Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1I.[N:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[N:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: N#Cc1nccc(I)c1F
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1nccc(-c2cncnc2)c1F
Temperature: 85 °C
Yield: 44.5 %

Procedure:
A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (3.0 g, 12.10 mmol), pyrimidin-5-ylboronic acid (5.23 g, 42.2 mmol), and cesium carbonate (8.28 g, 25.4 mmol) in dioxane (Ratio: 2.0, Volume: 24.44 ml) and water (Ratio: 1.000, Volume: 12.22 ml) was degassed with N2 for 5 min, then PdCl2(dppf)-CH2Cl2Adduct (0.524 g, 0.641 mmol) was added. The solution was heated at 85° C. for 21 hr, and then allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (120 g column, 85 mL/min, 50-90% EtOAc in hexanes over 25 min, tr=10 min) gave the title compound (1.089 g, 5.39 mmol, 44.5% yield) as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:15])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Nc1nccs1
Reactant: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (187 mg, 0.7 mmol), 2-aminothiazole (70 mg, 0.7 mmol), HBTU (303 mg, 0.8 mmol) and 0.2 mL of Et3N in DMF (5 mL) was stirred at room temperature for 2 hours to provide the title compound, which purified by HPLC. 1H NMR (400 MHz, CD3OD) δ: 8.03 (dd, J=1.2, 8.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.27-7.17 (m, 2H), 7.15 (d, J=4.0 Hz, 1H), 5.76 (dd, J=4.8, 9.2 Hz, 1H), 2.29-2.20 (m, 1H), 2.11-2.01 (m, 1H), 1.61-1.49 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). [M+H] calc'd for C17H18N4O3S, 359; found, 359.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CN1CCNCC1
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(-c3cccc4cc(C(=O)N[C@H]5CN6CCC5CC6)oc34)c2)CC1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 23.5 mg (0.23 mmol) of N-methylpiperazine are reacted together by general method E. 29.6 mg (41.9% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[C:21]1([P:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:2]2[CH2:3][C:4](=[O:6])[NH:5][C:1]2=[O:7])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1C=CC(=O)N1
Solvent: CC(C)=O
Product: O=C1CC(=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Maleimide (0.60 g, 6.05 mmol) and triphenylphosphine (1.57 g, 5.97 mmol) were dissolved in 40 mL of acetone and the reaction mixture was stirred at 65° C. for 1 h. After cooling down to room temperature, the solid was collected by filtration, washed with acetone, and dried to afford compound 11 in 82.5% (1.77 g) yield as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C:17]2[N:18]=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1>CN(C)C=O>[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C:17]2[N:18]=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[C:28]([CH3:34])[C:29]([O:33][CH2:8][CH2:9][OH:10])=[C:30]([CH3:32])[CH:31]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1
Reactant: OCCBr
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCCO)c(C)c3)nc12
Temperature: 60 °C
Yield: 4.9 %

Procedure:
130 mg of potassium carbonate and 32.4 mg of 2-bromo-ethanol were added to a solution of 100 mg of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]2,6-dimethyl-phenol in 3 ml of dimethylformamide. The reaction mixture was heated to 60° C. for 3 h. After filtration, the solvent was removed in vacuo. Preparative HPLC (method HPLC1) of the residue yielded 5.4 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1.C([O-])([O-])=[O:11].[K+].[K+]>O>[F:9][C:5]1[N:4]=[C:3]([CH2:2][OH:11])[CH:8]=[CH:7][CH:6]=1
Reactant: Fc1cccc(CCl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1cccc(F)n1
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 2-chloromethyl-6-fluoro-pyridine I-3c (1.43 g, 9.84 mmol) in H2O (22 mL) was added K2CO3 (1.77 g, 12.8 mmol). The reaction mixture was stirred overnight at reflux. The cooled aqueous mixture was first extracted with heptane (2×20 mL)and then ethyl acetate (2×50 mL). The ethyl acetate layers were combined, washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was chromatographed over silica gel (15 g) using 2% methanol/methylene chloride with 0.5% NH4OH as the eluant to yield 518.7 mg of the title compound (I-3d) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.N.CO>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.7 %

Procedure:
To solution of 2-amino-4-fluorobenzoic acid (4.0 g, 25.8 mmol) in degassed DMF (50 mL) were added HOBt (4.19 g, 31 mmol), DIEA (5.4 mL, 31 mmol), EDCI (5.94 g, 31 mmol) and 2N NH3/MeOH (18 mL, 36.1 mmol). The solution was stirred at rt for 48 h, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 2-amino-4-fluorobenzamide as a solid (2.89 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 6.28 (m, 1H), 6.44 (m, 1H), 6.90 (br s, 2H), 7.08 (m, 1H), 7.58 (m, 1H), 7.71 (br d, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([Cl:2])=[O:25])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCOc1ccc(CC(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(CC(=O)Cl)cc1
Temperature: 80 °C

