Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][CH:22]3[CH2:31][N:25]4[CH2:26][CH2:27][NH:28][C:29](=[O:30])[CH:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][C@H:22]3[CH2:31][N:25]4[CH2:26][CH2:27][N:28]([C:2]5[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=5)[C:29](=[O:30])[C@@H:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1
Reactant: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: O=C1[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN2CCN1c1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Yield: 25.5 %

Procedure:
A 4 mL vial was charged with 2-bromo-5-(trifluoromethyl)pyridine (99 mg, 0.437 mmol), 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one [3:1 (7R,8aS: 7R,8aR) diastereomer ratio](100 mg, 0.365 mmol) from Example 163 Step 3, palladium(II) acetate (4.09 mg, 0.018 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS, 21.09 mg, 0.036 mmol), and cesium carbonate (178 mg, 0.547 mmol). The mixture was purged with nitrogen, and anhydrous dioxane (0.5 mL) was added. The reaction mixture was purged with nitrogen again and was subsequently heated at 110° C. for 16 hours. The mixture was directly loaded and separated by flash chromatography [12 g cartridge, gradient 0-5% methanol/dichloromethane over 20 minutes] to give crude oily product. The crude product was further purified on 12 g cartridge eluted with 100% ethyl acetate over 20 minutes to give the title compound (39 mg, 0.093 mmol, 25.5% yield) as the first eluting diastereomer as a white foam. 1H NMR (500 MHz, CDCl3) δ ppm 8.71-8.63 (m, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.11 (d, J=1.1 Hz, 1H), 7.95 (d, J=1.3 Hz, 1H), 7.90 (dd, J=8.8, 2.3 Hz, 1H), 5.50 (dd, J=6.5, 5.0 Hz, 1H), 4.45 (ddd, J=5.2, 4.3, 2.5 Hz, 1H), 4.00 (d, J=7.1 Hz, 2H), 3.33 (dd, J=11.0, 5.2 Hz, 1H), 3.32-3.25 (m, 1H), 3.10 (ddd, J=12.2, 6.1, 4.1 Hz, 2H), 2.70-2.60 (m, 1H), 2.47 (dd, J=14.4, 8.0 Hz, 1H), 2.00 (tt, J=8.0, 5.1 Hz, 1H), 1.00-0.90 (m, 4H); MS (ESI+) m/z 420 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][CH2:22][C:9]21[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)C1C=CC=CC=1>CO.[Pd]>[O:14]1[C:9]2([CH2:22][CH2:23][CH2:24][NH:8]2)[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCOC2(CCCN2Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC2(CCCN2)C1

