Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(N(CC)CC)C.Cl>CN(C)C=O>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:29]2[C:13](=[O:14])[C:12]([C:7]3[NH:6][C:5]4[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)=[C:21]([OH:20])[C@H:23]3[C@@H:28]2[C@H:27]2[CH2:38][C@@H:24]3[CH2:25][CH2:26]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852; 2.51 g, 6.86 mmol), (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (For the preparation of β-amino acid intermediates see Examples 2f-1 described below) (2 g, 6.86 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.74 g, 7.2 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (18 mL). N-Methylmorpholine (3 mL, 27.44 mmol) was added and the mixture was stirred at 25° C. for 2 h. Triethylamine (3.82 mL, 27.44 mmol) was added and the mixture stirred at 60° C. for 16 h. Upon cooling, the mixture was slowly added to a 1.0 M aqueous hydrochloric acid solution (200 mL) while stirring. The product precipitated immediately. Stirring was continued for 5 min. The solid was collected by vacuum filtration, rinsed with water (2×60 mL) and dried in vacuo for 16 h to afford the desired product, (1S,2R,3S,4R)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (1.94 g, 3.27 mmol, 48%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.20-1.23 (1H, m), 1.38-1.61 (5H, m), 2.50-2.53 (1H, m), 2.62 (1H, d, J=3.2 Hz), 2.98 (1H, d, J=9.3 Hz), 3.52 (1H, d, J=9.4 Hz), 4.40 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=14.9 Hz), 7.12-7.16 (2H, m), 7.30-7.34 (3H, m), 7.97 (1H, dd, J1=8.6 Hz, J2=1.4 Hz), 8.07 (1H, d, J=1.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([C:9]([NH2:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:14]2[C:15]3[C:10](=[C:9]([NH2:16])[C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:11]([C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)=[C:12]([C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)[C:13]=2[C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: Nc1c2ccccc2c(N)c2ccccc12
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c2ccccc2c(N)c2c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)c12
Reaction time: 96 h
Yield: 86 %

Procedure:
In dimethylformamide, 0.05 mol of 9,10-diaminoanthracene, 0.35 mol of p-nitroiodobenzene, 0.14 mol of anhydrous potassium carbonate, and copper powder were added and refluxed with stirring for 4 days. After the reaction was completed, the reaction mixture was filtered, and the filtered product was thoroughly washed with dimethylformamide, water and acetone, followed by drying. Thus, 0.043 mol of brown tetrakis(p-nitrophenyl)-9,10-diaminoanthracene was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2ccc(C(F)(F)F)o2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 2-(bromomethyl)-5-(trifluoromethyl)furan: MS (ESI) m/z 375 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[I-].[Li+].Cl>N1C(C)=CC(C)=CC=1C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2occc2c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Oc1ccc2occc2c1
Yield: 49.1 %

Procedure:
To a solution of 5-methoxybenzofuran (3.6 g) in collidine (20 ml) was added lithium iodide (6.5 g), and the mixture was refluxed, under argon atmosphere, overnight, cooled, made acidic (pH=4) with hydrochloric acid and extracted with ethyl acetate (three times). The organic layer was washed with 1N hydrochloric acid (twice) and then washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give yellow oil of 5-hydroxybenzofuran (1.6 g).
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([CH3:14])=[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:8]=[C:7]2SC.[I-].[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH3:33])=[N+:30]([CH3:34])[C:29]=2[CH:35]=1.C(N(CC)CC)C>CN(C)C=O>[I-:1].[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]=[C:7]3[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=4)[N:10]([CH3:14])[C:9]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8]3)=[N+:30]([CH3:34])[C:29]=2[CH:35]=1
Reactant: Cc1sc2ccc(F)cc2[n+]1C
Reactant: COc1ccc2c(c1)c(SC)nc(-c1ccccc1)[n+]2C
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=Cc1sc3ccc(F)cc3[n+]1C)N=C(c1ccccc1)N2C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (1.41 mmol) 6-Methoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 436 mg (1.41 mmol) 5-fluoro-2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 3.0 ml dimethylformamide and 571 mg (0.79 ml, 5.64 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue was washed with water and methanol.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].O=C1CCCCC1C(OCC)=O.[Cl:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:22]([Cl:29])[C:21]=1I.[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34]>CS(C)=O.CC(=O)OCC>[Cl:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:22]([Cl:29])[C:21]=1[O:34][CH2:33][C:32]([F:36])([F:35])[F:31]
Reactant: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
A Mixture of Cs2CO3 (17.22 g, 52.84 mmol), CuBr (361 mg, 2.52 mmol) and ethyl 2-oxocyclohexanecarboxylate (856 mg, 5.03 mmol) in DMSO (30 mL) under N2 was stirred for 0.5 h at rt. Then a solution of 1,3-dichloro-2-iodo-5-nitrobenzene (8.0 g, 25.16 mmol) and 2,2,2-trifluoroethanol (3.02 g, 30.19 mmol) in DMSO (20 mL) was added to it. The reaction mixture was stirred at 80° C. for 18 h and cooled to room temperature, and then directly passed through celite. After rinsed with 250 ml of EA, the combined filter was washed by brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (100:1) to provide 1,3-dichloro-5-nitro-2-(2,2,2-trifluoroethoxy)benzene (1.93 g, yield 12.6%) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1>>[Br:1][C:2]1[C:3]([N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 19.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.01 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=496.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][CH2:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[K+].C(OCC)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[C:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[N:7][CH2:6][CH2:5]2
Reactant: O=C(NCCc1cccc(F)c1)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1ccc2c(c1)CCN=C2c1ccc(C(F)(F)F)cc1
Temperature: 170 °C
Reaction time: 0.08 h

