Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:19]=2[N:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:15])[C:17]2[C:18]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2c(Cl)ncnc2N1
Reactant: CN[C@H]1CCCN(Cc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A solution of (S)-1-benzyl-N-methylpiperidin-3-amine (0.2 g, 1.0 mmol), 4-chloro-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (90 mg, 0.5 mmol) and DIEA (253 mg, 2.0 mmol) was heated in a sealed tube at 100° C. overnight. The reaction mixture was cooled to rt and poured into ice water. The reaction mixture was extracted with EtOAc (3×15 mL) and the combined EtOAc layer was dried over Na2SO4, evaporated in vacuo to give the crude product which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford (100 mg, 29%) of the titled intermediate. 1H NMR (400 MHz, CD3OD): δ 7.97 (s, 1H), 7.33-7.26 (m, 5H), 4.60-4.57 (m, 1H), 4.01-3.99 (m, 2H), 3.53 (s, 2H), 2.92 (s, 3H), 2.58-2.53 (m, 3H), 2.25-2.21 (m, 1H), 2.07-2.01 (m, 2H), 1.76-1.69 (m, 2H), 1.43-1.33 (m, 3H). LC-MS: m/z [M+1]=451 & [M+23]: 473.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[OH-].[K+].[CH3:25][N:26]([CH3:43])[CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>C(O)C.CC(C1C=CC=C(C(C)C)C=1N1[CH-]N(C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1C=NC=C(Cl)C=1.Cl[Pd]Cl>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][N:26]([CH3:43])[CH3:25])[CH:33]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: CC(C)c1cccc(C(C)C)c1N1[CH-]N(c2c(C(C)C)cccc2C(C)C)CC1
Agent: Clc1cccnc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)C)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.24 g, 0.650 mmol), potassium hydroxide (1.300 mL, 1.300 mmol), N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (for a preparation see Intermediate 115) (0.190 g, 0.715 mmol) and (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride (0.03 g, 0.044 mmol) were dissolved in ethanol (10 mL) and 1,2-dimethoxyethane (DME) (10.00 mL) and the resulting mixture was degassed under house vacuum with several quenches with nitrogen then refluxed for three hours, cooled to room temperature, allowed to stand for 16 h then concentrated in vacuo. The residue was partitioned between water (30 mL) and EtOAc (30 mL) and the layer were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of this residue by SP4 using a 25 G silica cartridge (gradient: 0 to 10% (2M NH3 in MeOH) in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (137 mg, 0.320 mmol, 49.3% yield) as an amber oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C=CC=CC=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>O1CCCC1>[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)=[O:19]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C(=O)n1cnc2ccccc21)c1ccccc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1H-benzo[d]imidazole (354 mg, 3 mmol) in tetrahydrofuran (15 ml) was added pyridine (0.367 ml, 4.50 mmol) followed by addition of methyl(phenyl)carbamic chloride (534 mg, 3.15 mmol). The reaction was heated to 80° C. for 20 hours. THF was removed by vacuum, the residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was chromatographed in petroleum ether:EtOAc=2:1.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2CN[C@@H]2CCCC[C@H]2NCC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:49][C:50]([F:89])([F:88])[C:51]1[CH:52]=[C:53]([CH:81]=[C:82]([C:84]([F:87])([F:86])[F:85])[CH:83]=1)[CH2:54][N:55]([CH2:62][C:63]1[CH:68]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:66]=[CH:65][C:64]=1[C:73]([CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1)=[O:74])[C:56]1[N:57]=[N:58][N:59]([CH3:61])[N:60]=1.[OH-].