Procedure:
13.7 g (41 mmol) of tert-butyl 7-benzyl-1-oxa-4,7-diazaspiro[5.4]decane-4-carboxylate are dissolved in 300 ml of methanol, 3.0 g of 10% palladium on activated carbon are added, and hydrogenation is carried out at 100° C. and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated, and residue is distilled under high vacuum. 7.6 g (75% of theory) of the product are obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>CO>[CH3:1][CH:2]([CH3:14])[CH:3]([OH:13])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C=CC(=O)C(C)C)cc1
Solvent: CO
Product: Cc1ccc(/C=C/C(O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a solution of 4-methyl-1-p-tolyl-pent-1-en-3-one (77.0 g, 0.41 mol) in methanol (400 mL) was added slowly under argon sodium borohydride (31 g, 0.82 mol). The reaction was stirred at room temperature overnight and methanol (200 mL) was evaporated. The solution was neutralized with hydrochloric acid (2N), extracted with ethyl acetate. The organic layer was successively washed with water, aqueous NaHCO3, water and brine, dried (Mg2SO4), filtered and evaporated to give 80.4 g of trans-4-methyl-1(p-tolyl)-1-penten-3-ol and used without further purification in the next step (step h). 1H NMR (300 MHz; CDCl3): 0.94 (d, J=6.9 Hz, 3 H), 0.99 (d, J=6.6 Hz, 3 H), 1.83 (m, 1 H), 2.33 (s, 3 H), 4.01 (br, 1 H), 6.16 (dd, J1=7.0 Hz, J2=16.0 Hz, 1 H), 6.53 (d, J=16.0 Hz, 1 H), 7.12 (d, J=7.8 Hz, 1 H), 7.28 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:12])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:62][C:63]1[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=1>CN(C=O)C.CCOC(C)=O>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:7])[NH:62][C:63]2[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=2)=[CH:3][C:2]=1[Br:1])[CH3:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1Br
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid (7496 to 61011 μmol) in DMF (10 to 30 ml) were added DIEA (2 eq.), TBTU (1.3 eq.) and HOBt (0.3 eq.). The reaction mixture was stirred at RT for 5 minutes. 4-Aminopyridine (1.5 eq) was added and the reaction mixture was stirred at RT for 2.5 hours up to overnight. When there was still starting material observed, more DIEA (0.39 eq), TBTU (0.25 eq), HOBt (0.06 eq) and 4-aminopyridine (0.28 eq) were added and the reaction mixture was stirred at RT for another 2 hours. The reaction mixture was diluted with EtOAc, washed with 0.1 M HCl and saturated Na2CO3 or with saturated NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1>[Pd].CO.C1COCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:13]=[N:14][C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:10][CH:11]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cn2)nc(N)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cn2)nc(N)n1
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a suspension of 11 (790 mg, 2.16 mmol) in 1:1 MeOH/THF (100 ml) was added 10% Pd/C (100 mg) and hydrogenated at 45 Hg mm. for 20 h. The reaction mixture was filtered and evaporated to dryness and recrystallized from DCM/Pert.ether to give 12 (695 mg, 96%); mp (DCM/pet.ether)>300° C.; 1H NMR [(CD3)2SO] δ 9.78 (s, 1 H, NH), 9.45 (s, 1 H, NH), 8.63 (dd, J=2.4, 0.3 Hz, 1 H, H-2′), 8.09 (d, J=9.0 Hz, 1 H, H-5′), 7.98 (dd, J=9.0, 2.6 Hz, 1 H, H-4′), 7.72 (d, J=8.7 Hz, 2 H, H-2,6), 6.61 (d, J=8.7 Hz, 2 H, H-3,5), 6.43 (s, 1 H, H-5″), 6.13 (s, 2 H, NH2), 5.73 (s, 2 H, NH2), 2.12 (s, 3 H, CH3); HRMS (FAB+) calc. for C17H18N7O (M+1) m/z 336.1573, found 336.1578; Anal. calc. for C17H17N7O-0.25H2O: C, 60.1; H, 5.2; N, 28.9; C, 60.2; N, 5.3; N, 29.0%.
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.Cl.Cl.[F:24][CH:25]([F:34])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.CN(C)C=O.C(N(CC)CC)C>ClCCl>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:33][CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][CH:25]([F:34])[F:24])[CH2:32][CH2:31]2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Reactant: NC1CCN(CC(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(CC(F)F)CC2)ccc1N
Reaction time: 20 h
Yield: 88.6 %

Procedure:
To a mixture of 1.07 g (3.78 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester, 0.90 g (3.78 mmole) of 1-(2,2-difluoro-ethyl)-piperidin-4-ylamine dihydrochloride and 5 mL of dimethylformamide was added 2.63 mL of triethylamine. The mixture was stirred for 20 hours, then taken up in dichloromethane and washed twice with 100 mL of saturated aqueous sodium bicarbonate, once with 50 mL water, once with 50 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) to give 1.05 g of 4-amino-N-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=O)[N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](S(NC(NC3CCC(C)CC3)=O)(=O)=O)=[CH:16][CH:15]=2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].CCC1[C:41](=[O:42])N(C(NCCC2C=CC(S(NC(N[C@@H]3CC[C@@H](C)CC3)=O)(=O)=O)=CC=2)=O)CC=1C.C1(CCN=C=O)C=CC=CC=1>>[CH2:1]([CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[C:4]1=[C:41]=[O:42])[CH3:2]
Reactant: CCC1=C(C)CN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)NC3CCC(C)CC3)cc2)C1=O
Reactant: CCC1=C(C)CN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)N[C@H]3CC[C@H](C)CC3)cc2)C1=O
Agent: O=C=NCCc1ccccc1
Product: CCC1C(=C=O)N(C(=O)NCCc2ccccc2)CC1C

Procedure:
U.S. Pat. No. 4,379,785 (hereinafter referred to as the '785 patent) discloses heterocyclic substituted sulfonylureas, particularly N-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]-benzenesulfonyl]-N′-4-methylcyclohexylurea i.e. glimepiride. The '785 patent teaches the preparation of glimepiride starting from 3-Ethyl-4-methyl-3-pyrrolidin-2-one and 2-phenylethylisocyanate to give [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene. The [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene is converted to the 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene sulfonamide, a compound of formula 4, by reacting with chlorosulfonic acid, followed by treatment with ammonia solution. This intermediate compound of formula 4 is further reacted with trans-4-methylyclohexyl isocyanate to form glimepiride. The '785 patent teaches a three step process for preparation of the intermediate compound of formula 4, i.e. 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido)ethyl]benzene sulfonamide, which is represented in Scheme 1.
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[C:1]([N:11]1[CH2:19][C@@H:18]([O:20][S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1

