Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@H:3]1[NH:8][CH2:7][C@@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:24]1[N:29]=[C:28]([NH2:30])[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][CH:25]=1.O>C(#N)C>[NH2:30][C:28]1[N:29]=[C:24]([N:8]2[C@H:3]([CH3:2])[CH2:4][CH2:5][C@H:6]([C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:10])[CH2:7]2)[CH:25]=[CH:26][C:27]=1[N+:31]([O-:33])=[O:32]
Reactant: C[C@@H]1CC[C@H](C(=O)N2CCCC2)CN1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CC[C@H](C(=O)N2CCCC2)CN1c1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of cis-(6-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (0.5 g, 2.15 mmol) in acetonitrile (10 mL) was added triethylamine (0.89 mL, 6.46 mmol). The mixture was stirred at room temperature for 10 min. Then 6-chloro-3-nitropyridin-2-amine (260 mg, 1.50 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h and then at room temperature for 12 h. Water was added and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate and concentrated under reduced pressure to afford cis-(1-(6-amino-5-nitropyridin-2-yl)-6-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (0.5 g). MS (ES+APCI) (M+H) 334.2; LCMS retention time 4.028 min (Method S1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.C1COCC1>[ClH:1].[CH2:13]([O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]2[NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:20][CH3:21])=[N:24][CH:25]=1)[CH3:14]
Reactant: CCOc1ccc(N)cn1
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Nc1ccc(OCC)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate (2.1 g), 2-ethoxy-5-aminopyridine (1.08 g), anhydrous potassium carbonate (2.17 g) and THF (60 ml) was stirred at ambient temperature for 48 hours. The mixture was evaporated to dryness and water added to the residue. The mixture was extracted with dichloromethane to give an oily solid. This solid was dissolved in IMS (20 ml) and the solution saturated with hydrogen chloride gas while cooling in ice. Ether was added to induce precipitation. The mixture was filtered to give ethyl 6-ethoxy-4-(2-ethoxy-5-pyridylamino)-1,5-naphthyridine-3-carboxylate hydrochloride, m.p. 187°-189° C. Borderline active (1/1) at 30 mg/kg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:39])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[C:10]([I:39])[N:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(F)cc3)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nc(I)c2snc(-c3ccc(F)cc3)c2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (400 mg, 1.25 mmol) in CH2Cl2 (12.5 mL) was added bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.29 g, 2.51 mmol). The reaction mixture was allowed to stir at r.t. for 20 h. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title product (382 mg) as a yellow solid: MS (m/z) 442.9 (M−1).
Reaction SMILES: [OH-].[Ba+2:2].[OH-].[NH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9](=[O:11])=[O:10]>O.C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1>[Ba+2:2].[C:9](=[O:11])([O-:10])[NH2:4].[NH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9](=[O:11])([O-:10])[NH2:4]
Reactant: O=C=O
Agent: NCC(=O)O
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Ba+2]
Solvent: O
Product: NC(=O)[O-]
Yield: 84 %

Procedure:
To a solution of barium hydroxide (160 g, 0.93 mole) in water (3.5 L), a solution of glycine (37.5 g, 0.5 mole) in water (200 ml) was added. After adding phenolphthalein (several drops), carbon dioxide gas was bubbled into the reaction mixture, at a constant rate, until the pink color of the indicator disappeared. The reaction mixture was cooled and filtered to obtain 105 g (84%) glycine carbamate barium salt (Ba++ - O2CNHCH2CO2-)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[C:21]=1F.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[F:19][C:20]1[CH:21]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:24][C:25]=1[O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(S(C)(=O)=O)cc4F)cc23)n1
Temperature: 77 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (250 mg; 1.033 mmol) and 424 mg (2.219 mmol) of the above-prepared sulfone compound were added to a solution of 320 mg (2.857 mmol) of tert-butoxy potassium in 24 ml of N,N-dimethylacetamide and the mixture was stirred at 77° C. for 12 hours. To the reaction solution was added water followed by extracting with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a reversed phase preparative HPLC (0.1% TFA-containing water:acetonitrile=90:10→10:90) to give 120 mg (yield: 28%) of the title compound as a yellow solid.
Reaction SMILES: ClCI.[CH2:4]=[C:5]1[CH2:9][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[C@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1.[Zn](CC)[CH2:21]C>ClCCCl>[C:14]1([C@@H:7]2[CH2:6][C:5]3([CH2:21][CH2:4]3)[CH2:9][C@H:8]2[C:10]([O:12][CH3:13])=[O:11])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Reactant: CC[Zn]CC
Agent: ClCI
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CC2(CC2)C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloroiodomethane (6.3 g, 35.5 mmol) was added to a 0° C. mixture containing 2.4 g (11.1 mmol) of methyl trans-4-methylene-2-phenylcyclopentanecarboxylate (J. Am. Chem. Soc. 1983, 105, 2315) in 25 mL of DCE followed by the addition of 17.8 mL (17.8 mmol) of Et2Zn (1M in hexanes). The reaction was stirred at 0° C. for 1 h before it was quenched with 1N HCl. The mixture was extracted with DCM (three times) and the combined extracts were dried over MgSO4 and concentrated. Column chromatography (9:1 Hexanes/EtOAc) afforded the desired compound as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:1][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=2)=[N:3][CH:4]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: COC(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 105 °C
Yield: 39.5 %

