Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>N1C=CC=CC=1>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=2)=[O:21])=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0 g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl 4-(chlorocarbonyl)benzoate (TCI) (948 mg, 4.78 mmol) at rt. After 50 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 960 mg) was added and the resulting mixture was stirred for 22 hrs at rt After filtration and rinsing the resin, water (160 mL) was added into the filtrate and a white solid precipitated out. Filtration and washing with water gave a white solid, which was dried under vacuo at 60° C. for 15 hrs. The title compound (1.41 g) was obtained as a white solid (85%) in 98.7% purity by HPLC (MaxPlot detection between 230 and 400 mn).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH:11]([C:28]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][C:31]2([O:35][CH2:34][CH2:33][O:32]2)[CH2:30][CH2:29]1)[CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)(=O)C>CO.O>[C:38]1([C:28]2([CH:11]([OH:10])[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=3)[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH2:29]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)OC(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1(c2ccccc2)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OC(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.5 %

Procedure:
Potassium carbonate (1.75 g, 12.7 mmol) was added to a solution of (RS)-1-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)-3-[3,5-bis(trifluoromethyl)phenyl]propan-1-yl ethanoate (Example 23, 410 mg, 0.773 mmol) in methanol (15 mL) and water (2 mL) and the mixture was stirred at room temperature for 48 hours, then at 50° C. for 24 hours. The mixture was cooled and the methanol was evaporated under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (334 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.68 (1H, s), 7.53 (2H, s), 7.4-7.3 (4H, m), 7.3-7.2 (1H, m), 3.95-3.8 (4H, m), 3.36 (1H, br d, J 9 Hz), 2.91 (1H, ddd, J 14, 10, 5 Hz), 2.64 (1H, ddd, J 16, 9, 7.5 Hz), 2.5-2.4 (1H, m), 2.3-2.2 (1H, m), 1.9-1.7 (3H, m) and 1.65-1.20 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]#[N:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1.[CH:27]([N-]C(C)C)([CH3:29])[CH3:28].[Li+].C(Br)C#C.O>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][C:9]([CH2:29][C:27]#[CH:28])([C:14]#[N:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C#N)C3)c1C
Agent: C#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCC1(C#N)Cc2nn(Cc3ncc(C)c(OC)c3C)c3nc(N)nc(c23)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
4-Amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carbonitrile of Example 4 (50 mg) was dissolved in tetrahydrofuran (5 ml). A 2 N solution of lithium diisopropylamide in tetrahydrofuran (0.050 ml) was added at −78° C., and the mixture was stirred at the same temperature for 15 minutes. Then, propargyl bromide (0.015 ml) was added and the mixture was stirred at the same temperature for three hours. Water was added to the reaction solution, and then the mixture was heated to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by reversed phase liquid chromatography. The resulting solid was dissolved in a 50% solution of trifluoroacetic acid in dichloromethane (1 ml), followed by stirring for one hour. The reaction solution was concentrated under reduced pressure and azeotropically distilled with ethanol. The resulting solid was washed with ether to obtain the title compound (2 mg, 99%) as a solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>O>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CNCCO
Reactant: Clc1nc2ccccc2s1
Solvent: O
Product: CN(CCO)c1nc2ccccc2s1
Temperature: 120 °C

Procedure:
A mixture of 2-chlorobenzothiazole (8.5 g) and 2-methylaminoethanol (20 ml) was heated at 120° C. under pressure in a sealed, glass lined, stainless steel reaction vessel for 18 hours. After cooling, the oil was added to water (100 ml), extracted with dichloromethane (2×100 ml), the organic extracts were dried (MgSO4), filtered and evaporated to dryness. Chromatography of the residual oil on silica-gel in 2½% methanol in dichloromethane gave the title compound which was used in Preparation 1 without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].O>CC(N(C)C)=O.C(#N)C.CCCCCC>[C:30]([N:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[S:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:33])[CH2:31][CH3:32]
Reactant: c1ccc(OCCCCCSc2nc3ccccc3[nH]2)nc1
Reactant: CCC(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCCCCC
Product: CCC(=O)n1c(SCCCCCOc2ccccn2)nc2ccccc21
Reaction time: 0.5 h
Yield: 72 %

