Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:44]#[C:43][CH2:42][NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCNC(=O)OC(C)(C)C)cc2C(F)(F)F
Yield: 83 %

Procedure:
The title compound (170 mg, 83%) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (195 mg, 0.343 mmol) and 3-t-butoxycarbonylamino-1-propyne by the procedure similar to that described in Reference Example 21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C:12]3=[C:11]([C:28](=[O:39])[NH:29][C@@H:30]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:31]([NH:33][CH3:34])=[O:32])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][NH:17][CH2:18][C:12]3=[C:11]([C:28]([NH:29][C@@H:30]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:31]([NH:33][CH3:34])=[O:32])=[O:39])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccc(F)c(F)c2)n2c1CN(C(=O)OC(C)(C)C)CC(C)(C)C2)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccc(F)c(F)c2)n2c1CNCC(C)(C)C2)C(C)(C)C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
The product from step 1 above (128 mg, 0.23 mmol) was dissolved in 2 mL of DCM and carefully treated with 2 mL of TFA. The mixture was stirred for 45 minutes and concentrated in vacuo. The residue was suspended in 5 mL of toluene and concentrated in vacuo. The residue was dried in a vacuum oven overnight to give the title compound (182 mg, 99%) as a poly-TFA salt. LCMS (+ESI) m/z: 448.3 [MH]+1
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:31]([O:32][CH3:33])=[O:34])=[CH:20][CH:21]=1)(=[O:4])=[O:3]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(S(C)(=O)=O)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Methyl 2-(4-(methylsulfonyl)benzyl)piperidine-4-carboxylate (5.88 g, 18.88 mmol) was dissolved in DIPEA (4.93 mL, 28.32 mmol) and dichloromethane (150 mL). Methyl carbonochloridate (2.141 g, 22.66 mmol) was added dropwise and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between 1 M KHSO4 and diethyl ether. The organic layer was dried over Na2SO4, filtered through celite and evaporated to yield dimethyl 2-(4-(methylsulfonyl)benzyl)piperidine-1,4-dicarboxylate (5.5 g, 79%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][CH:15]1[CH2:20][CH2:19][Si:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C2C=CC=CC=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][C@H:15]1[CH2:20][CH2:19][Si@H:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:17][CH2:16]1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Reactant: CCOc1ccc(O)c(F)c1F
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(OCC)c(F)c2F)CC1

Procedure:
The general procedure of Example 9 was repeated using 2,3-difluoro-4-ethoxyphenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9](Cl)=O>N1C=CC=CC=1>[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]1[NH:5][C:3](=[S:4])[NH:2][N:1]=1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: NNC(N)=S
Solvent: c1ccncc1
Product: Cc1ccc(-c2n[nH]c(=S)[nH]2)c(C)c1
Temperature: 150 °C
Yield: 43 %

Procedure:
A suspension of thiosemicarbazide (800 mg, 8.78 mmol) in 9 mL of pyridine was added 2,4-dimethylbenzoyl chloride (1.68 g, 10 mmol). The reaction was heated at 150° C. for 10 min using a microwave synthesizer. The yellow solution was evaporated to dryness and then diluted with water. The white solid was then collected and washed with water. The solid was suspended in 20 mL of 1 M aq. NaHCO3. The suspension was heated at 180° C. for 1 h using a microwave synthesizer. Then the mixture was filtered hot and the aqueous solution was cooled in ice and acidified to pH 3 with conc. HCl. The solid was filtered and washed with water and dried to give white powder (43%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(Cl)cc2)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccc(Cl)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-chloro-phenyl)-methanone (Example 362) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4-chloro-phenyl)-methanone. MS (M+H)+, 410
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])=[CH:14][CH:13]=1
Reactant: CC1(C)NC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2C(=O)NC(C)(C)C2=O)cc1

Procedure:
Using 5,5-dimethylimidazolidine-2,4-dione (3.00 g) and 4-methoxybenzyl chloride (3.81 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (4.32 g) was obtained.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:22]=[C:21]([C:4]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=2[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: N#Cc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1cccc(C#N)c1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (iv) and 3-bromobenzonitrile.
Reaction SMILES: [CH:1]1([NH:7][C:8](SC)=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][CH2:20][CH:21]1[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:22]1>>[CH:1]1([NH:7][C:8]([NH:19][CH2:20][CH:21]2[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:22]2)=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C#N)=C(NC1CCCCC1)SC
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Product: CCOC(=O)C(C#N)=C(NCC1CN(Cc2ccc(F)cc2)CCO1)NC1CCCCC1
Yield: 10 %