[K+]>C(O)(C)C>[F:89][C:50]([F:49])([F:88])[C:51]1[CH:52]=[C:53]([CH:81]=[C:82]([C:84]([F:85])([F:86])[F:87])[CH:83]=1)[CH2:54][N:55]([CH2:62][C:63]1[CH:68]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:66]=[CH:65][C:64]=1[C@H:73]([CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1)[O:74][CH3:1])[C:56]1[N:57]=[N:58][N:59]([CH3:61])[N:60]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCCC2)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2CN[C@@H]2CCCC[C@H]2NCc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A mixture of [IrHCl2(COD)]2 (54.4 mg, 0.073 mmol) and (1R,2R)—N,N′-bis[2-(diphenylphosphino)benzyl]cyclohexane-1,2-diamine (44.8 mg, 0.067 mmol) in isopropanol was stirred at room temperature for 30 minutes. A solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone in isopropanol was added to mixture followed by potassium hydroxide (44.8 mg, 0.799 mmol) and stirred at room temperature for 18 hours. Isopropanol was removed in vacuo and the crude product was purified on Biotage 40+M silica column, eluted with 0-30% ethyl acetate in heptane, to afford 3.7 g (92%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.92-1.17 (m, 5H) 1.24 (d, J=15.77 Hz, 1H) 1.54-1.60 (m, 1H) 1.61-1.67 (m, J=2.07 Hz, 2H) 1.73-1.79 (m, 1H) 1.93 (d, J=12.86 Hz, 1H) 2.25 (s, 1H) 4.20 (s, 3H) 4.65 (d, J=7.05 Hz, 1H) 4.70 (d, J=15.77 Hz, 1H) 4.76 (t, J=15.35 Hz, 2H) 4.86 (d, J=15.77 Hz, 1H) 7.34 (s, 1H) 7.50-7.59 (m, 2H) 7.65 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1). 95.9% ee determined by chiral HPLC on Chiralpak AD-H (4.6 mm×25 cm) eluted at 6.912 min using 90/10 heptane/IPO (1 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69](O)=[O:70])=[C:64]([F:72])[CH:63]=1>CN(C)C(=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69]([NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[CH:9][C:10]2[N:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[O:70])=[C:64]([F:72])[CH:63]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2ccc(Cl)cc2F)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 57 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 M in N,N-dimethylacetamide, respectively, 275 μL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 μL, 0.063 mmol), and 2-(4-chloro-2-fluorophenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0126 g (57%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.06 (d, J=2.44 Hz, 1H), 7.56 (s, 1H), 7.45 (t, J=8.24 Hz, 1H), 7.40 (dd, J=8.54, 2.44 Hz, 1H), 7.31 (dd, J=9.77, 2.14 Hz, 1H), 7.25 (dd, J=8.24, 2.14 Hz, 1H), 7.17 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.58 (m, 2H), 4.05 (s, 3H), 3.77 (s, 2H). MS (APCI+) m/z 531.1 (M+H)+.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24]>>[CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:30][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][N:28]=3)[CH2:32][CH2:33]2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)N2CCN(c3ncc(S(C)(=O)=O)s3)CC2)c1
Yield: 38 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (Example A7) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light red crystalline solid (yield 38%). MS (m/e): 528.3 (M+H+, 100%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]3)=[N:6][C:7]([N:10]3[C:18]4[CH:17]=[C:16]([C:19]5[CH:20]=[N:21][CH:22]=[C:23]([CH2:25][CH3:26])[CH:24]=5)[N:15]=[CH:14][C:13]=4[CH:12]=[N:11]3)=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]3)=[N:6][C:7]([N:10]3[C:18]4[CH:17]=[C:16]([C:19]5[CH:20]=[N:21][CH:22]=[C:23]([CH2:25][CH3:26])[CH:24]=5)[N:15]=[CH:14][C:13]=4[CH:12]=[N:11]3)=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](N)C3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.0597 mmol; 32.2 mg) in Methanol (10 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 139 as an off-white solid (20 .mg, 7.4%). MS (ESI) m/z: 440.3 [M+H]+
Reaction SMILES: C[O:2][C:3](=O)[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.N>>[Cl:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:3](=[O:2])[NH:4][CH2:5][CH2:6]2
Reactant: COC(=O)NCCc1cccc(Cl)c1
Agent: N
Product: O=C1NCCc2cc(Cl)ccc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
Under N2 protection, a mixture of [2-(3-chloro-phenyl)-ethyl]-carbamic acid methyl ester (5.0 g, 23.4 mmol) and PPA (polyphosphoric acid) (20 g) in a 250 mL round-bottom flask was vigorously stirred at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the pH to 8. Then, the mixture was then extracted with EtOAc, and the organic layer was washed with brine, dried over anhy. Na2SO4 and filtered. After removal of solvent under reduced pressure, the crude product obtained was further washed with ethyl ether to give title compound (1.66 g, 39%) as a white solid. MS: 182.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]2[NH:7][C:15](=[O:16])[NH:14][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2

