Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Br:23])[C:21]=1[OH:22])[CH:17]=O.C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[CH:17][C:16]3[CH:15]=[C:14]([Br:13])[C:21]([OH:22])=[C:20]([Br:23])[CH:19]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)NC(=O)C2=Cc1cc(Br)c(O)c(Br)c1
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
6-cyano-1,3-dihydro-indol-2-one (46.3 mg, 0.29 mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (80 mg, 0.39 mmol) and p-toluenesulfonic acid monohydrate (1 mg, 0.005 mmol) were treated with toluene (30 mL) and the reaction refluxed with stirring with a Dean-Stark water trap attached for 1.5 h. During this time an orange solid deposited, which, on cooling, was filtered off, washed with toluene and dried in vacuo at 125° C. for 3 days to give 80 mg of 6-cyano-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one; 1H-NMR (DMSO-d6): δ11.05 (bs, 1H), 8.86 (s, 2H), 7.97 (s, 1H), 7.85 (d, J=7.9 Hz, 1 H), 7.50 (d, J=7.9 Hz, 1 H), 7.20 (s, 1H). Mass spectrum (negative ion electrospray): m/z=417 (M−1, 48%), 419 (M−1, 100%), 421 (M−1, 48%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:13]=2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:2]3[CH:3]=[C:4]([C:12]4[CH:17]=[CH:16][N:15]=[C:14]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH:13]=4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN(c2cc(-c3cc(Br)c4c(N)ncnn34)ccn2)CC1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1CCN(c2cc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)ccn2)CC1
Temperature: 80 °C
Yield: 20.6 %

Procedure:
To a stirred solution of 5-bromo-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (60 mg, 0.16 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (103 mg, 0.31 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) complex with dichloromethane (5.6 mg, 0.008 mmol) in degassed DME (1.2 mL) was added aqueous sodium carbonate solution (2 M, 232 □L). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL) and the layers were separated. The organic phase was washed with brine (25 mL), dried (Na2SO4), and concentrated. The crude material was purified by preparative HPLC using a gradient elution from 5% to 35% acetonitrile in water to obtain 17 mg (21%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.81-8.79 (m, 1 H), 8.58 (s, 1 H), 8.28-8.21 (s, 1 H), 7.98-7.94 (m, 1 H), 7.87-7.81 (m, 1 H), 7.68 (s, 1H), 7.41-7.29 (m, 5 H), 7.24-7.19 (m, 1H), 7.12-7.08 (m, 1 H), 6.97-6.91 (m, 1 H), 5.67 (s, 2 H), 3.58-3.52 (m, 4 H), 2.44-2.37 (m, 4 H), 2.22 (s, 3 H); ES-MS m/z 516.24 [M+H]+, HPLC RT (min) 2.28.
Reaction SMILES: [CH2:1]([CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])[CH2:2][CH2:3][CH3:4].[NH2:12][NH2:13]>C(O)C>[CH2:1]([C:5]1[C:9]([CH3:10])=[N:12][NH:13][C:6]=1[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C(C)=O)C(C)=O
Reactant: NN
Solvent: CCO
Product: CCCCc1c(C)n[nH]c1C
Yield: 102.6 %

Procedure:
At room temperature, to a mixture of 3-butyl-pentane-2,4-dione 7 g and ethanol 70 ml was added hydrazine one hydrate 3.3 g and the resulting mixture was stirred for twelve hours. The reaction mixture was subjected to a silica gel column chromatography to give 4-butyl-3,5-dimethyl-1H-pyrazole 7 g.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.[Br:11][CH2:12][C:13]([OH:15])=[O:14].C1(C(C)C)C=CC=CC=1>CC(C)=O>[Br-:11].[C:13]([CH2:12][N+:6]1[C:5]2[S:10][C:2]([Cl:1])=[CH:3][C:4]=2[S:8][C:7]=1[CH3:9])([OH:15])=[O:14]
Reactant: O=C(O)CBr
Reactant: Cc1nc2sc(Cl)cc2s1
Solvent: CC(C)c1ccccc1
Solvent: CC(C)=O
Product: Cc1sc2cc(Cl)sc2[n+]1CC(=O)O
Product: [Br-]
Temperature: 135 °C
Yield: 59.2 %