Procedure:
Phosphorus pentachloride (1.lg, 0.0053 mol) was added to 4-n-octyloxyphenylacetic acid (1.3g, 0.0049 mol) and the mixture was allowed to react by heating at 80° C. POCl3 and excess phosphorus pentachloride were completely removed by evaporation in vacuo to obtain 4-n-octyloxyphenylacetyl chloride. This chloride was dissolved in toluene (10 ml) and to the mixture were added S-(-)-α-(4-n-heptyloxyphenyl)ethyl alcohol (1.0g, 0.0042 mol) and pyridine (1 ml, a dehydrochlorinating agent). The mixture was permitted to stand for 10 hours at room temperature, warmed at 60° C. and maintained as such for 3 hours, and then cooled. The resulting mixture was added to diluted hydrochloric acid and the resultant was extracted with ether. The ether layer was washed with an aqueous solution of NaHCO3 and then with water, and dried over Na2SO4. The ether was distilled off and the residue was purified by means of a column chromatography (solvent : chloroform) and the resultant was recrystallized from ethanol to obtain the above compound of α-(4-n-heptyloxyphenyl)ethyl 4-n-octyloxyphenylacetate. The infrared spectrum of this compound is shown in FIG. 3. This compound did not show any liquid crystalline phase, and it was a liquid at room temperature. The angle of rotation [α]25D of the compound was -52.4° (solvent : chloroform).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]([O:21][CH3:22])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:23][O:24][C:25]1[CH:32]=[C:31]([CH2:33][CH:34]=O)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([BH3-])#N.[Na+].CC(O)=O>CO.CCOC(C)=O>[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]([O:21][CH3:22])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:34][CH2:33][C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([O:24][CH3:23])[CH:32]=2)[CH2:17][CH2:16]1
Reactant: COC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Reactant: COc1cc(CC=O)ccc1C#N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCN2CCN(CC(OC)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Reaction time: 12 h

Procedure:
4-Methyl-5-[1-(methyloxy)-2-piperazin-1-ylethyl]-2-benzofuran-1(3H)-one hydrochloride (50 mg, 0.17 mmol), 2-(methyloxy)-4-(2-oxoethyl)benzonitrile (60 mg, 0.34 mmol), sodium cyanoborohydride (108 mg, 1.72 mmol) and a stir bar were added to a 25 mL flask and few drops of AcOH. The resulting mixture was then dissolved in MeOH (3 mL) and stirred for 12 h; analysis by LC indicated that reaction had gone to completion. The reaction mixture was treated with EtOAc (20 mL) and washed with aq. NaHCO3, aq. NaCl. The organic phase was then dried over Na2SO4, filtered and concentrated to dryness; the resulting residue was then dissolved in MeOH (3.5 mL), filtered and shot into Mass-directed HPLC for separation to give the desired product. LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cccc(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 3-chloroaniline to yield 2-[(3-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[C:11]([C:27](=[O:29])[NH2:28])[CH:12]=[C:13]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=4)[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)(=O)C.C[O-].[Na+]>CO.CN(C=O)C>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2[CH:12]=[C:11]([C:27]([NH2:28])=[O:29])[C:10]3[NH:9][C:8]4[C:16]([C:15]=3[CH:14]=2)=[CH:17][CH:18]=[C:6]([CH2:5][OH:4])[CH:7]=4)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: CC(=O)OCc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(Cl)c(Cl)c3)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)cc2c1[nH]c1cc(CO)ccc12
Reaction time: 0.5 h
Yield: 48 %

Procedure:
(8-Carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazol-2-yl)methyl acetate (150 mg, 0.211 mmol, Example 139) was dissolved in a mixture of MeOH (3 mL) and DMF (6 mL). To this solution was added sodium methanolate (140 mg, 0.648 mmol) and the reaction left stirring for 0.5 h. The product was isolated by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=90:10 and ending with A:B=30:70 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of solvent to afford 39 mg of 3-(3,4-dichlorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide as a light yellow solid. MS (ESI) m/z 383.1 (M−H). 1H NMR (DMSO-d6) δ ppm 11.44 (1H, s), 8.73 (1H, d, J=1.53 Hz), 8.36 (1H, br. s.), 8.30 (1H, d, J=1.53 Hz), 8.22 (1H, d, J=2.14 Hz), 8.19 (1H, d, J=7.93 Hz), 7.94 (1H, dd, J=8.55, 2.14 Hz), 7.77 (1H, d, J=8.24 Hz), 7.71 (1H, s), 7.56 (1H, br. s.), 7.18 (1H, d, J=7.93 Hz), 5.24 (1H, t, J=5.80 Hz), 4.66 (2H, d, J=5.80 Hz).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([CH2:22][CH2:23]C)[N:18]=1)(C)(C)C>C(Cl)Cl>[CH2:22]([C:19]1[N:18]=[C:17]([CH2:16][CH2:15][NH2:14])[O:21][N:20]=1)[CH3:23]
Reactant: CCCc1noc(CCNC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1noc(CCN)n1

