Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:33][C:34](=[O:36])[CH3:35])[C@H:11]([OH:32])[CH2:12][NH:13][C@@H:14]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=3)[O:17][C:16]3([CH2:31][CH2:30][CH2:29]3)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37](OC)(OC)OC.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:33][C:34](=[O:36])[CH3:35])[C@H:11]([OH:32])[CH2:12][N:13]([C@@H:14]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH:22]=3)[O:17][C:16]3([CH2:31][CH2:30][CH2:29]3)[CH2:15]2)[CH3:37])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)N[C@@H](Cc1ccc(F)c(Br)c1)[C@H](O)CN[C@H]1CC2(CCC2)Oc2ncc(CC(C)(C)C)cc21
Reactant: COC(OC)OC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(F)c(Br)c1)[C@H](O)CN(C)[C@H]1CC2(CCC2)Oc2ncc(CC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 15-mL RB flask, N-((1S,2R)-1-((3-bromo-4-fluorophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide (0.027 g, 0.048 mmol) was dissolved in DCM (1.5 mL). Trimethyl orthoformate (0.13 ml, 1.2 mmol) was added, followed by addition of Formaldehyde (37%, 0.0089 ml, 0.12 mmol) as an aqueous solution. The mixture was stirred at ambient temperature for 2 h. Then sodium triacetoxyborohydride (0.036 g, 0.17 mmol) was added, and the mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with 10% aqueous sodium carbonate (5 mL), stirred vigorously for 2 h, and diluted with DCM (60 mL). The organic layer was separated and extracted with dilute brine (5 mL), dried over sodium sulfate and concentrated. The residue was purified by passing it through silica gel (20 g; deactivated with triethylamine (2.0 mL)), eluting with 95% EtOAc-hexane to provide the title compound. MS m/z 576/578 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.O>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: Cc1ccc(CO)cn1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C=O)cn1
Yield: 42.7 %

Procedure:
Chromium trioxide (11.5 g) is slowly added to 170 ml of pyridine at 20° C., and 10 g of the crude 5-hydroxymethyl-2-methylpyridine in 70 ml of pyridine is added in one portion to the complex. The temperature is raised to reflux temperature for 2 hours, and the mixture is refluxed for 1.5 hours. After cooling, 250 ml of water is added, and the mixture is extracted with five 150-ml portions of diethyl ether. The combined extracts are dried over magnesium sulfate and concentrated to give 4.2 g of crude 6-methyl-3-pyridinecarbaldehyde.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH:7]([CH3:14])[CH2:6]2)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl.O>[CH3:14][C@@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH:1]3[CH2:2][O:23]3)[CH:4]=2)[C:9](=[O:13])[O:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)CC(C)OC2=O
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1

Procedure:
A solution of 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one (1.69 g, 8.98 mmol) in DCM (60 mL) was treated with mCPBA (3.100 g, 17.96 mmol) overnight at room temperature. The reaction was then diluted with water (50 mL) and DCM (50 mL). The organic layer was further washed successively with saturated aqueous sodium bicarbonate (30 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated. The residue was purified via MPLC (15-40% EtOAc/Hex) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].[CH2:23]([O:25][CH2:26][C:27]([NH:29][NH2:30])=O)[CH3:24]>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:27]([CH2:26][O:25][CH2:23][CH3:24])=[N:29][N:30]=[C:12]3[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: CCOCC(=O)NN
Solvent: CCCCO
Product: CCOCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-7-nitro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with ethoxyacetic acid hydrazide to give 8-nitro-1-(ethoxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1)[OH:18]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1ccncc1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 5-fluoroindole (3.10 g, 23.0 mmol) in methanol is treated with 4-pyridinecarbox-aldehyde (2.20 ml, 23.0 mmol), then treated with aqueous NaOH (2.5 ml, 50%) at 0° C., stirred for 1 hr at 0° C., warmed to room temperature, stirred for 3 hr. and diluted with water. The resultant mixture is filtered. The filtercake is dried under vacuum to afford the title product as a light yellow solid, 5.2 g (93%) mp 171-173° C., identified by mass spectral and NMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:5]=[CH:6][C:7]=1[Cl:8].O.C(OCC)C.[BrH:24]>>[Br:24][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCCCCCCCc1ccc(Cl)c(Cl)c1
Reactant: Br
Solvent: CCOCC
Solvent: O
Product: Clc1ccc(CCCCCCCCBr)cc1Cl

