-yl)methyl 4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate. LC/MS: m/z 474.30 (M+H)+ at 1.19 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)[C@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](COS(C)(=O)=O)[C@H](O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-3-hydroxy-4-hydroxymethylpiperidine (6.5 g) and triethylamine (5.87 ml) in dichloromethane (100 ml) was added dropwise methanesulfonyl chloride (3.54 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to give 4.44 g of cis-l-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpiperidine and 0.93 g of trans-1-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpiperidine.
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:12](=[O:26])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C@@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.CN1CCOCC1.Cl>C(OCC)(=O)C>[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C@@H:34]([NH:36][C:12](=[O:26])[C@H:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:35])=[CH:30][CH:29]=1
Reactant: O=C(CC[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1)OCc1ccccc1
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1ccc([C@H](C)NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
(S)-3-Benzoyl-4-benzyloxycarbonylethyl-2,5-oxazolidinedione (L-N-benzoyl-O-benzylglutamic acid-NCA)(100 mg, 0.27 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (37 mg, 0.27 mmol) and N-methylmorpholine (28 mg, 0.27 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (106 mg, 85%) as white crystals.
Reaction SMILES: [CH3:1][O-].[Na+].[OH:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]1=[O:11].C[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[NH:16].O>CO>[O:11]=[C:6]1[CH2:7][CH2:8][C:9](=[O:10])[N:5]1[O:4][C:15](=[N:16][CH3:1])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:13]=1
Reactant: Cc1ccccc1C(=N)Cl
Reactant: O=C1CCC(=O)N1O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN=C(ON1C(=O)CCC1=O)c1ccccc1
Yield: 43.8 %

Procedure:
1.7 g (0.03 mol) of sodium methylate are added to a solution of 3.45 g (0.03 mol) of N-hydroxy succinimide in 25 ml of methanol. The reaction mixture is stirred for one h, concentrated under vacuo and the residue is taken up in 15 ml of DMF. 4.6 g (0.03 mol) of methyl benzimidoyl chloride are added on stirring. The reaction mixture is stirred at room temperature for 12 h and then poured into 120 ml of water. The so formed precipitate is sucked off and dried in vacuo to obtain 3.8 g of a crude product which is then taken up and recrystallised in 9 ml of toluene to give 3.05 g of N-methyl-benzimidic acid 2,5-dioxopyrrolidine-1-yl ester in form of colorless crystals; mp. 119-120° C.
Reaction SMILES: C(OC(=O)CNC(=O)[C@H](CC1C=CC([N+]([O-])=O)=CC=1)NC(OC(C)(C)C)=O)C1C=CC=CC=1.[O:34]=[C:35]([CH3:43])[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=O.[CH2:44]([O:51][C:52](=[O:70])[CH2:53][NH:54][C:55](=[O:69])[C@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=1)[NH:57][C:58](=[O:60])[CH3:59])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CO>[CH2:44]([O:51][C:52](=[O:70])[CH2:53][NH:54][C:55](=[O:69])[C@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([NH:68][C:40](=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][C:35](=[O:34])[CH3:43])=[CH:64][CH:63]=1)[NH:57][C:58](=[O:60])[CH3:59])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(=O)CCCCC(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)NCC(=O)OCc1ccccc1
Solvent: CO
Product: CC(=O)CCCCC(=O)Nc1ccc(C[C@H](NC(C)=O)C(=O)NCC(=O)OCc2ccccc2)cc1

Procedure:
The mixed anhydride coupling was performed as described for the synthesis of compound 13 with 6-oxo-n-heptanoic acid (97 mg, 0.67 mmol) and the product from above, compound 15 (238 mg, 0.67 mmol). Each component was dissolved in 10 ml of dry tetrahydrofaran. Yield 111 mg (34%), mp 177.5°-180.5° C., [α]D25 =+19.5 (c.=1.4, methanol). Anal. calc. for C27H33N3O6 (493.58): C, 65.44; H, 6.71; N, 8.48. Found: C, 65.46; H, 6.74; N, 8.61.