Procedure:
TFA (0.5 ml) is added to a stirred solution of [2-(3-propyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (0.093 g, 0.39 mmol) in DCM (1 ml). After 1 hour the solvents are removed to afford the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([O-])=[O:5].CC(C[AlH]CC(C)C)C.CCOC(C)=O>CCOCC>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH3:14])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: CCOc1cc(C(=O)[O-])c(Br)cc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOc1cc(CO)c(Br)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of 2-bromo-5-ethoxy-4-methylbenzoate (660 mg, 2.23 mmol) in ether (20 mL) at 0° C. was added DIBAL (5.75 mL, 5.75 mmol, 1 M in toluene). The reaction was stirred at 0° C. for 10 minutes. EtOAc (20 mL) and wet silica gel (˜50 g silica gel and 3 mL of water) were added portion wise at 0° C. The resulting slurry was stirred for ˜15 minutes and was filtered, washed with EtOAc (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with EtOAc/hexanes (20/80) to give the title intermediate (550 mg) as colorless liquid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:12][C:13]([CH3:15])=[O:14])=[C:8]([CH:11]=1)[CH2:9]Br)(=[O:3])[CH3:2].[CH2:16]([NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:17]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:12][C:13]([CH3:15])=[O:14])=[C:8]([CH:11]=1)[CH2:9][N:18]([CH2:16][CH3:17])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1CBr
Reactant: CCNC1CCCCC1
Product: CCN(Cc1cc(C(C)=O)ccc1NC(C)=O)C1CCCCC1

Procedure:
5-Acetyl-2-acetamino-N-ethyl-N-cyclohexyl-benzylamine, m.p. 98-100° C was prepared from 5-acetyl-2-acetamino-benzyl bromide and N-ethyl-cyclohexylamine analogous to Example 8.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)=[O:24])[CH:17]=2)([CH2:14][F:15])[N:13]=1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:17]=[C:18]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)=[O:24])[CH:19]=[CH:20][CH:21]=2)([CH2:14][F:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1=N[C@](CF)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1

Procedure:
A solution of 117 mg (0.231 mmol) ((R)-5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester in 2 ml 4N HCl in dioxane was stirred at 45° C. overnight. The mixture was concentrated and crystallized from EtOAc/hexane to yield the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si:19]([O:26][CH2:27][CH:28]1[O:33][CH2:32][CH2:31][NH:30][CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:19]([O:26][CH2:27][CH:28]1[CH2:29][N:30]([C:2]2[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:31][CH2:32][O:33]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCCO1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCOC(CO[Si](C)(C)C(C)(C)C)C2)c1Cl
Temperature: 100 °C
Yield: 42 %

Procedure:
A round bottom flask was charged with tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (2.020 g, 6.09 mmol), (+/−)-2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine (1.692 g, 7.31 mmol), Pd2(dba)3 (0.558 g, 0.609 mmol) and BINAP (0.379 g, 0.609 mmol) in toluene (20.31 ml). The flask was evacuated and purged with nitrogen (4×) and heated at 100° C. 8 h and cooled to room temperature ON. The reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on the ISCO system (80 g, 0-100% EtOAc/CH2Cl2) to provide (+/−)-tert-butyl (3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-5-cyanophenyl)carbamate (1.2321 g) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8]2)=[N:3]1.[Li+].[OH-]>CO.O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8]2)=[N:3]1
Reactant: COC(=O)c1cc(C)c2nn(C)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)cc2cn(C)nc12
Temperature: 50 °C
Yield: 106.7 %

Procedure:
To a solution of methyl 2,7-dimethyl-2H-indazole-5-carboxylate (140 mg, 0.69 mmol) in methanol/water (V:V 1:1, 2 mL) was added LiOH (38 mg, 1.6 mmol). The solution was heated at 50° C. for 1 hour, cooled to room temperature, concentrated and acidified to pH 2 with KHSO4. The solid material was isolated by filtration to provide the title compound as a white solid (140 mg, 107%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH2:19][CH2:20][NH2:21])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8]2.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH2:19][CH2:20][NH:21][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8]2
Reactant: COCOc1c(C)c(C)c2c(c1CCN)CCC(C)(C)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COCOc1c(C)c(C)c2c(c1CCNS(=O)(=O)c1ccc(C)cc1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 37.2 %