Procedure:
A solution of 8-(3,4-dichlorophenyl)octan-1-ol (0.66 g) in 48% hydrobromic acid (7 ml) was stirred under reflux for 2 h. Water (20 ml) and diethyl ether (20 ml) were added. The organic layer was separated and the aqueous layer reextracted with diethyl ether (10 ml). The combined organic extracts were washed with water (10 ml), sodium hydrogen carbonate solution (10 ml) and brine (10 ml) and dried over magnesium sulfate. The solution was treated with charcoal, filtered and evaporated under reduced pressure to give 1-bromo-8-(3,4-dichlorophenyl)octane (0.74 g). 1H-NMR (CDCl3) δ 1.2-1.8 (12H, m), 2.55 (2H, t), 3.41 (2H, t), 7.00 (1H, dd), 7.25 (1H, dd) and 7.33 (1H, d).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](I)[CH2:23][CH3:24]>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:22][CH2:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reactant: CCCI
Product: CCCN(C(C)=O)c1cccc2c1CCC(N(CCC)CCC)C2

Procedure:
Starting from 2.88 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 2.04 g (0.012 mol) of n-propyliodide, the title compound is obtained analogously to Example 4.7.1 in the form of a non-crystallising gum in a yield of 2.70 g (89.4% of theory) and with an Rf value of 0.67 (solvent mixture as specified in 4.7.1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:24]2[N:28]=[CH:27][S:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1>>[S:26]1[CH:27]=[N:28][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][C:19]=2[C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)=[N:25]1
Reactant: Brc1cccc(-c2ncsn2)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3-c3ncsn3)cc21
Yield: 35 %

Procedure:
According to procedure B, (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid was coupled with 3-[3-bromo-phenyl]-[1,2,4]thiadiazole to yield 6-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one as an off-white solid (0.5 g, 35%): mp 214-216° C.; 1H-NMR (DMSO-d6) δ10.40 (s, 1H), 10.36 (s, 1H), 8.49 (s, 1H), 8.23 (d, 1H, J=7.7 Hz), 7.83 (d, 1H, J=7.9 Hz), 7.66-7.61 (m, 3H), 7.02 (t, 1H, J=4.4 Hz), 1.70 (s, 6H); MS ((+)APCI) [M+H]+ @ m/z 338.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[N:10][C:9]=2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=O.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[N:10][C:9]=2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=[O:2])[CH3:27]
Reactant: CCN
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)c2s1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NCC)c2s1
Temperature: 100 °C
Yield: 5 %

Procedure:
A stirred mixture of 2-Amino-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (125 mg, 0.439 mmol), ethyl isocyanate (0.21 ml, 2.187 mmol) and dibutyltindiacetate (12 drops) in anhydrous 1,4-dioxane (10 ml) was heated in a sealed vessel at 100° C. for 16 h. After cooling to ambient temperature, the solvent was removed in vacuo to give 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester which was used without further purification. A stirred mixture of 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (78 mg, 0.22 mmol) and aqueous ethylamine solution (70% w/v, 3 ml) was heated by microwave irradiation in a CEM Discover reactor at 100° C. for 1 h. The reaction mixture was purified by Preparative HPLC to provide the 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid ethylamide as a white solid (8.7 mg, 5%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]([CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH3:36])[CH:15]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[C:18]([CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:22])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:31]3[CH:35]=[CH:34][N:33]=[C:32]3[CH3:36])[CH:15]=2)[N:10]=1
Reactant: COc1ccc(CNc2nc3ccc(-n4ccnc4C)cc3cc2CCC(=O)NCC2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccn1-c1ccc2nc(N)c(CCC(=O)NCC3CCCCC3)cc2c1