Procedure:
0.2 g of (Compound 1) was dissolved in 0.8 ml of dimethylacetamide and 1.6 ml of acetonitrile, added with 0.14 ml of triethylamine and then added with 74 mg of propionyl chloride at 50° C. After 30 minutes, the reaction mixture was cooled and added with water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by using a silica gel column (ethyl acetate:methylene chloride=1:5) and crystallized from ethyl acetate:hexane to obtain 0.17 g of the title compound (yield: 72%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([CH2:19][C:20]#[N:21])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.Cl.O.[Pt]=O>[NH2:21][CH2:20][CH2:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[CH:18]=1
Reactant: COC(=O)c1ccc(CC#N)cc1S(=O)(=O)NC(C)(C)C
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CCN)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 10 h

Procedure:
After 0.5 g of platinum oxide hydrate had been added to a solution of 2.5 g (8.05 mmol) of methyl 2-(tert-butylaminosulfonyl)-4-cyanomethylbenzoate in 200 ml of methanol and 4 ml of concentrated HCl, the mixture was hydrogenated for 10 hours at room temperature and under a hydrogen pressure of 20 bar. For working-up, the catalyst was removed by filtration and the filtrate was concentrated. After the residue had been taken up in ethyl acetate, the solution was washed four times with 2 N HCl. The combined acidic aqueous phases are brought to pH 10-11 with concentrated ammonia and extracted three times with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated in vacuo. This gave 1.9 g (75%) of methyl 4-(2-aminoethyl)-2-tert-butylaminosulfonylbenzoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16](OC)[O:17]C)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16]=[O:17])[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1
Reactant: COC(CCn1cc(-c2ccc(C)nc2Cl)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(CCC=O)c(=O)[nH]c2=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(2-Chloro-6-methyl-pyridin-3-yl)-1-(3,3-dimethoxy-propyl)-1H-pyrimidine-2,4-dione (Prep108, 90 mg, 0.26 mmol) was dissolved in THF (4 ml) and 1N HClaq (265 μl) was added. The solution was then stirred at room temperature for one hour and then warmed at 40° C. for 2.5 hours. TEA (45 μl) was added and the solvent was carefully removed in vacuum at room temperature. Residue was freeze dried to give a white powder that was used in the next step without further purification (quantitative yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:15]([O:27][CH3:28])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].FC1C=C(F)C=CC=1C1C=CC(OCC2C=CC=C([N+]([O-])=O)C=2)=CC=1>CC(C)=O>[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=3)=[CH:24][CH:25]=2)=[C:15]([O:27][CH3:28])[CH:14]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Yield: 39.6 %

Procedure:
1-Bromomethyl-3-nitro-benzene (455 mg, 2.11 mmol), 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (0.5 g, 2.11 mmol), and dried, finely ground potassium carbonate (363 mg, 2.63 mmol) in 30 mL acetone were refluxed under argon for 16 hrs similar to 2,4-difluoro-4′-(3-nitro-benzyloxy)-biphenyl above. The crude product was purified by trituration with 5% ethyl acetate in hexanes to yield 0.31 g (38%) of 4,5-difluoro-2-methoxy-4′-(3-nitro-benzyloxy)-biphenyl. LC-MS (ES) calculated for C20H15F2NO4, 371.34; found m/z 370 [M−H]−.
Reaction SMILES: [CH3:1][C:2](=[CH:7][C:8]#[C:9][C:10]([CH3:23])=[CH:11][CH:12]=[C:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][C:16](=[O:21])[CH:15]=[C:14]1[CH3:22])[CH:3]=[CH:4][CH:5]=[O:6].C1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CC(C)=O>[CH3:1][C:2](=[CH:7][CH:8]=[CH:9][C:10]([CH3:23])=[CH:11][CH:12]=[C:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][C:16](=[O:21])[CH:15]=[C:14]1[CH3:22])[CH:3]=[CH:4][CH:5]=[O:6]
Reactant: CC(C#CC=C(C)C=CC=O)=CC=C1C(C)=CC(=O)CC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CC(C=CC=O)=CC=CC(C)=CC=C1C(C)=CC(=O)CC1(C)C