Procedure:
This compound was synthesized as a yellow oily substance from ethyl 3-cyclohexylamino-3-methylthio-2-cyanoacrylate and 2-aminomethyl-4-(p-fluorobenzyl)morpholine according to the same procedure as in Example 8. Yield=10%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C@H:28]2[CH2:30][C@H:29]2[CH2:31]I)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([C@H:28]2[CH2:30][C@H:29]2[CH2:31][O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CI)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(Methylsulfonyl)benzyl alcohol (1.0 g, 5.4 mmol) was dissolved in DMF (12 mL), and sodium hydride (60 wt % dispersion in oil, 320 mg, 8 mmol) was added. The iodide from step A (2.35 g, 6.4 mmol) in DMF (12 mL) was added and the resulting solution was stirred at RT for 15 h. The solution was quenched with sat. NH4Cl, and EtOAc. The organic layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) which provided the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].Cl.[F:17][C:18]([F:24])([F:23])[O:19][CH2:20][CH2:21][NH2:22]>C(N(CC)CC)C>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:22][CH2:21][CH2:20][O:19][C:18]([F:24])([F:23])[F:17])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: NCCOC(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(NCCOC(F)(F)F)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (Step C of Example 2), 2-(trifluoromethoxy)ethanamine hydrochloride (J. Org. Chem. 2001, 66, 1061-1063.) and triethylamine.
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=1)N)([CH3:8])([CH3:7])[CH3:6].[I-:18].[K+]>O>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([I:18])[CH:15]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1ccc(C(C)(C)C)cc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1I
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
A solution of 8 g (0.11 mol) of sodium nitrite in 25 ml of water was added dropwise to a solution of 20 g (0.11 mol) of 5-tert-butyl-2-methoxyaniline in 120 ml of water/conc. HCL (1:1) cooled to 5° C. After stirring at 5° C. for 15 min, a solution of 19.1 g (0.11 mol) of potassium iodide in 25 ml of water was added dropwise and the solution obtained was stirred at RT for 4 h. It was extracted several times with DCM, and the separated organic phase was washed with 10% strength NaHSO3 solution and water, dried over Na2SO4, and concentrated. Chromatographic purification of the residue which remained on SiO2 using EA/heptane (1:40) yielded 27 g of the title compound in the form of a pale red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([C:21]2[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=2)([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(N)cccc32)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NS(C)(=O)=O)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step D above (0.080 g, 0.17 mmol) and N-methylmorpholine (0.035 g, 0.35 mmol) in DCM (1.0 mL) was added methanesulfonyl chloride (0.019 g, 0.17 mmol) at 0° C. After stirring at RT for 30 min, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=504.1[M+H]+.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[C:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:20])[CH3:19]>>[C:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:20])[CH3:19]
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: CC(=O)NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-acetyl-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 12.0 (s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 8.1 (d, 1H), 7.9 (m, 3H), 7.6 (d, 2H), 7.1 (d, 1H), 2.0 (s, 3H); ESI-MS m/z 413 (M−H)−.
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:18]([CH3:28])[CH2:19][NH:20][C:21]([O:23]C(C)(C)C)=O)[C:8]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]1[C:9]=2[CH2:10][CH2:11][CH2:12]1)=O)C.FC(F)(F)C(O)=O>ClCCl>[CH3:28][C@@H:18]1[CH2:19][NH:20][C:21](=[O:23])[C:6]2[N:7]1[C:8]1[C:9]3[CH2:10][CH2:11][CH2:12][C:13]=3[CH:14]=[CH:15][C:16]=1[CH:17]=2
Reactant: CCOC(=O)c1cc2ccc3c(c2n1[C@H](C)CNC(=O)OC(C)(C)C)CCC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC(=O)c2cc3ccc4c(c3n21)CCC4
Reaction time: 1 h
Yield: 63.6 %