Procedure:
5- Chloro-2-methylthieno[2,3-d]thiazole (15.2 g), 13.3 g of bromoacetic acid and 24 ml of cumene were mixed and stirred with heating at outer temperature of 135° C. for 8 hours. After cooling the reaction mixture, 100 ml of acetone was added thereto. The crystals precipitated were filtered out by suction, washed with 50 ml of acetone, dried under reduced pressure, thereby 15.6 g of 3-carboxymethyl-5-chloro-2-methylthieno[2,3-d]thiazolium bromide (A) was obtained as yellow powder. To 7.4 g of (A), 18.5 g of 3-[5-chloro-2-(2-ethoxy-1-butenyl)-3-benzoxazolio]propanesulfonate and 70 ml of benzyl alcohol were added and stirred at room temperature. After that, 10.1 ml of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the above mixture and stirred at outer temperature of 50° C. for 20 minutes, 1,000 ml of ethyl acetate was then added thereto, a supernatant was removed by decantation to obtain a residue. The residue was dissolved in methanol and refined by Sephadex column chromatography. The refined product was dissolved in 150 ml of methanol, 3 g of potassium acetate was added thereto, after heating under reflux for 10 minutes, the mixture was allowed to be cooled, and the crystals precipitated were filtered out by suction. Methanol (300 ml) was added to the above-obtained powder, and the solution was heated under reflux for 50 minutes, then the solution was concentrated by distilling off 100 ml of the solvent. After cooling, the obtained crystals were recoveredby suction filtration, the filtrate was washed with 50 ml of methanol and dried under reduced pressure, thereby 2.65 g of orange powder of S-96 was obtained. The structure of S-96 was confirmed by 1H-NMR, FAB-MS, and elemental analysis. λmax (MeOH)=535 nm (ε=8.3×104)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:21])[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1.[Cl:24][C:25]1[N:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:28]2[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(O)CCC(C)(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
3-[4-(1-Hydroxy-4,4-dimethyl-pentyl)-benzoylamino]-propionic acid methyl ester (546 mg, 1.7 mmol) and 6-chloro-pyridin-3-ol (270 mg, 2.09 mmol) are combined in anhydrous toluene (10 mL), degassed, filled with nitrogen for 3 times, and cooled in an ice bath. Tributylphosphine (TBP) (630 uL, 2.55 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (ADDP) (643 mg, 2.55 mmol). The reaction mixture is allowed to warm to room temperature and stirred over night, the mixture is loaded on silica gel column. Chromatography gave the title compound (722 mg, 1.67 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:12][C:6]1[N:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([NH:1][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1
Temperature: 30 °C
Yield: 58.4 %

