Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[CH:5]([CH2:6][CH:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1>[H][H]>[CH:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=[CH:2][CH:3]=1
Reactant: C1=CCC2CC3CCCCC3=CC2=C1
Reactant: [H][H]
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 480 °C
Yield: 101 %

Procedure:
In the dehydrogenation apparatus described in Example 2 the preheating zone was heated to a temperature of 480° C. and the reaction and afterheat zone were heated to a temperature of 520° C. 400 ml molten sym.-octahydroanthracene (385 g) of Example 3 were added drop by drop per hour from a drip funnel heated to 95° C. At the same time about 4 liter hydrogen per hour were added as a carrier gas. 372 g of raw anthracene were obtained per hour, which contained as impurities 1.8 percent 9,10-dihydroanthracene, 2.5 percent 1,2,3,4-tetrahydroanthracene, 2.6 percent sym.-octahydroanthracene and 2.9 percent phenanthrene.
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12].C(N(C(C)C)C(C)C)C.[C:29](Cl)(=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[F:6][C:7]1[CH:8]=[C:9]([CH2:10][CH:11]([NH:12][C:29](=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([OH:15])=[O:14])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCCC/C=C/C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC/C=C/C(=O)NC(Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are added slowly and then, dropwise, 3.64 g (24.9 mmol) of trans-2-heptenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for 2 days. For working up, it is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aqueous sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with ether, and the combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue is washed by stirring with diethyl ether and filtered. The filter residue is isolated, the filtrate is concentrated and again treated with diethyl ether. After repetition twice, a total of 6.12 g (79% of th.) of product are obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([CH3:12])[CH:3]=1.[H-].[Na+].Cl[C:16]([F:23])([F:22])C(OCC)=O>CN(C)C=O>[F:22][CH:16]([F:23])[O:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: COc1nc(C)cc(O)c1C#N
Reactant: CCOC(=O)C(F)(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(C)cc(OC(F)F)c1C#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 4-hydroxy-2-methoxy-6-methylnicotinonitrile (2.0 g, 12.2 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (880 mg, 36.6 mmol) at 0° C. and the mixture was stirred for 0.5 hour, Ethyl 2-chloro-2,2-difluoroacetate (5.4 g, 39.0 mmol) was added with vigorous stirring, over the course of 20 min. The suspension was warmed to 80° C. overnight under N2. The mixture was quenched into Na2CO3 (200 mL). It was partitioned between water (500 mL) and ethyl acetate (500 mL), the organic layer was dried and concentrated to afford the crude, which was purified by flash column (PE:EA=20:1) to afford 4-(difluoromethoxy)-2-methoxy-6-methylnicotinonitrile (550 mg yellow solid, 22.0% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([N:13]3[C:14]([CH3:18])([CH3:17])[CH2:15][O:16][C:27]3=[O:29])[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2)ns1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2)ns1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85.9 %

Procedure:
2-{[3-(4-Bromophenyl)-1,2,4-thiadiazol-5-yl]amino}-2-methylpropan-1-ol (0.80 g, 2.4 mmol), prepared in the previous step, was dissolved in methylene chloride (20 mL), triethylamine (3.3 mL, 24 mmol) was added, and the mixture was cooled to 0° C. Triphosgene (1.8 g, 6.1 mmol) was added and the mixture was stirred for 2.5 h. The mixture was then diluted with methylene chloride and washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (7.5% acetone/hexane) afforded the title compound (730 mg, 86%). Analytical HPLC: purity 100% at 210-370 nm, 11.0 min; 100% at 246 nm, 11.0 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.CC([O-])=O.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:6][C:7]=12
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3nccc3n2)cc1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (21.60 g, 65 mmol) in acetic acid (130 mL) containing anhydrous NaOAc (6.045 g, 74 mmol), was slowly added iodine monochloride (19.65 mL, 3.75M in HOAc). The reaction mixture was stirred at rt overnight. The suspension was diluted with water, the yellow crystalline filtrated, washed with water and dried in vacuum overnight to give 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (31.1 g, 100%) as yellow crystalline solid. MS (ISP) 458.2 [(M+H)+].
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:18][OH:19].C(O)(C)C.O>CC(C)=O>[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:18]([OH:3])=[O:19]
Reactant: CON=C(CO)c1ccccc1Cl
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CON=C(C(=O)O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
10 ml of Jones reagent (chromic anhydride in dilute sulfuric acid) were added to a solution in acetone of 0.40 g of 2'-chloro-2-hydroxyacetophenone O-methyloxime (the less polar isomer prepared above). The resulting mixture was stirred at room temperature for an hour and then 10 ml of isopropanol were added to it with ice-cooling. The reaction mixture was poured into 100 ml of water and extracted three times with 10 ml portions of ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give 320 mg (75%) of the title compound as a crude product.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11]CC2CCC[N+]2(C(C2C=CON=2)C(=O)N)C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]C1.[Br-].OC[C@H]1CCC[N+]1(CC(=O)NC1C=CON=1)C.[Br-].[OH:54][CH:55]1[CH2:60][CH2:59][N+:58]([CH3:70])([CH2:61][CH2:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:57][CH2:56]1.C1(C(C2C=CC=CC=2)(O)C(O)=O)CCCC1>>[Br-:1].[CH:2]1([C@@:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:54][CH:55]2[CH2:56][CH2:57][N+:58]([CH3:70])([CH2:61][CH2:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH2:59][CH2:60]2)=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+]1(CCCc2ccccc2)CCC(O)CC1
Reactant: C[N+]1(C(C(N)=O)c2ccon2)CCCC1COC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Agent: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [Br-]
Product: C[N+]1(CCCc2ccccc2)CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,2R)-2-((R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-pyrrolidinium bromide (Example 1) by replacing (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate B) with 4-Hydroxy-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (Intermediate K) and by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([NH:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([C:33]2[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=2[CH3:38])=[O:32])[CH2:23][CH2:22]1>N1CCCCC1.C(O)C>[CH:21]1([NH:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([C:33]2[C:34]([CH3:41])=[C:35](/[CH:39]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:36][C:37]=2[CH3:38])=[O:32])[CH2:22][CH2:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (27 mg), 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (25 mg) and piperidine (1 drop) in ethanol (2mL) was stirred at rt for 4 hours, the precipitate was collected by vacuum filtration and purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:38])(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16][CH:17]=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 816.6 %