Procedure:
Methy 6-aminonicotinate (2 g, 13.1 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.94 g, 13.1 mmol, Eq: 1), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis-(diphenylphosphine) (400 mg, 691 μmol, Eq: 0.0526) were dissolved in DMF (300 ml) under heating. Cesium carbonate (12.8 g, 39.4 mmol, Eq: 3) was added followed by Pd2(dba)3 (301 mg, 329 μmol, Eq: 0.025) under an argon atmosphere. The reaction mixture was heated to 105° C. over night. The crude reaction mixture was poured into water (400 ml) and the resulting precipitate was filtered off and washed with water. The resultant filter cake was dissolved in dichloromethane. The organic phase was washed with brine, dried over sodium sulfate; filtered and concentrated to give the desired product as an off-white solid (1.523 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].Cl.C(=O)([O-])O.[Na+].[Na+].[Cl-].O>C(Cl)Cl.CO.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
In a mixture of 17 mL of methylene chloride and 13 mL of methanol was dissolved 5.79 g of pivaloyloxymethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate and the solution was cooled to 5° C. To this solution was added 3.7 mL of methanol containing 0.344 g of hydrogen chloride dropwise and the mixture was stirred at 5°-6° C. for 2 hours. Then, 11 mL of ethyl acetate and 11 mL of water were added and the mixture was adjusted to pH 6.2 with a saturated aqueous solution of sodium hydrogen carbonate. Then, 6 mL of ethyl acetate and 20% NaCl-H2O were added. The aqueous layer was taken and extracted with 12 mL of ethyl acetate. The organic layers were combined and redistributed into 22 mL of ethyl acetate and 20% NaCl solution. The organic layer was separated and concentrated and the residue was stirred in 15 mL of toluene at room temperature for 30 minutes. Then, 100 mL of hexane was added and the mixture was stirred under ice-cooling for 1 hour. The resulting crystals were collected by filtration, washed with 20 mL of toluene-hexane (1:9), and dried to provide 3.65 g of pivaloyloxymethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 91%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[C:4]([NH:8]C(=O)C)[CH:5]=[CH:6][CH:7]=1.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:20]
Reactant: CC(=O)Nc1cccc(F)c1C(=O)c1ccccc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)c1c(N)cccc1F
Temperature: 70 °C
Reaction time: 4 h

Procedure:
142 mg (0.52 mmol) N-[3-fluoro-2-(2-methyl-benzoyl)-phenyl]-acetamide are dissolved in 2 ml of ethanol, combined with 2 ml of conc. hydrochloric acid and stirred for 4 h at 70° C. Then the reaction mixture is stirred into 30 ml dist. water, adjusted to pH 7 with sodium carbonate and extracted three times with 10 ml of ethyl acetate. Then the organic phase is dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:10]([C:11]([CH3:13])=[CH2:12])[CH2:9][CH2:8][C:7]=1[CH3:14])[CH:3]=[O:4].C>O1CCOCC1.[Pd]>[CH3:1][CH:2]([CH2:5][C:6]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][C:7]=1[CH3:14])[CH:3]=[O:4]
Reactant: C=C(C)C1CCC(C)=C1CC(C)C=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CC1=C(CC(C)C=O)C(C(C)C)CC1
Yield: 94.2 %

Procedure:
19.2 g (0.1 Mole) of 2-methyl-3-(2-methyl-5-isopropenyl-cyclopent-1-en-1-yl)-propanal in 100 ml of dioxan were reduced by catalytic hydrogenation in the presence of traces of palladium over charcoal. After absorption of 2300 ml of hydrogen (10 hours) the reaction mixture was filtered and the clear filtrate evaporated under reduced pressure. The obtained residue was then distilled to give 18.3 g of the desired aldehyde;
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([C:12]#[N:13])=[C:4]([CH3:14])[N:3]=1.Cl[Sn]Cl.C(OCC)(=O)C>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([C:12]#[N:13])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1C#N
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(N)c(N)c(C)c1C#N
Temperature: 70 °C
Yield: 41.9 %