Procedure:
A suspension of N-(3-fluorophenethyl)-4-(trifluoromethyl)benzamide (2.8 g, 8.9 mmol) and phosphoric pentoxide (0.6 g, 0.45 mmol) in polyphosphoric acid (62.0 g, 8.9 mmol) was heated at 170° C. for 75 min. The hot reaction mixture was poured into ice and KOH (20% W/V, 50 mL) was added followed by diethyl ether (100 mL) and stirred for 5 mins. Additional KOH was added until pH˜11.0 was achieved. Then, EtOAc (200 mL) was added and the mixture continued stirring at RT for an additional 5 min. and the ethyl acetate layer was separated. The aqueous layer was back-extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under vacuum to provide 6-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline as a yellow oil. MS (ESI pos. ion) m/z: 294 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].[C:15]([C:19]1[CH:20]=[C:21]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:22]([O:40][CH3:41])=[C:23]([NH:25][C:26]([C:28]2[N:29]([CH3:39])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][C:31]=3[CH:37]=O)=[O:27])[CH:24]=1)([CH3:18])([CH3:17])[CH3:16]>>[Cl:14][C:2]([Cl:1])([Cl:13])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:37][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:30]=2[N:29]([CH3:39])[C:28]([C:26](=[O:27])[NH:25][C:23]2[CH:24]=[C:19]([C:15]([CH3:18])([CH3:16])[CH3:17])[CH:20]=[C:21]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:22]=2[O:40][CH3:41])=[CH:36]3)[CH2:9][CH2:8]1)=[O:6]
Reactant: COc1c(NC(=O)c2cc3cccc(C=O)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCNCC1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OCC(Cl)(Cl)Cl)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Piperazine-1-carboxylic acid 2,2,2-trichloro-ethyl ester and 7-formyl-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide were reacted under the reductive amination conditions described in Example 2 to provide the desired 4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylic acid 2,2,2-trichloro-ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][CH:17]1[CH2:22][NH:21][CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=O)=O>>[CH3:16][CH:17]1[CH2:22][N:21]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH:20]([CH3:23])[CH2:19][N:18]1[S:24][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CC1CN(C(=O)C2CCN(c3ccncc3)CC2)C(C)CN1Sc1ccc2ccccc2c1
Yield: 13 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)piperazine to give (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphanyl)-4-[1-(4-pyridyl)-piperidin-4-ylcarbonyl)piperazine in 13% yield;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1[N:12]=[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12.C(N(C(C)C)CC)(C)C.O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][N:14]3[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][N:11]=[C:15]3[CH2:16]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)c1nnc2n1CCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1nnc2n1CCN(c1ccc([N+](=O)[O-])cn1)C2
Temperature: 80 °C
Yield: 73.9 %