Procedure:
2 g. of pure 4,8-dimethyl-10-(4-oxo-2,6,6-trimethyl-2-cyclohexenylidene)-2,4,8-decatrien-6-ynal in 50 ml. of benzene was hydrogenated in the presence of 0.5 g. of Lindlar catalyst and 0.5 ml. of a 1% solution of quinoline in acetone. After consumption of 240 ml. of hydrogen, which took place within 21/2 hours, the suspension was filtered and concentrated. The residue crystallized only partially after chromatography on 200 g. of silica gel G with benzene ethyl ether in a volume ratio of 3:2.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:33][C:34]1[N:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][N:35]=1.[H-].[Na+].[CH3:47]I>CN(C=O)C>[CH:19]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[C:3]([CH3:47])([CH2:33][C:34]2[N:38]=[C:37]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:36][N:35]=2)[C:4](=[O:32])[N:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:6]2[CH:25]=[CH:24][CH:23]=[CH:22][C:7]1=2)([CH3:20])[CH3:21]
Reactant: CI
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2noc(-c3ccccc3)n2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2noc(-c3ccccc3)n2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
To a stirring solution of 65 mg (0.11 mmol) of 2-[2,4-Dioxo-5-phenyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylmethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 40, in 2 mL of DMF at 0° C. is added 8 mg (0.17 mmol, 1.5 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 10 mL (0.17 mmol, 1.5 equiv) of methyl iodide is added. The reaction mixture is stirred 30 min at 0° C. then 3 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL Et2O and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil via reverse phase MPLC using a C-18 column and 70% acetonitrile/30% H2O with 0.1% TFA as eluent followed by lyophilization afforded 35 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.11 (m, 2H), 7.63-6.86 (m, 17H), 5.08 (m, 1H), 4.43 (m, 0.66H), 4.03 (d, br, 0.66H, J=16.3), 3.83 (d, 0.33H, J=16.9), 3.55 (d, 0.33H, J=16.9), 2.87 (dd, 2H, J=15.4, 33.0), 1.62 (s, 2H), 1.35 (s, 1H), 1.11 (m, 6H); low resolution MS (FAB)m/e 600 (MH+), 465, 223.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]CC)=[O:26])[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[S:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[S:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CSc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CSc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.5 %

Procedure:
1.2 g of 3-(1-ethoxycarbonyl-3-phenylpropylamino)-5-ethoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was dissolved in 15 ml of ethanol, and 6 ml of 1N NaOH was added thereto. The resulting mixture was stirred at room temperature, so that white crystals were precipitated. After 1.5 hours, the ethanol was distilled off under reduced pressure and water was added to the residue. After a small amount of insoluble matter was filtered off, the filtrate was adjusted to pH 3-4 with 6N hydrochloric acid. The precipitated crystals were separated by filtration and washed with cold water and then with ether to obtain 650 mg of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: CNCCOC
Solvent: CCN(CC)CC
Product: COCCN(C)CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (80 mg, 0.27 mmol) and (2-methoxyethyl)methylamine (450 mg, 5.04 mmol) are heated 100° C. for 2 h. Additional (2-methoxyethyl)methylamine is added and heating is continued for 1 hr. The reaction mixture is cooled and treated with triethylamine (10 drops). The reaction mixture is loaded onto silica gel and purified by chromatography (silica gel, MeOH-Chloroform). The product containing fractions are concentrated and triturated with EtOAc-hexane. The solid obtained is collected by filtration and dried to provide the title compound (55 mg, 53%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:34]=1[N:48]1[CH2:53][CH2:52][C:51]2[C:54]3[CH2:60][CH2:59][CH2:58][CH2:57][C:55]=3[S:56][C:50]=2[C:49]1=[O:61])(=[O:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:28]([O:31][CH2:32][C:33]1[C:38]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][NH:16][CH2:15][CH2:14][C:13]=4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:37][CH:36]=[CH:35][C:34]=1[N:48]1[C:49](=[O:61])[C:50]2[S:56][C:55]3[CH2:57][CH2:58][CH2:59][CH2:60][C:54]=3[C:51]=2[CH2:52][CH2:53]1)(=[O:30])[CH3:29]
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCNC4)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 158c (300 mg, 0.689 mmol), boronic ester 111a (365 mg, 0.758 mmol), Pd(PPh3)4 (39.8 mg, 0.034 mmol), Na2CO3 aqueous solution (1.0 N, 2.27 mL. 2.27 mmol), 1,2-dimethoxyethane (3.0 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:methylene chloride=5:95) gave 158d.
Reaction SMILES: CC(C[Al]CC(C)C)C.[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]1[CH2:34][C:35](OCC)=[O:36])=[O:16])([CH3:13])([CH3:12])[CH3:11].O>C1(C)C=CC=CC=1>[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]1[CH2:34][CH2:35][OH:36])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CC1C(NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCO
Temperature: -78 °C
Yield: 67.4 %