Procedure:
In a sealed tube was combined 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)propanamide (0.32 g, 0.63 mmol, prepared as in Example 3), copper (II) acetate monohydrate (0.025 g, 0.13 mmol), cesium carbonate (0.61 g, 1.9 mmol), hippuric acid (0.016 ml, 0.13 mmol), 2-methyl-/H-imidazole (0.062 g, 0.75 mmol) and DMF (5 mL). The tube was sealed and heated to 140° C. for 48 h. The mixture was cooled to room temperature, transferred to a flask and concentrated to remove the DMF. Adsorbtion onto silica and purification via flash chromatography (slow gradient, 2-10% MeOH/DCM) provided 3-(2-(4-methoxybenzylamino)-6-(2-methyl-1H-imidazol-1-yl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide. Step 2 A solution of 3-(2-(4-methoxybenzylamino)-6-(2-methyl-1H-imidazol-1-yl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide in TFA (10 mL) was heated at 45° C. for 30 min until complete by LC/MS. After concentrating under reduced pressure to remove the TFA, the oil was dissolved in MeOH and purified by reverse phase HPLC to afford 3-(2-amino-6-(2-methyl-1H-imidazol-1-yl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide. MS (ESI, pos. ion) m/z: 392 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)[Cl:23]>>[Cl:23][CH2:22][CH:24]([OH:26])[CH2:25][N:17]1[CH2:16][CH2:15][N:14]([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1
Reactant: ClCC1CO1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Product: OC(CCl)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
4,4'-Dichlorobenzhydrylpiperazine ((6.0 g, 18.7 mmol) was reacted as above with epichlorohydrin to give the title compound as an amber oil, 3.67 g (49.8%). 100 MHz 1H NMR (CDCl ) δ: 7.3 (s, 8H), 4.2 (s, 1H), 3.9 (m, 1H), 3.6 (d, 2H, J=10 Hz), 2.9 (m, 2H), 2.7-2.4 (m, 10H).
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2N)([O-:7])=[O:6].[F:19][P-](F)(F)(F)(F)F.[H+]>O>[F:19][C:13]1[C:14]2[C:9](=[C:8]([N+:5]([O-:7])=[O:6])[CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc2c([N+](=O)[O-])cccc12
Reactant: F[P-](F)(F)(F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc2c(F)cccc12
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Sodium nitrite (660 mg, 9.57 mmol) was added portionwise to a suspension of 5-nitronaphthalen-1-amine (1.2 g, 6.38 mmol) in a 1:1 mixture of water/concentrated hydrochloric acid (10 mL) at −5° C. The mixture was stirred for 15 min at −5° C. and a 60% w/w hexafluoro phosphoric acid solution (6 mL) was added. The brown precipitate was filtered and washed with cold water and diethyl ether and then allowed to dry in vacuo. The resulting solid was suspended in toluene and heated to 110° C. for 2 h before the mixture was then allowed to cool to ambient temperature and the solvent removed in vacuo to afford the crude product. Purification by column chromatography over silica gel (100-200 mesh) using petroleum ether as eluent afforded 1-fluoro-5-nitro-naphthalene (450 mg, 37%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Mg]Cl)(C)C.[CH2:15]([O:17][C:18](=[O:32])[C:19](=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([CH:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:32])[CH3:24]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Reactant: c1cc2cc[nH]c2cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.9 %

