Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Br)[N:17]=1)S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:33][O:34][C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)=[O:36].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[C:41]([C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH:5]=[CH:4][C:3]([O:2][CH3:1])=[O:26])[N:17]=2)[CH:40]=[N:39][CH:38]=1)=[O:36]
Reactant: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1nc(-c2cncc(C(=O)OC)c2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 99.9 %

Procedure:
3-(6-Bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester (1.2 g, 2.7 mmol), Pd(PPh3)2Cl2 (190 mg, 0.27 mmol), Na2CO3 (572 mg, 5.4 mmol) and 3-(methoxycarbonyl)pyridine-5-boronic acid pinacol ester (926 mg, 3.5 mmol) were dissolved in 1,4-dioxane (4.0 mL) and the resulting reaction mixture was heated at 120° C. for 3 hours before it was poured into H2O (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 6-(2-methoxycarbonyl-vinyl)-5-nitro-[2,3′]bipyridinyl-5′-carboxylic acid methyl ester (926 mg, quant.) as a light yellow solid. MS: 344.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][NH2:11].CC([O-])(C)C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CC(O)(C)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH3:10])=[CH:3][CH:4]=1
Reactant: CN
Reactant: COc1ccc(Cl)cc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Product: CNc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following general procedure A, a mixture of 4-chloroanisole (123 μL, 1.0 mmol), 2M methylamine (1 mL, 2.0 mmol), NaOt-Bu (120 mg, 1.2 mmol), BrettPhos precatalyst 10 (8 mg, 0.01 mmol), and t-BuOH (1 mL) was stirred at room temperature for 2 h. The crude product was purified via column chromatography (20:1 CH2Cl2/MeOH) to provide the title compound as a yellow liquid that turned into a tan solid upon standing (126 mg, 92%). 1H NMR (400 MHz, CDCl3) δ: 6.80 (dt, J=9.0, 2.3 Hz, 2H), 6.59 (dt, J=9.0, 2.3 Hz, 2H), 3.76 (s, 3H), 3.46 (bs, 1H), 2.81 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 152.2, 143.9, 115.1, 113.8, 56.1, 31.8 ppm. Ali, H. I.; Tomita, K.; Akaho, E.; Kambara, H.; Miura, S.; Hayakawa, H.; Ashida, N.; Kawashima, Y.; Yamagishi, T.; Ikeya, H.; Yoneda, F.; Nagamatsu, T. Bioorg. Med. Chem. 2007, 15, 242.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(O)cc(=O)o1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC1CC(O)=CC(=O)O1
Yield: 90 %

Procedure:
6-t-Butyldimethylsilyloxymethyl-4-hydroxypyran-2-one (25.9 parts) was dissolved in ethanol (1600 parts) and the solution purged with nitrogen. 10% Palladium on carbon catalyst (5.2 parts) was added and the mixture hydrogenated at 20°-25° C. When the reaction was complete as judged by GC analysis the catalyst was filtered off and the solvent was distilled off under reduced pressure at 40° C. to leave 6-t-butyldimethylsilyloxymethyl-5,6-dihydro-4-hydroxy pyran-2-one (23.0 parts, 90%) m.p. 119°-122° C. as a light brown residue.
Reaction SMILES: N([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]N2C=NC=N2)=[CH:5][CH:4]=1)N.COC(OC)CC[CH2:20][N:21]1CCC1.C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O>[NH:21]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=2)[CH:9]=[CH:20]1
Reactant: COC(CCCN1CCC1)OC
Reactant: NNc1ccc(Cn2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A solution of 1-(4-hydrazinophenyl)methyl-1,2,4-triazole (0.92 g, 4.1 mmol) and 4-(1-azetidinyl)butanal dimethylacetal (0.65 g, 3.8 mmol), in 4% H2SO4 (30 ml), was refluxed for 4.5 h. The solution was cooled to room temperature, basified with K2CO3 and extracted with EtOAc (4×100 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed on silica-gel eluting with CH2Cl2 /MeOH/NH3 (40:8:1) to give the title-indole. The hydrogen oxalate hemihydrate salt was prepared (30 mg); m.p. 128°-129° C. Found: C, 57.28, H, 5.95; N, 18.05. C16H19N5.C2H2O4.0.45 H2O requires C, 56.97; H, 5.82; N,18.45%). δ (360 MHz, D2O) 2.30-2.54 (2H, m, CH2), 3.07 (2H, t, J=7.0 Hz, CH2), 3.52 (2H, t, J=7.0 Hz, CH2), 3.94-4.13 (4H, m, 2 of CH2), 5.51 (2H, s, CH2), 7.20 (1H, dd, J=1.5 and 8.4 Hz, Ar--H), 7.30 (1H, s, Ar--H), 7.51 (1H, d, J=8.4 Hz, Ar--H), 7.62 (1H, s, Ar--H), 8.05 (1H, s, Ar--H), 8.56 (1H, s, Ar--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([OH:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23].Br[CH2:40][CH2:41][CH3:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:40][CH2:41][CH3:42])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CCC2
Reactant: CCCBr
Product: CCCOc1cc2c(cc1OC)CCCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide with 1-bromopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:12]([C:14]([O:16][CH3:17])=[O:15])[NH2:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:11])[NH:13][NH:12][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)NN
Solvent: Cc1ccccc1
Product: COC(=O)NNC(=O)Nc1cc(Cl)cc(Cl)c1
Reaction time: 28 h
Yield: 81.9 %