Procedure:
To a solution of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (450 mg, 1.8 mmol) in THF (4.2 mL) at 23° C. was added tosyl chloride (390 mg, 2.0 mmol) and pyridine (270 μL, 3.4 mmol). The reaction mixture was stirred at room temperature for 45 min, diluted in 50 mL EtOAc, washed with 1 M aqueous citric acid (2×25 mL) and brine (1×25 mL). The remained organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution 5→35% EtOAc/Heptane) to produce 300 mg N-(2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethyl)-4-methylbenzenesulfonamide. 1H NMR (CDCl3, 400 MHz) 7.48 (d, 2H), 7.09 (m, 8H), 5.20 (s, 1H), 4.82 (s, 2H), 3.55 (s, 3H), 3.10 (q, 2H), 2.70 (t, 2H), 2.45 (t, 2H) 2.35 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.65 (t, 2H), 1.20 (s, 6H) ppm.
Reaction SMILES: O.O.O.O.[Cl-].[Mn+2:6].[Cl-].C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:59]3[NH:60][C:56](=[CH:57][CH:58]=3)[C:55]([C:61]3[CH:66]=[CH:65][C:64]([C:67]#[CH:68])=[CH:63][CH:62]=3)=[C:54]3[N:69]=[C:51]([CH:52]=[CH:53]3)[C:50]([C:70]3[CH:75]=[CH:74][C:73]([C:76]#[CH:77])=[CH:72][CH:71]=3)=[C:49]3[NH:78][C:46]([CH:47]=[CH:48]3)=[C:45]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[CH:86])=[CH:81][CH:80]=3)[C:44]3=[N:87][C:41]=2[CH:42]=[CH:43]3)=[CH:36][CH:35]=1)#[CH:33]>CN(C=O)C>[C:76]([C:73]1[CH:72]=[CH:71][C:70]([C:50]2[C:49]3[NH:78][C:46](=[CH:47][CH:48]=3)[C:45]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[CH:86])=[CH:81][CH:80]=3)=[C:44]3[N:87]=[C:41]([CH:42]=[CH:43]3)[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[CH:33])=[CH:35][CH:36]=3)=[C:59]3[NH:60][C:56]([CH:57]=[CH:58]3)=[C:55]([C:61]3[CH:62]=[CH:63][C:64]([C:67]#[CH:68])=[CH:65][CH:66]=3)[C:54]3=[N:69][C:51]=2[CH:52]=[CH:53]3)=[CH:75][CH:74]=1)#[CH:77].[Mn:6]
Reactant: [Mn+2]
Agent: C#Cc1ccc(-c2c3nc(c(-c4ccc(C#C)cc4)c4ccc([nH]4)c(-c4ccc(C#C)cc4)c4nc(c(-c5ccc(C#C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: [Mn]

Procedure:
A solution of 5.5 g (27.8 mmol) of manganese chloride tetrahydrate (MnCl2.4H2O) in 160 ml of DMF was added portionwise to a solution of 1 g (1.4 mmol) of porphyrin TEPP (2) as obtained in step 2) above and dissolved in 200 ml of DMF. The mixture was refluxed for 72 hours. After a return to ambient temperature, the solvent was evaporated off under reduced pressure. The residue was taken up in 50 ml of chloroform and the manganese salts were eliminated by filtration over celite. The liquid filtrate was evaporated and the residue was subsequently dissolved in 100 ml of ethanol and washed with 3×100 ml of water in order to eliminate the TBAF. After evaporation, the residue was dissolved in chloroform and this organic phase was in turn washed with a saturated aqueous solution of sodium chloride (3×100 ml) in order to be sure that the axial ligand of the manganese is a chlorine, and finally washed with 2×100 ml of water in order to eliminate the traces of sodium chloride. The organic phase was subsequently dried over sodium sulfate and the solvent was evaporated off. During the first extraction with ethanol and water as solvents, a part of the porphyrin precipitated. This precipitate was filtered off and kept. It was subsequently redissolved in chloroform so that it could be added to the organic phase during the washing with sodium chloride. 700 mg (0.88 mmol; yield 63%) of manganese tetrakis(4-ethynylphenyl)porphyrin (MnCl-TEPP) (5) were obtained in the form of a purple/black-colored powder which is green in solution in chloroform.