Procedure:
To a RT solution of 1H-pyrrolo[2,3-c]pyridine (595 mg, 5.04 mmol) in THF (20 mL) was added i-PrMgCl (1.5 M in THF, 5.0 mL, 7.6 mmol) followed by ZnCl2 (1M in Et2O, 7.6 mL). The resulting mixture was stirred at RT for 5 min then a solution of 2-benzylidene-malonic acid diethyl ester (2.2 mL, 10 mmol) in THF (20 mL) was added dropwise. The mixture was stirred at RT for 1 hour, quenched by addition of a saturated solution of NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH), affording 2-[Phenyl-(1H-pyrrolo[2,3-c]pyridin-3-yl)-methyl]-malonic acid diethyl ester (0.33 g, 18% yield).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:38])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[CH:18][CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:38])=[CH:21][CH:20]=1)([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of 350 mg (0.66 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 265 mg (96%) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]2[C:21]([CH3:30])=[C:22]([C:26]([F:29])([F:28])[F:27])[C:23]([CH3:25])=[CH:24][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.N1C=CC=CC=1.[CH3:46][O:47][C:48](=[O:52])[C:49](Cl)=[O:50]>ClCCl>[CH3:46][O:47][C:48](=[O:52])[C:49]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]2[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[C:15]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([F:27])([F:28])[F:29])=[C:21]([CH3:30])[C:16]1=2)=[O:50]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)c(C)c21
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Dissolve (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 148, Step 2) (0.200 g, 0.353 mmol) in dichloromethane (4 mL), cool the solution down with an ice-water bath. Add pyridine (0.143 mL, 1.77 mmol) followed by chloro-oxo-acetic acid methyl ester (0.162 mL, 1.77 mmol) dropwise. Warm up the reaction to room temperature and stir overnight. Dilute the reaction mixture with more dichloromethane (10 mL), and wash with aqueous NaHCO3 (10 mL). Extract back the aqueous layer with dichloromethane (10 mL). Combine the organic layers, dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-30%), to provide the title compound (0.187 g, 81%). MS (ES+): 653 (M+H).
Reaction SMILES: C([NH:8][C:9]1([CH2:12][O:13][CH:14]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]2([CH3:22])[CH3:21])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[CH3:21][C:15]1([CH3:22])[CH2:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH:14]1[O:13][CH2:12][C:9]1([NH2:8])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(COC2C(C)(C)CCC2(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(C)(C)C1OCC1(N)CC1
Reaction time: 8 h

Procedure:
N-Boc-O-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-hydroxymethylcyclopropane is dissolved in trifluoroacetic acid and stirred overnight. The solution is poured into water and neutralized with 20% aqueous KOH. The mixture is extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to give O-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-hydroxymethylcyclopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 92.7 %

Procedure:
Prepared according to the procedure described for Example 121 using 3,4-dichlorobenzenesulfonyl chloride (2.45 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol) and pyridine (25 mL) to afford the product (4.183 g); m.p. 191-193° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[C:17]2[C:9]([N:10]3[C:15](=[CH:16]2)[C:14](=[O:19])[NH:13][CH2:12][CH2:11]3)=[N:8][CH:7]=1.[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[C:17]2[C:9]([N:10]3[C:15](=[CH:16]2)[C:14](=[O:19])[NH:13][CH2:12][CH2:11]3)=[N:8][CH:7]=1
Reactant: C[C@H]1CCCN1
Reactant: O=C1NCCn2c1cc1cc(OCCCCl)cnc12
Product: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 2, from 7-(3-chloro-propoxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one and (S)-2-methylpyrrolidine (commercially available), to give the desired product as a colorless solid (19%).
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(#N)C>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[C:7]([C:12]3[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Clc1nccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)cc(-c2nccnc2-c2cc(C)cc(C)c2)c1
Reaction time: 1 h
Yield: 44 %

Procedure:
First, 5.00 g of 2,3-dichloropyrazine, 10.23 g of 3,5-dimethylphenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 2.55 g of 3,5-dimethylphenylboronic acid, 1.80 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and irradiation with microwaves (2.45 GHz, 100 W) was performed again for 60 minutes so that heating was performed. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1. The solvent was distilled off, and the obtained solid was purified by flash column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that Hdmdppr (abbreviation), which was the pyrazine derivative to be produced, was obtained as a white powder in a yield of 44%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is shown in (h-1).