Procedure:
A mixture of 1.16 g (6.04 mmol) of 2-amino-4,6-dimethyl-3-nitro-5-pyridinecarbonitrile (17) and 5.72 g (30.1 mmol) of SnCl2 in 15 mL of ethanol was heated at 70° C. for 1 h. The solution was evaporated and the residue was treated with 40% NaOH to pH=12. The mixture was filtered and the solid was dried to leave a yellow solid. The solid was stirred with ethyl acetate (100 mL) and the mixture was filtered. The filtrate was evaporated to leave a pale yellow solid (410 mg, 41%). 1H NMR (CDCl3), 2,334 (s, 3), 2.522 (s, 3), 3.151 (mb, 2), 4.65 (mb, 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[Cl:19].[Cl-].[NH4+]>C(O)C.O.[Fe]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([Cl:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccncc2Br)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccncc2Br)cc1F
Temperature: 70 °C

Procedure:
To a solution of 3-bromo-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine (2.00 g, 5.75 mmol) in ethanol/water (9:1, 50 mL) was added iron powder (2.00 g, 35.8 mmol) followed by ammonium chloride (2.00 g, 37.4 mmol). The mixture was heated at 70° C. for 2 h. The reaction mixture was filtered, and the solids were washed with EtOAc. The filtrate was evaporated to dryness. The residue was taken in ethyl acetate and washed with water and dried. The solvent was evaporated to provide 4-(3-bromopyridin-4-yloxy)-5-chloro-2-fluorobenzenamine as light brownish oil (0.98 g, 53.6% yield). MS (ESI) m/z: 317.0/319.0 (M+H+).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@:17]12[CH2:26][O:25][C@@H:24]([CH:27]=[O:28])[CH2:23][C@H:22]1[CH2:21][S:20][C:19]([NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[N:18]2.[Cl-].[NH4+]>CS(C)=O.ClCCl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@:17]12[CH2:26][O:25][C@@H:24]([CH:27]3[CH2:4][O:28]3)[CH2:23][C@H:22]1[CH2:21][S:20][C:19]([NH:29][C:30](=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[N:18]2
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CO3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 295 mg, 7.38 mmol) was added to a solution of trimethylsulfoxonium iodide (97%, 1.83 g, 8.07 mmol) in dimethyl sulfoxide (15 mL). After 30 minutes, the mixture was cooled in an ice bath, and a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (1.12 g, 2.69 mmol) in dimethyl sulfoxide (5 mL) was added. The reaction mixture was allowed to warm to room temperature and stir for 2 hours, at which time saturated aqueous ammonium chloride solution was added, followed by dichloromethane, and the mixture was washed twice with water and with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was obtained as a white foamy solid, estimated to be a roughly 4:3 mixture of diastereomers by LCMS analysis; this material was used without additional purification. Yield: 1.19 g, quantitative. LCMS m/z 431.1 [M+H+].
Reaction SMILES: C([Li])CCC.CCCCCC.[I-].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1.[CH2:46]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH2:59][CH:58]([CH:62]=O)[CH2:57]1)=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1.O>[CH2:46]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH2:59][CH:58]([CH:62]=[CH:26][C:22]2[S:21][C:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)=[N:24][C:23]=2[CH3:25])[CH2:57]1)=[O:55])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
In an argon atmosphere, a solution of 1.59 mol/Ln-butyl lithium in hexane (2.03 mL, 3.23 mmol), chilled to −78° C., was added to a suspension of [2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyltriphenylphosphonium iodide (1.80 g, 2.94 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred for 1 hour as it warmed from −78° C. to room temperature. Subsequently, the mixture was chilled again to −78° C. and 1-benzyloxycarbonyl-3-formylpiperidine (727 mg, 2.94 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred at −78° C. for 1 hour and at room temperature for the subsequent 6 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate and washed with brine. The washed product was dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 1.16 g (87%) of the desired compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9](C(OCC)=O)[C:10]([O:12]CC)=[O:11])=[C:4]([F:20])[CH:3]=1.