Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([O:20][C:8]2[C:9]3[O:10][C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=4[C:2]=3[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(OC2CCCC2)c(Oc2ccc([N+](=O)[O-])cc2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OC2CCCC2)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 130 °C
Reaction time: 7 h
Yield: 56.4 %

Procedure:
Intermediate 47 (500 mg, 1.09 mmol), anhydrous sodium carbonate (150 mg, 1.325 mmol) and palladium (II) acetate (25 mg, 0.096 mmol), in dimethylformamide (10 ml) are heated and stirred under nitrogen at 130° C. for 7 h. Water (90 ml) is added to the cooled reaction mixture and extracted with ethyl acetate (2×25 ml). The combined organic layer was washed with 5% hydrochloric acid followed by water and dried over anhydrous sodium sulfate to afford the product as a yellow solid (200 mg). mp: 230-240° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:23]([CH2:24][NH:25][CH2:26][CH3:27])=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=1)[CH3:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[C:43](OC(=O)C)(=[O:45])[CH3:44]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:23]([CH2:24][N:25]([C:43](=[O:45])[CH3:44])[CH2:26][CH3:27])=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc2ccccc2nc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(3-ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester; dihydrochloride and acetic anhydride.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:18][C:19]1[CH:20]=[C:21]([CH:26]([CH:31]2[CH2:34][NH:33][CH2:32]2)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:23]([F:25])[CH:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:33]2[CH2:34][CH:31]([CH:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)[C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:32]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A mixture of 263 mg (0.86 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 213 mg (0.574 mmol) of 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidine and 300 uL (1.72 mmol) of N,N-diisopropylethylamine in 6 mL of acetonitrile was heated to reflux for 3 h. Then the solution was concentrated and the residue was dissolved in 5 mL of hexane/ether. 1.5 mL of 1N HCl in ether was added to above solution to make salt. It was filtered and washed with hexane/ether. The residue was neutralized with base and was purified by silica gel chromatography with hexanes/ethyl acetate to afford one racemic diastereomer of the title compound; Mass Spectrum: m/e=465 (M+1 35Cl) and 467 (M+1 37Cl).
Reaction SMILES: [O:1]=[C:2]1[N:6](C(OC(C)(C)C)=O)[C:5]2=[CH:14][S:15][C:16]([C:17]3[S:18][C:19]([C:26]4[S:27][CH:28]=[C:29]5[C:33]=4[NH:32][C:31](=[O:34])[N:30]5C(OC(C)(C)C)=O)=[C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=34)=[C:4]2[NH:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[O:1]=[C:2]1[NH:6][C:5]2=[CH:14][S:15][C:16]([C:17]3[S:18][C:19]([C:26]4[S:27][CH:28]=[C:29]5[C:33]=4[NH:32][C:31](=[O:34])[NH:30]5)=[C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=34)=[C:4]2[NH:3]1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2c(-c3sc(-c4scc5c4[nH]c(=O)n5C(=O)OC(C)(C)C)c4c3OCCO4)scc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2csc(-c3sc(-c4scc5[nH]c(=O)[nH]c45)c4c3OCCO4)c2[nH]1
Reaction time: 3 h