Procedure:
3,5-Dichlorophenyl isocyanate (25 g, 133 mmol) was added dropwise to a cooled solution of methyl hydrazinocarboxylate (12 g, 133 mmol) in dry toluene (250 ml), with the temperature in the reaction flask maintained below 10° C. during the addition. After 28 h at RT, the precipitate was filtered, washed with toluene and isopropyl ether, and dried to yield the above compound as a white solid (30.3 g, mp=246° C.).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[C:1]([O:10][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCCCCO
Reactant: C=CCCCCCC(=O)O
Product: C=CCCCCCCCCOC(=O)CCCCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from oct-7-enoic acid and dec-9-en-1-ol. The resulting yellow oil was purified by silica gel chromatography (50:1 hexanes:diethyl ether) to afford the desired product as a colorless oil. IR (neat): 3077 (m), 2926 (s), 2855 (s), 1736 (s), 1641 (m), 1462 (m), 1417 (m), 1351 (m), 1255 (s), 1168 (s), 1113 (m), 1076 (m), 993 (s), 909 (s), 734 (m), 632 (m); NMR (400 MHz, CDCl3): δ 5.86-5.75 (2H, m), 5.02-4.91 (4H, m), 4.05 (2H, t, J=6.8 Hz), 2.29 (2H, t, J=7.6 Hz), 2.08-2.01 (4H, m), 1.67-1.59 (4H, m), 1.42-1.27 (14H, m); 13C NMR (100 MHz, CDCl3): δ 174.0, 139.2, 138.9, 114.5, 114.3, 64.5, 34.4, 33.9, 33.7, 29.5, 29.3, 29.1, 29.0, 28.8, 28.7, 28.6, 26.0, 25.0; HRMS (ESI+) [M+H]+ calcd for C18H33O2: 281.2481. found: 281.2475.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:9][N:10]=1)[CH:5]=[N:6][OH:7]>C(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:6]([O-:7])=[CH:5]2)=[CH:9][N:10]=1
Reactant: ON=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2cc(Cl)ncc2cc1-c1ccccc1Cl
Temperature: 60 °C
Yield: 84.8 %