Procedure:
(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-1,6,7,8-tetrahydro-1-aza-as-indacene-2-carboxylic acid ethyl ester (7.2 g, ˜17 mmol) was dissolved in dichloromethane (110 mL) and treated with trifluoroacetic acid (29 mL) at 0° C. After removal of the ice bath, the solution was stirred for 1 h, and evaporated under reduced pressure. The residue was dissolved in methanol (120 mL); after addition of saturated sodium bicarbonate solution (110 mL) and 2.6 g potassium carbonate the mixture was stirred for 20 h at room temperature. Water (100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Crystallization from diethyl ether yielded the title compound as a colorless solid (2.6 g, 57%). EI-MS: m/e 240.2 (M+).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][CH:15]1[CH2:19][CH2:18][CH:17]([CH3:20])[NH:16]1>>[CH3:14][CH:15]1[CH2:19][CH2:18][CH:17]([CH3:20])[N:16]1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC1CCC(C)N1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Product: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (300 mg; 1.62 mmol; 1 eq.) and 2,5-dimethylpyrrolidine (Maybridge AC11676DA; 0.70 mL; 5.72 mmol; 3.53 eq.) was stirred at 100° C. for 5 minutes in the MW. The solution was concentrated in vacuo and the residue taken up in water (100 mL). The aqueous phase was washed with diethyl ether (2×20 mL) then acidified to pH 5 with acetic acid. Extraction with diethyl ether (150 mL), drying over magnesium sulfate and concentration in vacuo afforded the title compound (360 mg, 84%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(c2ccc(N)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 4-(4-nitro-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 2.12 g, 8.00 mmol) and 10% Pd/C (1.06 g, 50 wt %) in 20 mL of MeOH was stirred at RT under H2 (balloon pressure) for 2 h. The Pd catalyst was removed by filtration on Celite and the filtrate was concentrated to give 1.69 g (90%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C13H17NO3, 236.1 (M+H). found 236.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([OH:6])=O.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([N:27]2[CH2:34][CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[CH2:28]2)[N:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([N:27]2[CH2:34][CH:33]3[CH:29]([CH2:30][N:31]([C:4]([C:3]4[C:7]([C:11]5[N:16]=[CH:15][CH:14]=[CH:13][N:12]=5)=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[O:6])[CH2:32]3)[CH2:28]2)[N:20]=1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4c(F)cccc4-c4ncccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 14 and Intermediate 39. MS (ESI) mass calcd. for C23H23FN6O3, 450.47; m/z found, 451.1 [M+H]+. 1H NMR (CDCl3): rotamers observed, 8.75-8.65 (m, 2H), 8.12-8.01 (m, 1H), 7.45-7.38 (m, 1H), 7.20-7.12 (m, 1H), 7.05 (t, J=4.9 Hz, 1H), 5.32 (s, 1H), 3.96-3.41 (m, 12.4H), 3.32-2.27 (m, 0.7H), 3.22-3.15 (m, 0.5H), 3.06-2.86 (m, 2.4H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:14])[C:3]=1[O:15]CC1C=CC=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:15][C:3]1[C:4](=[O:14])[O:5][C:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: CC1(c2ccccc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC1(c2ccccc2)OC(=O)C(O)=C1O

Procedure:
The 4-hydroxy-5-methyl-5-phenyl-3-phenylmethoxy-2-(5H)-furanone (1.2 g) was subjected to hydrogenation over 100 mg of 5% Pd/BaSO4 in 100 mL of MeOH at room temperature and under 30 psi H2. The reaction was monitored periodically by TLC analysis. The suspension was filtered through two #1 filter papers, concentrated to a white solid and recrystallized from MeOH/H2O to give 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone as a white crystalline material: mp 173-175° C. dec. 1H NMR (acetone-d6) δ 7.53-7.36 (m, 5H), 1.84 (s, 3H). Anal Calcd for C11H10O4+0.125 H2O: C, 63.38; H. 4.96. Found: C, 63.30; H, 4.96.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].N1C2C(=CC=CC=2)[CH:17]=N1.CO.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., “Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 ML of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H-NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73. (apparent q, 9.0 Hz, 2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][S:4][C:3]1=[O:7].[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1)=[O:9].II>O1CCCC1.[Zn]>[OH:9][CH:8]([CH:2]1[CH2:6][CH2:5][S:4][C:3]1=[O:7])[C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1
Reactant: O=C1SCCC1Br
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C(O)C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
3-Bromothiolan-2-one (315 mg) and ethyl 2-(4-formylphenyl)propionate (300 mg) were dissolved in tetrahydrofuran, and to the solution was added zinc (147 mg) and a catalytic amount of iodine, and the reaction mixture was heated until the mixture was refluxed. The reaction mixture was stirred overnight at room temperature, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (106 mg, 20%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>CCCCC.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:29]#[N:30])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCCCC
Product: N#CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
4-Fluorobenzoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.829 g of 4-fluorobenzoyl chloride (98%, Aldrich) (11.54 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.8 mL of trimethylsilyl cyanide (13 mmol) were added to a 100-mL round bottom flask. To this solution 0.29 mL of tin (IV) chloride (2.5 mmol) was added. On addition of the tin (IV) chloride, the color of the solution changed from clear to dark yellow and within 5 min the color of the solution was dark brown. The reaction mixture was stirred for 2 hr at room temperature, then quenched with 90 mL of ice-cold water, and finally extracted with two 90-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 90-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation. The dark brown residue which resulted was stirred with pentane. The pentane solution was decanted and the pentane removed by rotary evaporation to yield 0.911 g of 4-fluorobenzoyl cyanide as a yellow oil. The product was further purified by Kugelrohr vacuum distillation which afforded 0.666 g (39%) of 4-fluorobenzoyl cyanide as a colorless oil that solidified on standing in the freezer: IR (CCl4) (partial) 2220, 1685, 1600, 1505, 1410 cm-1.