Procedure:
To the obtained tert-butyl 4-[7-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-2,3-dihydrothieno[3,4-b]-1,4-dioxin-5-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was added 40 equivalents of trifluoroacetic acid, and then a reaction was performed at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then an organic layer was taken and the solvent was distilled off. The residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 4-[7-(2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-2,3-dihydrothieno[3,4-b]-1,4-dioxin-5-yl]-2,3-dihydro-1H-thieno[3,4-d]imidazol-2-one was obtained. The yield based on the charged tert-butyl 4-[7-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-2,3-dihydrothieno[3,4-b]-1,4-dioxin-5-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was 90%.
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C1C=CC=CN=1)C.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=1.C(N(CC)CC)C>ClCCl.O>[Cl:28][C:24]1[CH:23]=[C:22]([NH:21][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1ccnc(Cl)c1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
1.69 g (7.78 mmol, 1 eq) of tert-butyl dicarbonate dissolved in 50 ml of dichloromethane, in the presence of 95 mg of dimethylaminopyridine, are added to a solution of 1 g (7.78 mmol, 1 eq) of 4-amino-2-chloropyridine in 30 mL of dichloromethane in the presence of 1.19 mL (1.19 mmol, 1.1 eq) of triethylamine. The reaction mixture is stirred overnight at room temperature. The reaction is stopped by adding 100 ml of water and is then extracted with dichloromethane. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 to 50/50 heptane/ethyl acetate). The oil obtained is crystallized from pentane. 1.40 g of tert-butyl (2-chloropyrid-4-yl)carbamate are obtained. Yield=80%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1>C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1)=[O:1]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1)OCc1ccccc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl ((2R,3S)-2-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (360 mg, 1.09 mmol) and MnO2 (2.36 g, 27.2 mmol) in THF (11 mL) was stirred at room temperature for 2 h, whereupon the mixture was filtered through celite and concentrated. The resulting material (340 mg, 95%) was used as such in step 3.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5].C(Cl)Cl.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)=CCCC(C)CC(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(C)CCC=C(C)C
Reaction time: 3 h

Procedure:
A solution of 47 g. of 4,8-dimethylnon-7-en-2-ol in 250 ml. of methylene chloride is cooled to about 10° as a solution of 46.4 g. of sodium dichromate in 125 ml. of water is added. The mixture is at about 10° as a solution of 46.3 g. of sulfuric acid in 100 ml. of water is added over about 45 minutes. The mixture is allowed to attain room temperature and, after about 3 hours, the organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic materials are washed with saturated potassium bicarbonate, water and saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 4,8-dimethylnon-7-en-2-one.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[C:8]([N+:16]([O-])=O)[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>[Pd]>[CH:1]1([C:6]2[CH:7]=[C:8]([NH2:16])[C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Nc1ccc(C2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C2CCCC2)cc1N
Temperature: 90 °C
Reaction time: 5 h
Yield: 49.5 %

Procedure:
A suspension of N-(4-cyclopentyl-2-nitrophenyl)acetamide (Preparation 86, 19.48 g, 78.46 mmol) in aqueous sodium hydroxide (6.0M, 100 mL, 600 mmol) was heated at 90° C. for 4 days. The reaction was allowed to cool and extracted with methylene chloride (3×). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The resulting residue was suspended in methanol (300 mL) and treated with palladium (2 g, 20 mmol, 10% on carbon, Degussa type). The reaction mixture was hydrogenated at 40 psi for 5 hours before filtering through celite and concentrating in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (6.85 g, 50%) as a purple solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.CON(C)[C:36]([C:38]1([CH3:44])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:37]>>[CH3:44][C:38]1([C:36]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=4)[N:9]=3)[NH:4][CH:3]=2)=[O:37])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CON(C)C(=O)C1(C)CCOCC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCOCC4)c3n2)cc(OC)c1OC

Procedure:
(4-Methyl-tetrahydro-pyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 4-methyl-tetrahydro-pyran-4-carboxylic acid methoxy-methyl-amide following general procedures as described in these Examples. 66, to afford a pale yellow solid. M+H=412.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.CC1C=CC(S(O[CH2:55][CH2:56][N:57]2[CH2:61][CH2:60][O:59][C:58]2=[O:62])(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:62]=[C:58]1[N:57]([CH2:56][CH2:55][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[CH2:61][CH2:60][O:59]1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1OCCN1CCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(2-oxooxazolidin-3-yl)ethyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (46%) as a colorless solid: mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.08 (dd, J=7.3, 7.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.78 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.33-4.22 (m, 1H), 4.21-4.00 (m, 2H), 3.93-3.58 (m, 4H), 3.57-3.43 (m, 1H), 3.05-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 161.8, 161.3, 158.7, 141.7, 132.4, 129.0, 124.1, 123.7, 120.0, 119.0, 108.3, 93.2, 80.5, 72.5, 62.1, 57.7, 44.3, 41.7, 37.3, 29.0; MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.[CH:39]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][N:41]([C:48](=O)[CH2:49]Cl)[CH2:40]2>>[CH:39]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][N:41]([CH2:48][CH2:49][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=1)[CH2:40]2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CC2CCC(CC2)C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CC4CCC(CC4)C3)cc2)c1
Yield: 41.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 1-(3-azabicyclo[3.2.2]non-3-yl)-2-chloroethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.7 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)(C)C>[CH3:9][O:8][C:6]([CH:5]1[CH2:10][CH2:11][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
One mole of methyl 4-hydroxybenzoate was reacted with two moles of hydrogen in the presence of 5% palladium-carbon catalyst. This reaction was carried out in isoproyl alcohol at a temperature of 170°-180° C. and a hydrogen pressure of 20-40 kg/cm2. After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to obtain cyclohexanone-4-carboxylic acid methyl ester as the distillate at 140° C./20 mmHg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si](C(C)C)(C(C)C)C(C)C)[N:18]=[CH:17]3)[CH:10]([CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)[CH:10]([CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(N3CCN(Cc4ccccc4)C(=O)C3CC3CCOCC3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(c3ccc4[nH]ncc4c3)C(CC3CCOCC3)C2)cc1
Temperature: 120 °C
Yield: 58.9 %