Procedure:
A mixture of 2-chloro-5-((2-chlorophenyl)ethynyl)isonicotinaldehyde oxime (235 mg, 0.81 mmol) and silver nitrate (˜10 wt. % on silica gel, +230 mesh, 275 mg, 0.16 mmol) in chloroform (7 mL) was heated at 60° C. for 1 hour. The cooled reaction mixture was treated with silica gel (1 g), concentrated in vacuo, and purified by flash chromatography (silica, 12 g, ISCO, 0-90% ethyl acetate in heptane) to afford the title compound as pale yellow solid (200 mg, 80%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][S:64]([C:67]1[CH:73]=[CH:72][C:70]([NH2:71])=[CH:69][CH:68]=1)(=[O:66])=[O:65]>>[CH3:63][S:64]([C:67]1[CH:73]=[CH:72][C:70]([NH:71][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:69][CH:68]=1)(=[O:65])=[O:66]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(S(C)(=O)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.59 g, 4.6 mmol), diphenylphosphinic chloride (0.54 g, 2.3 mmol), then reacted with 4-(methylsulfonyl)aniline (Oakwood) (0.098 g, 0.57 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-methanesulfonyl-phenyl)-amide as a off white foam (Yield 0.11 g, 31%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]#[N:14].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.ClCCl>>[C:12]([CH2:13][NH:14][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)#[N:11]
Reactant: O=C(O)c1ccncc1
Reactant: N#CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCNC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of isonicotinic acid (1.00 g, 8.12 mmol), 2-aminoacetonitrile hydrochloride (0.902 g, 9.75 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (1.24 g, 8.12 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.71 g, 8.94 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.95 ml, 28.4 mmol) in dichloromethane (20.3 ml, 8.12 mmol) was allowed to stir at room temperature for 24 hours. The mixture was concentrated and the residue was purified by CombiFlash using 0-10% methanol/DCM as the eluent to 1.31 g of N-(cyanomethyl)isonicotinamide 5.3B. 400 MHz 1H NMR (CDCl3) δ: 9.62 (br s, 1H), 8.87 (d, J=8.0 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H), 4.30 (d, J=2H). LCMS (ES+) m/z 162.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:20][CH2:21][OH:22])[CH2:18][OH:19])=[CH:13][CH:12]=1)([OH:10])=[O:9].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[C:8]([C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[CH2:20][CH2:21][O:22][C:18]2=[O:19])=[CH:15][CH:16]=1)([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(C(CO)CCO)cc1
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc([C@H]2CCOC2=O)cc1

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-(4-carboxyphenyl)-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (2R)-2-(4-carboxyphenyl)butyrolactone as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]1[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=CCCCOc1nc2c(cc1Cl)CCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1CCc2cc(Cl)c(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of 4-(3-chloro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (400 mg, approx. 1.49 mmol, crude from previous reaction) in DCE (7 mL) was added 1-naphthalen-1-yl-piperazine hydrochloride (370 mg, 1.49 mmol) followed by Et3N (0.42 mL, 2.98 mmol). The solution was stirred for 15 min and NaBH(OAc)3 (410 mg, 1.94 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (0–3% MeOH/CH2Cl2) afforded the title compound as an off-white foam (324 mg, 0.697 mmol, 47%). Et2O was added and the foam turned into a white solid after 5 minutes of stirring. The solid was collected by filtration, washed with Et2O and dried to give a white solid. MS: APCI: M+1: 465.2 (Exact Mass: 464.20).
Reaction SMILES: Br[C:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([CH3:21])[N:13]=3)[CH2:8][CH2:7]2)[O:4][N:3]=1.[CH3:22][CH:23]([CH3:26])[C:24]#[CH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:22][CH:23]([CH3:26])[C:24]#[C:25][C:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([CH3:21])[N:13]=3)[CH2:8][CH2:7]2)[O:4][N:3]=1
Reactant: C#CC(C)C
Reactant: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(Br)=NO3)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(C#CC(C)C)=NO3)n1
Temperature: 120 °C
Yield: 33.1 %

Procedure:
A mixture of Compound 19a (50 mg, 0.141 mmol), 3-methyl-1-butyne (48 mg, 0.705 mmol), sodium carbonate (74.6 mg, 0.704 mmol) and Cu (44.8 mg, 0.705 mmol) was heated in a sealed vessel at 120° C. for 32 h, adding every 8 h additional equal amounts of amounts of 3-methyl-1-butyne, sodium carbonate and Cu. Afterwards, the mixture was cooled, added with CH2Cl2, filtered on celite and evaporated to dryness in vacuo. The residue was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 75:25 then isocratic Petroleum Ether-EtOAc from 9:1 giving 16 mg of the title product. Yield: 33.1%.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C(N2CCCCC2)C1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2cc(N)c(N)cc2C(N2CCCCC2)C1O
Yield: 94.7 %