Procedure:
Following the procedure of Example 19(b), the methyl ester product from part (b) is treated with 12.4 g. of tosyl chloride in 45 ml. of pyridine to give 13.2 g. of cream-colored product; m.p. 114°-117° (s. 105°). 13 g. of this material are recrystallized from 70 ml. of ethanol to 8.4 g. of colorless cis-N-carbobenzyloxy-4-tosyloxy-L-proline, methyl ester; m.p. 133°-135°; [α]D25 -26° (c=1%, chloroform).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>[Zn].CO>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:8])[CH:14]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 50 °C

Procedure:
23.6 g of zinc powder are added to a suspension of 22.0 g of N-tert.-butyl-2-dimethylaminocarbonyl-5-nitro-benzenesulfonamide (Example d), 18.2 g of ammonium chloride, 70 ml of water and 150 ml of methanol. The mixture is then stirred at 50° C. When the reaction has ended, the solid is filtered off. After the solid has been washed with ethyl acetate, the filtrate is concentrated, the residue is taken up in ethyl acetate and the mixture is washed with water. After drying over MgSO4, the organic phase is concentrated and the residue is washed with diisopropyl ether; yield: 17.5 g; m.p.: 205-208° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15]C(=O)C)[NH:13][CH:14]=2)=[CH:6][CH:5]=1>O.CO.S(=O)(=O)(O)O>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1
Yield: 94.9 %

Procedure:
N-[4-(4-Trifluoromethoxy-phenyl)-1H-imidazol-2-yl]-acetamide (0.7 g, 2.6 mmol, 1.0 eq) was dissolved in water (18 mL) and methanol (18 mL), and 20 drops of sulfuric acid were added. The reaction was refluxed for 2 days, then the mixture was dried; the residue was diluted with water, the pH adjusted to 8 with NaOH 2N, the product was extracted with DCM and concentrated under reduced pressure to give 0.6 g of the title compound (yield 98%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.[C:21]([C:26]([C:55]([O:57]CC)=O)=[C:27]1[NH:32][C:31](=[C:33]([C:39](OCC)=[O:40])[C:34](OCC)=[O:35])[NH:30][C:29](=[C:44]([C:50](OCC)=[O:51])[C:45](OCC)=[O:46])[NH:28]1)(OCC)=[O:22]>>[CH2:11]([O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:21]([C:26]([C:55]([NH:1][CH:2]2[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]2)=[O:57])=[C:27]2[NH:28][C:29](=[C:44]([C:45]([NH:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)=[O:46])[C:50]([NH:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)=[O:51])[NH:30][C:31](=[C:33]([C:39]([NH:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)=[O:40])[C:34]([NH:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)=[O:35])[NH:32]2)=[O:22])[CH2:3][C:4]1([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)C(C(=O)OCC)=C1NC(=C(C(=O)OCC)C(=O)OCC)NC(=C(C(=O)OCC)C(=O)OCC)N1
Reactant: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)C(C(=O)NC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)=C2NC(=C(C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)NC(=C(C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)N2)CC1(C)C

Procedure:
The title compound is prepared from 4-amino-1-octyloxy-2,2,6,6-tetramethylpiperidine and 2,4,6-tris(dicarbethoxymethylene) hexahydro-1,3,5-triazine according to the general procedure of Example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH3:15])[CH:11]=[CH:10][C:9]=1[F:29])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH:11]=[CH:10][C:9]=1[F:29]
Reactant: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(NC(=O)OC(C)(C)C)c3)nc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(N)c3)nc2s1
Yield: 90 %