Procedure:
To a solution of 1-benzyl-3-(tetrahydro-pyran-4-ylmethyl)-4-(1-triisopropylsilanyl-1H-indazol-5-yl)-piperazin-2-one (0.55 g, 1.0 mmol) in 10 mL of THF in a 20 mL microwave vial at 0° C. was slowly added a 1.0 M solution of LiAlH4 (2.1 mL, 2.1 mmol). After gas evolution ceased the vial was capped and heated at 120° C. for 600 seconds in a microwave. The solution was quenched by slow addition to a slurry of NaSO4 decahydrate in THF. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. Purification via flash chromatography afforded 5-[4-benzyl-2-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-1H-indazole (0.23 g, 59%) as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1>[O-2].[Fe+3].[O-2].[O-2].[Fe+3].[Mo](=O)(=O)=O>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: O=[Mo](=O)=O
Agent: [Fe+3]
Agent: [O-2]
Product: CC1(C)COC(=O)C1=O

Procedure:
A mixture of iron (III) oxide and molybdenum trioxide (G-105 from Girdler) is used as the catalyst in the reactor described in Example 1 and the temperature of the air bath is adjusted to 225° C. 60 l of air and 33 g of pantolactone are subsequently added hourly to the evaporator. 96% of the pantolactone are transformed and ketopantolactone is formed with a selectivity of 83%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
Intermediate A (128 mg, 0.77 mmol) was added portionwise to a suspension of sodium hydride (60% in mineral oil, 92 mg, 2.30 mmol) in dry DMF (3 mL) at RT and stirred for 15 mins. Intermediate 5b (169 mg, 0.77 mmol) was then added in one portion and the mixture heated at 60° C. for 4 h. After cooling, saturated NH4Cl (ca 0.2 mL) was added. The mixture was partitioned between water (10 mL) and ethyl acetate (3×10 mL). The aqueous phase was concentrated in vacuo and the residue purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give the title compound as brown coloured foam (103 mg, 36%). LCMS (Method 1): Rt 1.34 min, m/z 364 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([OH:20])=O)[CH3:2].O=S(Cl)Cl.[NH2:25][C:26]1[C:43]([F:44])=[CH:42][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:32]=2)=[C:28]([F:45])[CH:27]=1.N1C=CC=CC=1>C(Cl)Cl.O>[F:44][C:43]1[CH:42]=[C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:32]=2)[C:28]([F:45])=[CH:27][C:26]=1[NH:25][C:18]([C:5]1[C:6](=[O:17])[N:7]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])=[O:20]
Reactant: CCC(=O)Nc1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(=O)CC)c2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A solution of Example B1, (5.2 g, 18.8 mmol) in SOCl2 (50 mL, 685 mmol) was heated at 60° C. for 2 h. The mixture was azeotroped with toluene and concentrated to dryness. The solid was dissolved in DCM (150 mL), cooled to 0° C. and treated with a solution of Example A3 (5 g, 17.1 mmol) and pyridine (0.14 mL, 1.74 mmol) in DCM (100 mL) over 20 min. The reaction mixture was stirred at 0° C. for 10 min and then warmed to RT for 2 h. Water (5 mL) was added and the mixture was concentrated in vacuo. The residue was triturated with water (200 mL) and the solids were collected by filtration, washed with water and dried under vacuum. The solids were dissolved in DCM (400 mL), washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), dried over Na2SO4, and concentrated to dryness. The solids were triturated with hexanes/EtOAc (1:1), collected by filtration and dried under vacuum to give N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (7.5 g, 82.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.52 (s, 1H), 8.33 (dd, J=12.6, 7.2 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.50-7.48 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 6.72 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 2.33 (q, J=7.5 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H), 0.99 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 553.2 (M+H+).
Reaction SMILES: [CH:1]1[C:14]2[S:13](=[O:16])(=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:21])CCC>O1CCCC1.CCCCCC>[Li:21][C:1]1[C:14]2[S:13](=[O:15])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)c2ccccc2Oc2ccccc21
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]c1cccc2c1S(=O)(=O)c1ccccc1O2
Temperature: -40 °C