Procedure:
0.28 g (0.87 mmol) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6-amino-7-nitro-2H-benzo[b]pyran was dissolved in 44.8 g of ethanol and hydrogen gas was blown in in the presence of 0.20 g of 5% palladium-carbon, as a catalyst, at room temperature for 3 hours under one atmospheric pressure while stirring. The reaction liquid was filtered under suction to remove the catalyst therefrom, and the solvent was removed by distillation to obtain 0.24 g (yield: 95%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6,7-diamino-2H-benzo[b]pyran as a dark red oil. 0.12 g (0.86 mmol) of thionylaniline and 4 g of benzenewere added thereto and heated under reflux for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate-ethanol=1:3) to obtain 60 mg (yield: 23%) of the intended compound as an yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH:20]=[O:21])[O:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH2:20][OH:21])[O:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(Oc1ccc(C=O)c(Cl)c1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(CO)c(Cl)c1)c1ccccc1
Yield: 91.8 %

Procedure:
A stirred solution of 1.49 g (4.90 mmol) of the product of Step A dissolved in 20 mL of methanol was treated with 0.093 g (2.46 mmol) of sodium borohydride at room temperature. After 5 minutes the reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was separated. The product was washed with water, brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 25% ethyl acetate/hexane to afford 1.380 g (92%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1C=Nc2c(Br)cccc21
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN1CS(=O)c2cccc(Br)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
4-Bromobenzothiazolone (5.75 g, 0.025 mole) was dissolved in a solution of sodium hydroxide (1.60 g, 0.0375 mole) in water (100 c.c.), and tetra-n-butylammonium bromide (0.24 g, 7.5×10-4 mole) and toluene (40 c.c.) were added thereto. Dimethyl sulfate (4.70 g, 0.0375 mole) was added fropwise thereto at room temperature, and the mixture was stirred at room temperature for 1 hour, followed by phase-separation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 6.00 g of 4-bromo-N-methylbenzothiazolone as white cyrstals. Yield 98.3%, purity 99.0%, m.p. 138°-140° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:34][N:35]3COCC[Si](C)(C)C)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)([CH3:22])[CH3:21].C(OCC)(=O)C>O1CCCC1>[CH3:22][C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)([CH3:19])[CH3:21]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C(C)(C)C)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(C(C)(C)C)cc3)ccc12
Temperature: 66 °C

Procedure:
14.6 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.13 g of N-[6-[4-(1,1-dimethylethyl)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 22 hours, the heating is then stopped and 75 cm3 of ethyl acetate are added, and the organic phase is washed with 75 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 10 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 10 cm3 of diisopropyl ether and then with 2×5 cm3 of ethyl acetate. After drying (90 Pa; 50° C.), 320 mg of N-[6-[4-(1,1-dimethylethyl)phenyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of a white product melting at 246° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:5]=1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>CC#N.O>[CH3:22][O:21][C:19]([N:10]1[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][CH:9]1[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:25])([F:26])[F:1])=[CH:24][CH:23]=1)=[O:20]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(OC(F)(F)F)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of dimethyl 2-(4-(trifluoromethoxy)benzyl)piperidine-1,4-dicarboxylate (9.72 g, 25.90 mmol) in MeCN (80 mL) and water (1.6 mL) was added lithium bromide (18.2 g, 209.57 mmol) and triethylamine (15 mL, 108.21 mmol). The resulting mixture was heated under reflux for 3 h, then cooled to room temperature. Water and MTBE were added. The organic phase was extracted with water twice. The pooled aqueous layers were adjusted to pH 1 with 3.8 M HCl and then extracted with DCM (3×). The mixture was filtered through a diatomeous earth filter carton. The combined organic layers were dried over MgSO4 and evaporated. 1-(Methoxycarbonyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-4-carboxylic acid (8.75 g, 94%) was isolated as a pale yellow solid. MS m/z 360 (M−H)−