Procedure:
Treat a solution of (R)-4-Benzyl-3-[(S)-2-(6-chloro-2,3-difluoro-4-trifluoromethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one (Preparation 45) (0.72 g, 1.5 mmol) in THF (9 mL) and water (3 mL) with 2.5% OsO4 in tBuOH (1.5 g, 0.15 mmol). Then, add sodium periodate (0.96 g, 4.5 mmol) to the solution and stir the reaction for 4 hr at room temperature. Quench the reaction with water and extract with EtOAc. Wash the organic with 1N sodium thiosulfate and brine. Separate the organic, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.60 g (82%) of desired product. MS (m/e): 490 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][S:30]([CH3:29])(=[O:32])=[O:31])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc(N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(NS(C)(=O)=O)cc21
Reaction time: 2.5 h

Procedure:
To a solution of 3-(7-amino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester, which can be prepared as described as in Example 45, (0.408 g, 1.36 mmol) and pyridine (0.162 g, 2.04 mmol) in dichloromethane (4 mL) at 0° C. is added methanesulfonyl chloride (0.168 g, 1.47 mmol) and the reaction is stirred for 2.5 hours. The solution is then washed with 10% aqueous HCl and water and the combined aqueous phases are extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to give a residue, which is purified by silica gel chromatography (dichloromethane-methanol mixtures) to give 3-(7-methanesulfonylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 378.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.38 (d, J=6.3 Hz, 3 H), 1.40 (d, J=6.3 Hz, 3 H), 1.84-1.93 (m, 2 H), 2.19-2.33 (m, 2 H), 2.87 (dt, J=16.9, 6.6 Hz, 1 H), 2.88 (s, 3 H), 3.01 (dt, J=16.9, 6.3 Hz, 1 H), 5.24 (sept, J=6.3 Hz, 1 H), 6.32 (t, J=6.1 Hz, 1 H), 6.81 (d, J=2.0 Hz, 1 H), 7.21 (dd, J=8.3, 2.0 Hz, 1 H), 7.26 (d, J=8.3 Hz, 1 H), 7.51 (s, 1 H), 7.75 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH:15](=O)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:15]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:16]
Reactant: CC=O
Reactant: Fc1ccc(NCc2c[nH]cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(Cc1c[nH]cn1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of (4-fluoro-phenyl)-(1H-imidazol-4-ylmethyl)-amine (0.20 g, 1.05 mmol) in 1,2-dichloroethane (6 ml) were added acetaldehyde (0.30 ml, 5.23 mmol), sodium triacetoxyborohydride (0.67 g, 3.14 mmol) and acetic acid (0.06 ml). The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/ethyl acetate/heptane gradient) to yield a white solid (131 mg, 57%); MS (ISP): 220.4 ((M+H)+.).
Reaction SMILES: [CH:1]([C@H:4]1[C:20](=[O:21])[O:19][C@H:18]([CH:22]=[CH2:23])[CH2:17][C:16](=[O:24])[NH:15][CH2:14][C:13]2=[N:25][C:10](=[CH:11][S:12]2)[C:9](=[O:26])[NH:8][C:7]([CH3:28])([CH3:27])[C:6](=[O:29])[NH:5]1)([CH3:3])[CH3:2].[Br:30][CH2:31][CH2:32]C=C>ClCCCl>[Br:30][CH2:31][CH2:32]/[CH:23]=[CH:22]/[C@@H:18]1[CH2:17][C:16](=[O:24])[NH:15][CH2:14][C:13]2=[N:25][C:10](=[CH:11][S:12]2)[C:9](=[O:26])[NH:8][C:7]([CH3:27])([CH3:28])[C:6](=[O:29])[NH:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:20](=[O:21])[O:19]1
Reactant: C=C[C@@H]1CC(=O)NCc2nc(cs2)C(=O)NC(C)(C)C(=O)N[C@@H](C(C)C)C(=O)O1
Reactant: C=CCCBr
Solvent: ClCCCl
Product: CC(C)[C@@H]1NC(=O)C(C)(C)NC(=O)c2csc(n2)CNC(=O)C[C@@H](/C=C/CCBr)OC1=O
Temperature: 85 °C