Procedure:
To a solution of 2-amino-7-chloro-1,8-naphthyridine (5.4 g) in pyridine (60 cc), benzoyl chloride (4.2 g) is added slowly, maintaining the temperature in the region of 30° C. After the solution has been maintained for 3 hours at a temperature in the region of 20° C., the product is precipitated in distilled water (340 cc). The solid produced after drying in the air is dissolved in boiling ethanol (88 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×5 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)benzamide (4.95 g) is thus produced, m.p. 198° C. EXAMPLE 9
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([OH:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)c(F)cc1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)cc(F)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylphenol (1.26 g, 6.15 mmol) in acetic acid (4 mL) and chloroform (2 mL) was added concentrated nitric acid (0.392 mL, 6.15 mmol) at −10° C. and the mixture was stirred at room temperature for 18 hours and then at 50° C. for 20 minutes (−50% desired product). The reaction mixture was diluted with ethyl acetate, then washed with water and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated and purified on silica gel (0-15% ethyl acetate/n-hexane) to afford 4-bromo-6-fluoro-3-methyl-2-nitrophenol (0.69 g, 2.76 mmol, 44.9% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d=7.57 (d, 1 H), 2.54 (d, J=1.2 Hz, 3 H); LC/MS (m/z) ES−: 247.96 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[C:44]1([CH2:50][C:51](Cl)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>O1CCCC1.C(OCC)(=O)C>[C:44]1([CH2:50][C:51]([NH:1][C@@H:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[CH2:7][S:8][C@H:3]23)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of benzhydryl 7β-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (500 mg) in tetrahydrofuran (12.5 ml) was added N-trimethylsilylacetamide (550 mg), and stirred at room temperature for 20 minutes. To the solution was added dropwise a solution of phenyl acetyl chloride (146 μl) above at -20° C. for 2 minutes. The mixture was stirred at -20~-15° C. for 50 minutes. To the reaction mixture were added water (50 ml), ethyl acetate (50 ml) and tetrahydrofuran (15 ml). The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give benzhydryl 7β-(2-phenylacetamido)-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (532 mg).
Reaction SMILES: O.[C:2]([NH:9][C:10](=[NH:19])[NH:11]C(OC(C)(C)C)=O)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>CC(OC)(C)C>[C:5]([O:4][C:2]([NH:9][C:10]([NH2:19])=[NH:11])=[O:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC(=N)N
Temperature: 57.5 °C

Procedure:
After addition of water (200.00 g) the resultant mixture was evaporated to yield a solid comprising the crude product together with inorganic salts and a small amount of bis-Boc-guanidine. The solids were suspended in 2-Me-THF (344.00 g), the suspension was stirred and heated to reflux and maintained at reflux for about 1 h. The suspension was then cooled to about 55-60° C. and filtered warm to remove the inorganic salts. Evaporation of the 2-MeTHF yielded a solid. This solid was re-suspended in MTBE (37.00 g) and the resultant suspension was stirred at ambient temperature for ˜1 h. The suspension was filtered, and the solid was washed with MTBE (18.5 g). The MTBE treatment was repeated again and the resultant product was air dried for several hours at ambient temperature. The product—N-(t-butyloxycarbonyl)-guanidine—was isolated as a solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]([F:22])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Cc2cccc(OC(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a solution of ethyl 4-[3-(trifluoromethoxy)benzyl]benzoate (Preparation 149, 950 mg, 2.93 mmol) in THF/MeOH/water (4:3:2, 27 mL) was added lithium hydroxide (246 mg, 5.86 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and acidified with 1M hydrochloric acid solution. The resulting precipitate was filtered off and dried to give the title compound as a white solid (600 mg, 69%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[F:21])=[N:8][N:9]([CH3:13])[C:10]=1[S:11][CH3:12].S(=O)(=O)(O)[OH:23]>>[Cl:5][C:6]1[C:7]([C:14]2[CH:19]=[C:18]([N+:1]([O-:4])=[O:2])[C:17]([Cl:20])=[CH:16][C:15]=2[F:21])=[N:8][N:9]([CH3:13])[C:10]=1[S:11]([CH3:12])=[O:23]
Reactant: CSc1c(Cl)c(-c2ccc(Cl)cc2F)nn1C
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1S(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of conc. sulfuric acid (1.65 g) and conc. nitric acid (sp. gr. 1.38, 8.4 mmoles) was added dropwise to a solution of 4-chloro-3-(4-chloro-2-fluorophenyl)-1-methyl-5-methylthio-1H-pyrazole (0.98 g, 3.4 mmoles) in 2 ml conc. sulfuric acid under cooling with ice. After the addition was finished, the reaction mixture was further stirred for 2 hours at room temperature, and allowed to stand overnight. Then the resulting mixture was poured into ice-cold water, and the formed crystals were filtered off, washed successively with water and ether, and dried, crystals (1.04 g) of the title compound, m.p. 151.0° C., yield 87.5%.
Reaction SMILES: O[CH2:2][CH:3]([CH:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]1[CH3:13])[C:4]#[N:5].N12CCCC=C1CCCCN2.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][CH:7]1[CH2:8][C:9]([CH3:12])([CH3:11])[CH2:10][CH:6]1[C:3](=[CH2:2])[C:4]#[N:5]
Reactant: CC1CC(C)(C)CC1C(C#N)CO
Agent: C1=C2CCCCNN2CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=C(C#N)C1CC(C)(C)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 3-hydroxy-2-(2,4,4-trimethylcyclopentyl)propanenitrile is placed in dichloromethane at 10° C. under an inert atmosphere. 2.2 eq. of DBU (diazabicyclo[5.4.0]undec-7-ene) and a few crystals of DMAP (4-dimethylaminopyridine) are added thereto, followed, dropwise, by 1.2 eq. of trifluoro-acetic anhydride. The reaction medium is stirred at ambient temperature overnight and is then poured onto water. The aqueous phase is extracted once with dichloromethane. The combined organic phases are washed with water. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([O-:17])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[N+:15]([C:18]1[CH:19]=[C:20]([NH:21][CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH:22]=[CH:23][CH:24]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc([N+](=O)[O-])c2)C1
Reaction time: 15 h
Yield: 55.5 %