Procedure:
Commercially available 4-methoxyaniline can be treated with chlorosulfonyl isocyanate followed by aluminum chloride to give the corresponding 7-methoxy-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one. Opening of the cyclic urea with a strong acid (e.g., sulfuric acid) gives the desired 2-amino-5-methoxy-benzenesulfonamide intermediate.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[C:17]([OH:20])[CH:18]=2)[NH:15][C:14]([C:21]([F:24])([F:23])[F:22])=[C:13]3[C:25]([O:27][CH3:28])=[O:26])[CH:10]([CH2:29][Cl:30])[CH2:9]1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](C(O)=O)=[CH:36]2>>[Cl:30][CH2:29][CH:10]1[C:11]2=[C:12]3[C:16](=[C:17]([OH:20])[CH:18]=[C:19]2[N:8]([C:6]([C:37]2[NH:38][C:39]4[C:35]([CH:36]=2)=[CH:34][C:33]([O:32][CH3:31])=[CH:41][CH:40]=4)=[O:5])[CH2:9]1)[NH:15][C:14]([C:21]([F:22])([F:24])[F:23])=[C:13]3[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)c1cc2cc(OC)ccc2[nH]1

Procedure:
Methyl 1-chloromethyl-5-hydroxy-3-(5-methoxy-1H-indol-2-ylcarbonyl)-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate was prepared in the same manner as above by using 11.2 mg (25 μmol) of methyl 3-t-butoxycarbonyl-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate and 4.8 mg (25 μmol) of 5-methoxyindole-2-carboxylic acid in a yield of 7.2 mg (55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=1.[NH2:16][C:17]1[O:18][C:19]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:20][N:21]=1.CO>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]([NH:16][C:17]2[O:18][C:19]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[N:20][N:21]=2)=[O:14])=[CH:10][CH:9]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(Cl)c1ccc(-c2ccccc2F)o1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1ccc(-c2ccccc2F)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
Commercially available 5-(2-fluorophenyl)-2-furancarbonyl chloride (93 mg, 0.41 mmol) was added to a solution of commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (50 mg, 0.33 mmol) in pyridine (1.3 mL) under ice-cooling, followed by stirring at room temperature for 2.5 hr and then at 60° C. for 2 hr. Methanol was added to the reaction solution. The solvent was distilled off, and water was added to the residue. The precipitated crystals were collected by filtration, washed with water, methanol, and ethyl acetate sequentially, and then dried to obtain the title compound (77 mg, 0.23 mmol) (yield: 70%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]([CH2:18][CH3:19])[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=2.[C:20](Cl)(=[O:22])[CH3:21]>O1CCOCC1>[C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[CH:9][CH:10]=2)[N:5]([CH2:18][CH3:19])[C:4]=1[NH:3][C:20](=[O:22])[CH3:21])#[N:14]
Reactant: CCn1c(N)c(C#N)c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1c(NC(C)=O)c(C#N)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Sodium hydride (44 mg, 1.10 mmol, 60% w/w in mineral oil) is washed with hexanes and suspended in 1,4-dioxane (3 mL). A solution of 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (120 mg, 0.521 mmol), prepared in step B, above, in dioxane (2 mL) is added, and the resulting mixture is allowed to stir for 30 min. Then, acetyl chloride (45 μL, 0.63 mmol) is added by syringe, and the solution is stirred for an additional 12 h. The reaction is partitioned between water and EtOAc (20 mL each), and the organic phase is washed with brine. The aqueous phases are back-extracted in sequence with ethyl acetate, and the organic extracts are combined, dried over MgSO4, filtered and evaporated. The resulting solid is triturated with Et2O, collected by filtration and dried under vacuum to afford N-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)-acetamide (100 mg, 71%), compound 25, as an off-white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[S:5][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: -78 °C
Yield: 96.4 %