Reaction SMILES: N.Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH2:13][CH2:14][C:15]#[N:16]>>[CH3:12][O:11][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][C:7]=1[O:9][CH3:10])[CH:14]([C:15]#[N:16])[CH2:13]2
Reactant: COc1cc(Br)c(CCC#N)cc1OC
Agent: N
Product: COc1cc2c(cc1OC)C(C#N)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a solution of NaNH2, prepared starting from 200 mL of liquid NH3 and 1 g of Na (catalyst: FeCl3) there are added, in portions, 5.4 g of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile and the reaction mixture is stirred at ambient temperature for 2 hours. After evaporating off the excess NH3, 2 g of NH4Cl and 200 mL of water are added in portions. The grey crystals formed are collected and recrystallised from ethanol to yield 2.38 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[OH:12].CN(C)C=[O:16]>C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[CH3:1][O:2][C:3]1[C:4](=[O:12])[CH:5]=[C:6]([CH3:11])[C:7](=[O:16])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C)cc(O)c1OC
Reactant: CN(C)C=O
Agent: [Co+2]
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Product: COC1=C(OC)C(=O)C(C)=CC1=O

Procedure:
To a dimethylformamide solution (30 ml) of 2,3-dimethoxy-5-methylphenol (3 g) is added bis(salicylidene)ethylenediiminocobalt(II) (35 mg) and the mixture is reacted and worked up in the same manner as Example 7. The resultant crude crystals are recrystallized from hexane. The above procedure yields 2,3-dimethoxy-5-methyl-1,4-benzoquinone (2.13 g) as orange-yellow needles melting at 59° C.-60° C.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.C([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[CH:22]=[C:23]([CH3:25])[CH3:24])(C)(C)C.[OH2:26]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH3:24][C:23]([OH:5])([CH3:25])[CH:22]([C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][CH:13]=1)[OH:26]
Reactant: CC(C)=Cc1ccc([N+](=O)[O-])cc1C(C)(C)C
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: CC(C)(O)C(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of N-methyl morpholine-N-oxide (1.5 g, 12.8 mmol) in 4.5 mL of water was added a solution of tert-butyl 1-(2-methylprop-1-enyl)-4-nitrobenzene (1.5 g, 8.5 mmol) in acetone/water (5:1, 36 mL), followed by the addition of a solution of osmium tetraoxide in water (2 mL, 4%). This mixture was allowed to RT and stirred for 16 h. The reaction was quenched by sat. Na2SO3. aq (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuo. The crude product (1.7 g, yield 100%) was obtained as a yellow foam, which was directly used into the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ ppm 8.20 (d, 2H, J=9.2 Hz), 7.57 (d, 2H, J=9.2 Hz), 4.63 (d, 1H, J=2.4 Hz), 2.69 (d, 1H, J=3.2 Hz), 2.03 (d, 1H, J=3.2 Hz), 1.19 (s, 3H), 1.08 (s, 3H).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=2)[N:10]=[N:9]1)C>CO.O>[Br:19][C:15]1[N:14]=[C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][CH2:6][OH:5])[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cn1cc(-c2cccc(Br)n2)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCCn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaBH4 (60 mg, 1.58 mmol) in MeOH (3.0 mL) at room temperature was added ethyl[4-(6-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetate (245 mg, 0.79 mmol) in MeOH (7.0 mL) The reaction was stirred at room temperature for 2 h. It was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (20-100% EtOAc/hexanes) afforded the title compound as a colorless gum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]1[C:17]([C:21]2[C:30]3[N:29]=[CH:28][CH:27]=[N:26][C:25]=3[C:24]([C:31](O)=[O:32])=[CH:23][CH:22]=2)=[CH:18][S:19][CH:20]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:31]([C:24]3[C:25]4[N:26]=[CH:27][CH:28]=[N:29][C:30]=4[C:21]([C:17]4[C:16]([CH3:15])=[CH:20][S:19][CH:18]=4)=[CH:22][CH:23]=3)=[O:32])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: Cc1cscc1-c1ccc(C(=O)O)c2nccnc12
Product: Cc1cscc1-c1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)nc2)c2nccnc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt, using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid (Example 67). Title compound: ESI-MS: 445.0 [M+H]+; tR=3.42 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[O:15][CH3:16].F>>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[O:6][CH:7]([CH3:12])[CH2:8][C:9]2=[O:11]
Reactant: COc1cc(OC(C)CC(=O)O)ccc1Cl
Agent: *CC*
Agent: F
Product: COc1cc2c(cc1Cl)C(=O)CC(C)O2
Reaction time: 72 h

Procedure:
In a polyethylene bottle were combined 3.3 g (13 mmol) 3-(4-chloro-3-methoxyphenoxy)butyric acid and 30 ml liquid hydrogen fluoride. The reaction mixture was allowed to stand at 23° C. for 72 hours, then poured over ice and extracted with 2×100 ml diethyl ether. The ether was washed with 2×100 ml water, 100 ml saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo to give the product as a yellow solid, 2.7 g (93%).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH2:19][CH2:18]1.C1C[O:37][CH2:36]C1>>[CH3:16][C:11]1[CH:10]=[C:9]([CH2:8][CH:2]([NH:1][C:36]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:33])[CH2:21][CH2:22]2)=[O:37])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: C1CCOC1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CCOC(=O)C(N)Cc1ccc(C)c(C)c1
Product: CCOC(=O)C(Cc1ccc(C)c(C)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.0 g (57.9 mmol) CDT were added to the solution of 11.0 g (49.7 mmol) ethyl 2-amino-3-(3,4-dimethyl-phenyl)-propionate in 250 mL THF cooled in the ice bath, stirred for 1 h while cooling with an ice bath and for 1 h at RT. Then 12.7 g (54.7 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one was added, the reaction mixture was refluxed for 2.5 h and evaporated down under reduced pressure. The residue was distributed between saturated NaHCO3 solution and EtOAc and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated down under reduced pressure.