Procedure:
A solution of the above-mentioned crude product of tert-butyl(5-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl](methyl)amino}-2-fluorophenyl)carbamate and anisole (1.5 mL) in trifluoroacetic acid (15 mL) was stirred at 0° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, to the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (638 mg, 90%) as a gray solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:23]=[CH:24][C:25]=1[C:26]#[C:27][Si](C(C)(C)C)(C)C>C1COCC1>[Br:19][C:20]1[CH:21]=[C:22]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:23]=[CH:24][C:25]=1[C:26]#[CH:27]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(-c2ccccc2)cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.99 mL (1.99 mmol) of a 1M tetrabutylammonium fluoride solution in THF is added batchwise at 5° C. to a solution of 495 mg (1.33 mmol) of (3-bromobiphenyl-4-ylethynyl)-tert-butyldimethylsilane in 8 mL of anhydrous THF. The reaction mixture is stirred for another 30 minutes at ambient temperature and evaporated down. The residue is combined with diethyl ether and water and the organic phase is dried over sodium sulfate. Yield: 0.34 g (99% of theory); C14H9Br (M=257.12); calc.: molecular ion peak (M−H)−: 255/257 (Br); found: molecular ion peak (M−H)−: 255/257 (Br).
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].[Br:8][C:9]1[C:18]([CH2:19]Br)=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1>C(O)C>[Br:8][C:9]1[C:18]([CH:19]=[O:3])=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21
Agent: [Na]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Reaction time: 8 h
Yield: 60.5 %

Procedure:
0.981 g (42.7 mmol) of sodium was dissolved in 50 mL of ethanol. To this solution was added 4.94 g (55.5 mmol) of 2-nitropropane followed by 17.3 g (42.7 mmol) of crude 2-bromo-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 75 mL ethanol. After 8 hours, this mixture was concentrated in vacuo and then partitioned between ethyl acetate and water. The organic layer was sequentially washed with 1M aqueous sodium hydroxide, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel with gradient elution (1-2% ethyl acetate/hexane) to afford 7.63 g (61%) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=113.9-114.3° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.[H][H]>C(O)C.[Ni]>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][N:2]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=2)[CH3:1])=[CH:10][CH:9]=1
Reactant: CN(CCOc1ccc(C(N)=O)cc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN(CCOc1ccc(C(N)=O)cc1)CCc1ccc(N)cc1
Yield: 93.9 %

Procedure:
A solution of 4-{2-[N-methyl-N-(4-nitrophenethyl)amino]ethoxy}benzamide (1.4 g) in ethanol (100 ml) was stirred for 16 hours at room temperature under three atmospheres of hydrogen in the presence of Raney nickel ("Nicat 102", Trade Mark). The reaction mixture was filtered and evaporated to dryness to give a yellow solid (1.2 g) which crystallised from ethyl acetate to give the title compound, (1.1 g), m.p. 110°-112°.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:26]3([CH2:30][O:29][C:28]([NH2:31])=[N:27]3)[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:32]#[C:33][C:34]4([CH3:38])[CH2:37][O:36][CH2:35]4)[CH:24]=3)[O:19][C:15]2=[CH:16][C:17]=1[F:18].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:17]1[CH:16]=[C:15]2[O:19][C:20]3[C:25]([C:26]4([CH2:30][O:29][C:28]([NH2:31])=[N:27]4)[C:14]2=[CH:13][C:12]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[CH:24][C:23]([C:32]#[C:33][C:34]1([CH3:38])[CH2:37][O:36][CH2:35]1)=[CH:22][N:21]=3
Reactant: CC1(C#Cc2cnc3c(c2)C2(COC(N)=N2)c2cc(Br)c(F)cc2O3)COC1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C#Cc2cnc3c(c2)C2(COC(N)=N2)c2cc(-c4cccnc4F)c(F)cc2O3)COC1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
A solution of Pd(PPh3)4 (0.077 g, 0.066 mmol), 2-fluoropyridin-3-ylboronic acid (0.19 g, 1.33 mmol), 7-bromo-8-fluoro-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.30 g, 0.66 mmol), and potassium carbonate (0.46 g, 3.32 mmol) in 4.5 mL dioxane was treated with 1.8 mL water and was heated to 80° C. overnight. The reaction mixture cooled to rt and diluted with EtOAc (50 mL). The layers were separated and the organics were dried over MgSO4, and concentrated in vacuo. Purification of the crude residue by column chromatography [0-80% (9:1 CH2Cl2:MeOH)/CH2Cl2] gave 8-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.067 g, 0.146 mmol). Chiral separation provided (4′R)-8-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.022 g, 0.048 mmol, peak 1) and (4′S)-8-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.022 g, 0.048 mmol, peak 2).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:20]=2[O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Oc1cccc2c1OCCN2CCCNCc1ccc2ccccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1OCCN2CCCNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
(4-(3-(2-naphthylmethylamino)propyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine (166 mg) was dissolved in DMF (3 ml), and potassium carbonate (63 mg) and methyl bromoacetate (0.045 ml) were added. to the resultant solution at 0° C., followed by stirring at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel:ethyl acetate/n-hexane=2:3) to obtain the object compound (140 mg, yield 73%).