Procedure:
Methyl 4-methyl-2-[4-(trifluoromethyl)phenyl]]thiazole-5-carboxylate (20.0 g, 66.4 mmol) obtained from Example 1 was dissolved in anhydrous dichloromethane (500 ml) under nitrogen atmosphere, and the reaction mixture was cooled to −78° C. Diisobutyl aluminum hydride (DIBAL-H, 166 ml, 1.0 M hexane solution, 2.5 eq.) was slowly added to the solution for 30 minutes, and the mixture was reacted for another 30 minutes at the same temperature. Subsequently, the temperature was raised to −10° C. and reacted for 30 minutes. After completion of the reaction, an excessive diisobutyl aluminum hydride was removed by ethyl acetate. The resultant residue was extracted by 10% sulfuric acid and ethyl acetate, followed by drying over magnesium sulfate. The resultant mixture was purified on silica flash column, followed by evaporation under reduced pressure to thereby yield 17.5 g of the title compound (yield: 96.4%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Yield: 89.1 %

Procedure:
A solution of 2.48 g (10.00 mmol) of methyl (S)-4-(tert-butyldimethylsilyloxy)-2-hydroxybutanoate (J. Am. Chem. Soc. 2005, 127, 1090) in 50 ml of dichloromethane was treated with 2.09 ml (15.00 mmol, 1.5 eq) of triethylamine and at 0° C. during 5 min with 0.82 ml (10.50 mmol, 1.051 eq) of methanesulfonyl chloride. After 1 h at 0° C. the reaction was partitioned between 10% aq. potassium dihydrogenphosphate solution/diethyl ether (×3), the organic phases were washed with sat. aq. sodium hydrogencarbonate solution (freshly prepared) and 10% aq. sodium chloride solution, dried over Na2SO4 and evaporated to give 2.91 g (89%) of the titled compound as yellow oil. MS: 327.1 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([CH2:12][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reaction time: 1.17 h
Yield: 82.3 %

Procedure:
N-methyl piperazine (1.97 mL, 17.8 mmol) was added dropwise to a solution of 3-fluoro-4-nitrobenzaldehyde (1.50 g, 8.88 mmol) and acetic acid (0.20 mL, 3.54 mmol) in toluene (8.4 mL) at room temperature. The reaction mixture was stirred for 1.5 h at room temperature before the addition of further toluene (3.15 mL) and sodium triacetoxyborohydride (2.97 g, 14.0 mmol). The reaction mixture was stirred for 70 min and then further sodium triacetoxyborohydride (0.40 g, 1.9 mmol) was added. The reaction mixture was stirred for 50 min, and then quenched by the addition of MeOH (2 mL) and saturated aqueous NaHCO3 (10 mL). The reaction mixture was stirred for 30 min. The phases were separated and the aqueous layer was extracted with toluene (2×20 mL, 1×10 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt3 19:1:0.1) to give the title compound (1.85 g, 82%) as an orange oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH:16][OH:17].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][N:16]([OH:17])[C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: ONCc1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)N(O)Cc1ccccc1Cl
Yield: 29 %

Procedure:
This compound was prepared in the manner of Example 1, Step C, using 6.0 grams (0.05 mole) of trimethylacetyl chloride, 9.5 grams (0.06 mole) of N-(2-chlorophenylmethyl)hydroxylamine (prepared in Example I, Step A), and 14.2 grams (0.18 mole) of pyridine in 60 ml of methylene chloride. The crude product was recrystallized from hexane to give 3.5 grams of N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide; mp 100°-102°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:30])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:14]=1)#[N:2].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[C:10](=[O:30])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=1
Reactant: [H][H]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccc2[N+](=O)[O-])cn(-c2ccccc2)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(-c2ccccc2N)cn(-c2ccccc2)c1=O
Yield: 67.7 %

Procedure:
3-(2-Cyanophenyl)-5-(2-nitrophenyl)-1-phenyl-1,2-dihydropyridin-2-one (32 mg) was dissolved in 15 ml of ethyl acetate, 5 mg of 10% palladium-carbon (water-containing substance) were added and the mixture was stirred at room temperature in a hydrogen atmosphere for 15 minutes. The catalyst was filtered off and the solvent was evaporated in vacuo to give 20 mg of the title compound.
Reaction SMILES: [Na].[CH2:2]([Sn:6](Cl)([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5]>C([Sn](CCCC)(CCCC)CCCC)CCC>[CH2:2]([Sn:6]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[Sn:6]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CCCC[Sn](CCCC)(CCCC)CCCC
Agent: [Na]
Product: CCCC[Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC
Yield: 93 %

Procedure:
BE A 672 867 disclosed the conversion of sodium in tetrabutyltin with tributyltin chloride followed by a complicated process which yields 93% of hexabutyl distannane.