Procedure:
To a solution of 1-Boc-3-piperidinone (256 mg) and 3-nitroaniline (190 mg) in methylene chloride (7 mL), sodium triacetoxyborohydride (438 mg) and acetic acid (80 μL) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 50% hexane in ethyl acetate) to obtain tert-butyl 3-((3-nitrophenyl)amino)piperidine-1-carboxylate (C21, 229 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](S(C)(=O)=O)=[CH:20][CH:19]=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3C=CC=C([O:92][CH2:93][CH2:94][N:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)C=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:92][CH2:93][CH2:94][N:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)[CH:19]=3)[S:17][C:10]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Yield: 29 %

Procedure:
Following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but substituting amine 49 for the amine 162, title compound 163a was obtained in 29% yield. Characterization of 163a is provided in the table 15. [LRMS (M+1) 643.3 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(O)C>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)ONCCC1CCNCC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)ONCCC1CCN(c2ccncc2)CC1

Procedure:
N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared as above) (14.4 g, 50 mmol), 4-chloropyridine HCl (1.0 eq., 8.0 g), TEA (2.2 eq.) are mixed in ethanol, and maintained under reflux overnight. The desired compound, N-t-butoxycarbonyloxy 2-[1-(pyrid-4-yl)piperidin-4-yl]-ethylamine, is isolated by column chromatography, (silica gel) eluted with EtOAc and carried to the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:25][C:26]1[CH:32]=[CH:31][C:29]([N:30]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=S(=O)(c1ccccc1)N1CCC(C(=Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 69 %

Procedure:
A mixture of 13.0 g (0.037 mol) of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone, 24.4 g (0.22 mol) of 4-fluoroaniline, and 0.7 g (0.004 mol) of benzenesulfonic acid in 500 mL of xylene was heated at reflux for 7 days. Water was removed with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 phase was dried (Na2SO4), and the solvent was removed in vacuo. The residue was recrystallized from CH2Cl2 /hexane to give 11.24 g (69%) of a light grey solid, mp 123°-124° C.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a cold (−50° C.) suspension of methyltriphenylphosphonium bromide (1.2 g, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of sodium bis(trimethyl-silyl)-amide (3.4 mL, 3.4 mmol), and the mixture was stirred for 1 h at room temperature. The resulting cloudy yellow solution was re-cooled to −30° C., and 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (0.5 g, 1.68 mmol) was added. The resulting slightly yellow solution was stirred at room temperature for 3 h, then diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and purified by column chromatography on silica gel using 15-30% ethyl acetate in hexanes as eluant to give 471 mg of the title compound as a colorless oil.