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH:11]=[CH2:12].[NH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=4[C:28](=[O:37])[N:27]4[CH2:38][CH2:39][CH2:40][C@H:26]4[C:25]=23)[N:17]=1>C(Cl)Cl>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=4[C:28](=[O:37])[N:27]4[CH2:38][CH2:39][CH2:40][C@H:26]4[C:25]=23)[N:17]=1)[CH2:6][CH:4]=[CH2:5])[CH:11]=[CH2:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCBr
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c-3ccc(F)c2F)no1
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c-3ccc(F)c2F)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
2.1 ml (10.5 mmol) of N-ethyldiisopropylamine and 0.6 ml (7 mmol) of allyl bromide were added to a solution of 650 mg (1.76 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 40 ml of methylene chloride and the mixture was stirred at room temperature for 20 hours. The reaction solution was subsequently diluted with methylene chloride and washed three times with water. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed twice (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:0.1). There were obtained 625 mg (78%) of (S)-1-[5-(diallylaminomethyl)-1,2,4-oxadiazol-3-yl]-7,8-difluoro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c]-[1,4]benzodiazepin-9-one as a colourless foam, Rf=0.45 (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:0.1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[NH2:10][CH:11]1[CH2:15][CH2:14][N:13]([CH3:16])[C:12]1=[O:17].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:10]/[CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[C:12]2=[O:17])[CH:3]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: CN1CCC(N)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CN1CCC(/N=C/c2cc(Br)ccn2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a stirred solution of 4-bromopyridine-2-carbaldehyde (2232.1 mg, 12 mmol) in anhydrous DCM (60 mL) under nitrogen at room temperature, was added racemic 3-amino-1-methyl-pyrrolidin-2-one (1506.8 mg, 13.2 mmol) [CAS: 2483-65-0] and magnesium sulfate (4500 mg, 37.4 mmol). The resulting mixture was left to stir at room temperature overnight. It was filtered and the filtrate washed with half saturated brine. The organic layer was dried (Na2SO4) and evaporated to give 3-[(E)-(4-bromo-2-pyridyl)methyleneamino]-1-methyl-pyrrolidin-2-one (D1) (3.15 g, 11.2 mmol, 93% yield), as a cream solid;
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:40](Br)[C:41]#[CH:42].CCOC(C)=O>C1COCC1.O>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:42][C:41]#[CH:40])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (500 mg, 1.07 mmol) and K2CO3 (196 mg, 1.6 mmol) in THF (5 mL) was stirred for 1 hour at ambient temperature, and was treated with propargylbromide (120 μL, 1.6 mmol). The resulting reaction mixture was stirred for 24 hours at 60° C. AcOEt and water was added. The phases were separated. The aqueous layer was extracted with AcOEt. The organic layers were washed with water, combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash-chromatography (SiO2, Toluene/AcOEt 7:3) afforded the title compound as a colorless crystalline solid. LC/MS: 506 (M+H)+, 528 (M+Na)+.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([CH3:17])[CH:5]=1)(=[O:3])[NH2:2].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([S:34]Cl)=[O:33]>O1CCOCC1>[CH3:17][C:6]1[CH:5]=[C:4]([C:1]2[O:3][C:32](=[O:33])[S:34][N:2]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: O=C(Cl)SCl
Reactant: Cc1cc(C(N)=O)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nsc(=O)o2)ccc1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a stirring solution of tert-butyl 4-carbamoyl-2-methyl-benzoate (10 g) in mixture of Toluene and Dioxane (3:1, 240 mL) was added potassium carbonate (5.88 g) then chlorocarbonylsulfenyl chloride (5.5 mL). The mixture was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give tert-butyl 2-methyl-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoate (11.12 g) as a solid. 1H-NMR (CDCl3, 400 MHz): δ=7.87-7.96 (m, 1 H), 7.79-7.87 (m, 2 H), 2.63 (s, 3 H), 1.56-1.64 ppm (m, 9 H).