Procedure:
To a mixture of (7S,10S)-7-isopropyl-4,4-dimethyl-10-vinyl-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-diene-2,5,8,12-tetraone (20 mg, 0.047 mmole) in 2 mL 1,2-dichloroethane was added 4-bromo-1-butene (25.6 mg, 0.19 mmole) and Zhan-1 catalyst (3.2 mg, 0.0047 mmole). The mixture was briefly degassed and then heated in a sealed tube at 85° C. overnight. The crude product was concentrated and passed through a silica gel plug to get a mixture of the desired product and recovered starting material (2:1 ratio). It was further purified by reversed phase chromatography, eluted with 0-80% water/CH3CN to get the desired product (8 mg, 32% yield).
Reaction SMILES: [OH:1][C@@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.C(#N)C>[OH:1][C@@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:12]([F:29])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Yield: 33 %

Procedure:
To a solution of (R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 6) (1 g, 2.06 mmol, 1 eq) in DMF (19 mL) was added dropwise a mixture of Selectfluor (801 mg, 2.26 mmol, 1.1 eq) in acetonitrile (9 mL) and DMF (5 mL) at ambient temperature while stirring under nitrogen. The reaction mixture was stirred for 10 minutes at ambient temperature and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH3CN in H2O) to give (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 18) as an off-white solid. The recovered starting material was subjected to the same reaction conditions to produce a second crop of product. The total yield of product was 347 mg (33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.36-3.40 (m, 1H) 3.43-3.50 (m, 1H) 3.58 (s, 3H) 3.61-3.72 (m, 1H) 3.72-3.82 (m, 1H) 4.27-4.37 (m, 1H) 4.78-4.87 (m, 1H) 5.14 (d, J=5.81 Hz, 1H) 6.93-7.03 (m, 1H) 7.53 (d, J=8.84 Hz, 1H) 7.65-7.74 (m, 1H) 8.52 (s, 1H) 10.25 (d, J=1.01 Hz, 1H). [M+H] calc'd for C17H15F2IN4O4, 505; found, 505.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([Cl:27])=[CH:11][C:12]([O:15][CH2:16][C:17]3[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([F:14])=[C:12]([O:15][CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(=O)O)csc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of methyl(4-chloro-7-fluoro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (133 mg), THF (dry) (2.0 mL) and MeOH (2.0 mL) was added 1N NaOH (0.913 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl. The resulting precipitate was collected by filtration to give a solid. The solid was crystallized from EtOAc-hexane to give the title compound (114 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:31](I)[CH3:32].CN(C)C=O>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 6.4 g of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid, 3.1 g of sodium hydrogencarbonate, 8.6 g of ethyl iodide and 20 ml of N,N-dimethylformamide is heated at 100° C. with stirring for 3 hours. Further, 2.9 g of ethyl iodide and 1 g of sodium hydrogencarbonate are added to the reaction solution, followed by heating at 100° C. for 2.5 hours. After cooling, 200 ml of water is added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with water, 0.1 N hydrochloric acid and dilute aqueous sodium hydrogen-carbonate solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl 7-(1-benzyloxycarbonyl-4piperidyl)heptanoate as an oily material.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][OH:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCCC1CO
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine (trans isomer) (0.50 g) was added to a stirred solution of acetic anhydride (0.16 g) in pyridine (5 ml) at room temperature, and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture and washed with 1N aqueous sodium hydroxide solution, water and saturated sodium chloride aqueous solution, then dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (50 g) with a mixture of chloroform and acetone (20: 1) as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-acetoxymethylpiperidine (trans isomer) (0.35 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=O)[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C@:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][C@H:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Reactant: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C

Procedure:
Reaction of 4 (50 mg, 37 mmol) according to the method described for the preparation of 5 using (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid tert.butyl ester instead of 2-amino-pentanoic acid tert.butyl ester provided the title compound as a slightly yellow oil (50 mg, 38%).