Procedure:
2-Chloro-5-nitropyridine (0.97 g, 5.5 mmol), ethyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (1.0 g, 5.1 mmol), and diisopropylethylamine (2 mL) were mixed in acetonitrile (5 mL), and heated to 80° C. for one h. The mixture was poured into water, and the precipitate was collected by filtration. The precipitate was washed with water, then by ether, and dried in a vacuum oven overnight to give 1.2 gram of product C-12 (75% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[C:33](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])=[O:34]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH:24]([N:14]([C:12](=[O:13])/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:33](=[O:34])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:2]=1)[NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C(=O)C(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (60 mg, 0.17 mmol, 1.0 equivalent), K2CO3 (71.6 mg, 0.51 mmol, 3.0 equivalent), and DMAP (cat, 0.12 equivalent) were introduced and dissolved in DMF, after which Piv-Cl (0.04 ml, 0.34 mmol, 2.0 equivalent) was introduced. After stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=7:3:1) and dried so that solid form of (E)-N′-(3-(1-acetyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (10.3 mg, 14%).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[C:18]([Br:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:9])([CH3:6])[CH3:5].Cl>C1COCC1.[OH-].[Na+].CO>[Br:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)=[C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:33])=[O:2])=[O:9])[CH:19]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1cc(Br)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1cc(Br)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
96 mg 2-{[4-bromo-1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 0.5 ml THF, 0.56 ml of 2 M sodium hydroxide and 1.4 ml methanol were reacted in a microwave at 120° C. for 6 min. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated. After purification of the residue by RP-HPLC 11 mg of 2-{[4-Bromo-1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid were obtained.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29]([NH2:31])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1>CO.[Pd]>[OH:38][C@@H:23]([C@H:22]([OH:39])[C@H:21]([OH:40])[C@@H:20]([NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH2:11])[CH2:41][OH:42])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29]([NH2:31])=[O:30])=[O:25]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(N)=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
To a solution of (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionamide (200 mg) in methanol (10 ml) was added 10% palladium on activated carbon (50 mg) and the mixture was stirred under hydrogen atmosphere at room temperature for 20 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. Recrystallization from methanol-diethylether provided the title compound (140 mg).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[CH3:21][O:22][CH2:23][C:24]1[N:25]=[C:26]([NH2:29])[S:27][CH:28]=1>>[CH3:21][O:22][CH2:23][C:24]1[N:25]=[C:26]([NH:29][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:27][CH:28]=1
Reactant: COCc1csc(N)n1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: COCc1csc(NC(=O)c2cc(-c3cc(F)cc(F)c3)cc(C)n2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Methoxymethyl-thiazol-2-ylamine (CAS: [640768-40-7]) instead of 3-chloro-aniline to yield the final compound as a light brown solid, MS (ISP): m/e=376.3 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1
Reactant: OCCCCCCCCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCCCCCCCCCCOC1CCCCO1
Reaction time: 24 h

Procedure:
To a solution of 12-bromo-1-dodecanol (1 mole) in dichloromethane containing pyridinium p-toluenesulfonate (P-TSA) is added dihydropyran (2 moles). The reaction mixture is stirred for 24 hours and then washed twice with water and dried over anhydrous MgSO4. The dichloromethane is removed under reduced pressure. If necessary the resulting product is purified by chromatography on silica gel.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)OCCO2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)OCCO2
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine (11.58 g) in 1,4-dioxane/water (600 ml/180 ml), cooled in ice, was treated with an aqueous solution of osmium tetroxide (4% w/v, 25 ml) and sodium periodate (43 g). This mixture was allowed to warm to room temperature and after 7 hours under stirring the mixture was evaporated to dryness and azeotroped with 1,4-dioxane. Silica gel, 1,4-dioxane and chloroform were added and the mixture was evaporated to dryness overnight, then added to a silica column (400 g) and chromatographed, eluting with chloroform then 0-100% ethyl acetate in hexane, to afford a white solid (7.55 g, 64%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:4]1[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(C)c(-n2cc(C)c3c(=O)[nH]c(C)nc32)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-n2cc(C)c3c(Cl)nc(C)nc32)c(C)c1
Temperature: 0 °C

Procedure:
A mixture of the compound of step C (1.030 g, 3.67 mmol) and POCl3 (3 ml) was heated at reflux for 2.5 hours and cooled. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with dilute sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give the title compound as a tan solid which was purified through silica gel to give an off-white solid. 1H NMR (CDCl3) δ 1.90(s, 6H), 2.35(s, 3H), 2.50(s, 3H), 2.65(s, 3H), 6.78(s, 1H), 7.00(s, 2H) ppm.
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH3:19])=[O:11])(OCC)=O)C.[H-].[Na+].[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:36]([CH:37]=O)=[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]3[N:29]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:36]([CH:37]=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[CH2:18][CH3:19])=[O:11])=[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]3[N:29]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1c(-c2ccncc2)nn2ccccc12
Reactant: CCOP(=O)(CC(=O)N1CCCCC1CC)OCC
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2ccncc2)nn2ccccc12
Temperature: 24 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
A solution of 1-(2-diethoxyphosphorylacetyl)-2-ethylpiperidine (0.99 g) in tetrahydrofuran (1.8 ml) was added dropwise to a suspension of sodium hydride (60%, 0.14 g) in tetrahydrofuran (4.5 ml) at 23° to 25° C. After being stirred at 24° C. for 30 minutes, 2-(4-pyridyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.63 g) was added to the mixture and then stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous potassium carbonate solution and extracted with ethyl acetate (×2). The combined extracts were washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (25 g) with a mixture of chloroform and methanol (100:1) as an eluent. The fractions containing objective compound were combined and evaporated in vacuo to give crystals. This was recrystallized from a mixture of ethanol and water (1:1) to give 1-[3-{2-(4-pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (0.38 g).