Procedure:
A mixture of phenoxathiin 10,10-dioxide (50.5 g) in dry tetrahydrofuran (500 mL) under nitrogen was cooled in an acetone/dry ice bath. To this slurry was added a 1.6 M solution of n-butyllithium in hexane (144 mL) at a rate which maintained the reaction temperature at -40° C., resulting after 30-45 min. in an orange solution of 1-lithiophenoxathiin 10,10-dioxide. To this solution was added ethyl iodide (35 mL), after which the reaction mixture was allowed to warm to room temperature. After about 3-4 hr the yellow solution was partially evaporated under reduced pressure and was then partitioned between methylene chloride and water. The methylene chloride phase was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to a yellow residue which was purified by column chromatography on Silica Gel 60 (E. Merck, Darmstadt, Germany) eluting with toluene. The desired fractions were combined and evaporated, and the residue was crystallized from ethyl acetate/pentane to give 1-ethylphenoxathiin 10,10-dioxide, mp. 112°-114° C. (del. 102°-104° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][C:6]([C:13]([OH:15])=[O:14])=[N:7]2.[C:17]1([S:23]([N:26]=C=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:26][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH:5]=[C:6]([C:13]([O:15][CH2:11][CH2:2][CH2:3][CH3:4])=[O:14])[NH:7]2
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C1=Nc2cc(Cl)cc(Cl)c2C(=O)C1
Solvent: CC#N
Product: CCCCOC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 16 h

Procedure:
Combine 5,7-dichloro-quinolin-4-one-2-carboxylic acid, butyl ester (1.00 g, 3.2 mmol) and benzenesulfonyl isocyanate (0.85 mL, 6.3 mmol) in acetonitrile (15 mL). Heat to reflux under an inert atmosphere. After 16 hours, quench with methanol (5 mL). Evaporate in vacuo. Chromatograph on silica gel eluting with 2% acetone/dichloromethane. Recrystallize from ethyl acetate/hexane to give the title compound as a solid: TLC Rf =0.38 (silica gel, 2% acetone/dichloromethane); mp; 94°-95° C. Elem. Anal. calculated for C20H18Cl2N2O4S: C, 52.98; H, 4.00; N, 6.18. Found: C, 53.27; H, 3.95; N, 6.12.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:14]1>>[F:25][C:22]([F:23])([F:24])[C:21]([NH:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:14][CH2:15]1)=[O:26]
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: CC(C)n1ncc([N+](=O)[O-])c1Cl
Product: CC(C)n1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 52 %

Procedure:
Reaction of 5-chloro-1-isopropyl-4-nitro-1H-pyrazole and (R)-N-(azepan-4-yl)-2,2,2-trifluoroacetamide gave (R)-2,2,2-trifluoro-N-(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide as a pale yellow gum (90 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 6.39 (s, 1H), 4.83-4.70 (m, 1H), 4.24-4.17 (m, 1H), 3.45-3.32 (m, 1H), 3.28-3.12 (m, 3H), 2.23-2.02 (m, 2H), 2.00-1.80 (m, 4H), 1.54-1.44 (m, 6H)