[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1cc(F)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Diethyl 2-(4-chloro-2,5-difluorophenyl)malonate (330 mg, 1.08 mmol) was dissolved in EtOH (1 mL), and then NaOH (0.6 mL, 5N) was added. The resulting solution was stirred at ambient for 12 hours. At this time, the reaction mixture was heated to 60° C. for 3 hours, after which it was acidified to a pH of 1 with HCl (1N). The reaction was diluted with water (1 mL) and then extracted twice with diethyl ether. The combined organics were dried over magnesium sulfate, filtered and concentrated to give 2-(4-chloro-2,5-difluorophenyl)acetic acid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH:7]=[CH2:8].C[O:19][C:20]([C@:22]1([CH:39]([CH3:41])[CH3:40])[CH2:26][C:25]2[CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:30][C:24]=2[O:23]1)=[O:21]>>[Cl:1][C:2]1[CH:12]=[C:11]([O:13][C:14]([F:16])([F:15])[F:17])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:28]1[CH:29]=[CH:30][C:24]2[O:23][C@:22]([CH:39]([CH3:40])[CH3:41])([C:20]([OH:21])=[O:19])[CH2:26][C:25]=2[CH:27]=1
Reactant: COC(=O)[C@]1(C(C)C)Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2O1
Reactant: C=CCCOc1ccc(OC(F)(F)F)cc1Cl
Product: CC(C)[C@@]1(C(=O)O)Cc2cc(CCCCOc3ccc(OC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the procedure described in Example 16, Step 3, employing the intermediate prepared in Step 1 instead of 5-[(buten-3-yl)oxy]-2-ethyl2,3-dihydro-1-benzofurancarboxylate and the triflate prepared in Step 2 instead of 2-chloro-4(trifluoromethoxy)phenyl trifluoromethanesulfonate.
Reaction SMILES: [H-].[Na+].Cl.[F:4][C:5]([F:24])([F:23])[C:6]([NH:8][C:9]1([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7].Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>CN(C=O)C>[F:19][C:18]([F:21])([F:20])[C:17]([NH:16][CH2:15][C:9]1([NH:8][C:6](=[O:7])[C:5]([F:4])([F:23])[F:24])[CH2:14][CH2:13][N:12]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH2:11][CH2:10]1)=[O:22]
Reactant: O=C(NCC1(NC(=O)C(F)(F)F)CCNCC1)C(F)(F)F
Reactant: BrCc1ccncc1
Agent: Br
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C(NCC1(NC(=O)C(F)(F)F)CCN(Cc2ccncc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NaH (170 mg of a 60% dispersion in mineral oil, 4.25 mmol) in anhydrous DMF (20 ml) is added 2,2,2-trifluoro-N-{4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidin-4-yl}-acetamide hydrochloride) (500 mg, 1.4 mmol) followed by 4-bromomethylpyridine hydrobromide (350 mg, 1.4 mmol). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is quenched with sat. NH4Cl solution and is concentrated in vacuo. The residue is purified by column chromatography (basic alumina, MeOH/DCM) to obtain 2,2,2-Trifluoro-N-[1-pyridin-4-ylmethyl-4-(2,2,2-trifluoro-acetylamino)-piperidin-4-ylmethyl]-acetamide as off-white solid; [M+H]+ 413
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)O>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:5][CH:6]([Cl:3])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(O)c1ccc(C2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
25 ml of thionyl chloride are added dropwise to a solution of 20.4 g of methyl-(para-cyclohexylphenyl)-carbinol in 100 ml of benzene and 3 ml of pyridine, and the mixture then refluxed for 5 hours. It is then poured on to ice, the aqueous mixture is extracted with ether, and the ethereal solution washed with sodium bicarbonate solution and water. When the solution is dried and the ether evaporated, α-methyl-para-cyclohexyl-benzyl chloride is obtained in the form of a dark viscous liquid which is processed directly.
Reaction SMILES: OO.[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][N:11]=[N+:12]=[N-:13])=[CH:6][CH:5]=1.C1(=O)OC(=[O:18])C=C1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[N+:9]([O-:18])[CH:8]=1)=[N+:12]=[N-:13]
Reactant: Cc1ccc(CN=[N+]=[N-])cn1
Reactant: O=C1C=CC(=O)O1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 756.4 %

Procedure:
After adding 30% aqueous hydrogen peroxide (7.5 ml, 6.6 mmol) dropwise to a solution of (6-methyl-3-pyridyl)methyl azide (8.9 g, 6.0 mmol) and maleic anhydride (6.5 g, 6.6 mmol) in methylene chloride (90 ml) over a period of 5 minutes while cooling on ice, the mixture was stirred at room temperature for 16 hours. Maleic anhydride (3.25 g) and 30% aqueous hydrogen peroxide (3.75 ml) were added in a similar manner while cooling on ice, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogencarbonate (100 ml) was added to the reaction mixture, NaHCO3 was further added to be basic, and extraction was performed with methylene chloride. The extract was washed with a brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off to yield crude 5-(azidomethyl)-2-methyl-1-pyridiniumolate (7.45 g). This was used without further purification for the following reaction.