Procedure:
1.0 M of a solution (3.15 mL) of Dibal-H in toluene was added dropwise to the compound 13 (440 mg) and toluene (8 mL) with stirring at −78° C. The reaction mixture was stirred at room temperature for 3 hours and then added water at 0° C. Generated salt was removed by filtration with Celite (trade name) and then the filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was dissolved in methanol (2 mL) and then sodium borohydride (40 mg) was added into the solution. The reaction solution was stirred at room temperature for 20 minuets, added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (267 mg) having the following physical properties.
Reaction SMILES: [C:1]([C:4]1[C:5]([C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]([CH3:14])[CH3:13])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CCO>[C:18]([O:17][C:16](=[O:22])[NH:15][C@H:11]([C:5]1[C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][C:8]([Cl:10])=[CH:7][N:6]=1)[CH:12]([CH3:14])[CH3:13])([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of tert-butyl(S)-(1-(3-acetyl-5-chloropyridin-2-yl)-2-methylpropyl)carbamate (62.3 mg, 191 μmol) in EtOH (1 mL) at 0° C. was added sodium borohydride (7.2 mg, 191 μmol) as a solid. The mixture was stirred at 0° C. for 90 min, then it was quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with EtOAc (20 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 100%) to afford 53.4 mg of tert-butyl((1S)-1-(5-chloro-3-(1-hydroxyethyl)pyridin-2-yl)-2-methylpropyl)carbamate (85% yield). LC-MS tR=1.01 min in 1 min chromatography, MS (ESI) m/z 329.4 [M+H]+. 1H NMR (CDCl3, 400 MHz, mixture of diastereomers): δ 8.44 (d, J=2.4 Hz, 0.3H), 8.41 (d, J=2.4 Hz, 0.7H), 7.86 (d, J=2.4 Hz, 0.7H), 7.77 (d, J=2.4 Hz, 0.3H), 5.44 (d, J=9.6 Hz, 0.7H), 5.31 (m, 0.7H), 5.23 (m, 0.7H), 4.73 (t, J=8.8 Hz, 0.3H), 4.63 (t, J=9.6 Hz, 0.3H), 4.56 (s, 0.3H), 2.18-2.12 (m, 0.3H), 2.08-2.00 (m, 0.7H), 1.56 (d, J=6.8 Hz, 0.9H), 1.52 (d, J=6.8 Hz, 2.1H), 1.40 (s, 9H), 1.11 (d, J=6.8 Hz, 0.9H), 1.00 (d, J=6.8 Hz, 2.1H), 0.80 (d, J=6.8 Hz, 2.1H), 0.69 (d, J=6.8 Hz, 0.9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[S:11][CH2:10][CH2:9][C:8]2=[O:13].[BH4-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[S:11][CH2:10][CH2:9][CH:8]2[OH:13]
Reactant: COc1cccc2c1SCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c1SCCC2O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
89 mmol of 8-methoxy-4-thiochromanone are dissolved in 70 ml of a mixture of methanol and tetrahydrofuran (3/4). 134 mmol of sodium borohydride dissolved in 50 ml of aqueous methanol (50%) are added. After stirring for 1 hour at room temperature and then extracting with methylene chloride, the resulting product is recrystallised from a mixture of methanol and diethyl ether (1/10).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([F:19])[F:18])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.[C:20]([Li])(C)(C)C.CI>O1CCCC1.CCCCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([F:19])[F:18])[C:10]2[CH:14]([CH3:20])[O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1OC(=O)C=C1N(Cc1ccc(Cl)nc1)CC(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
300 mg (1.04 mmol) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (1) are dissolved in 10 ml of tetrahydrofuran, the solution is cooled to −78° C. and 611 μl (1.04 mmol) of a 1.7 M solution of tert.-butyllithium in pentane are added. After 30 min of stirring at −78° C., 65 μl (1.04 mmol) of methyl iodide are added, stirring is continued at −78° C. for a further 30 min and the mixture is warmed to room temperature. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 152 mg (47% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]-5-methylfuran-2(5H)-one.