Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.OO.[C:18](=O)([O-])[O-:19].[K+].[K+].S(OC)(OC)(=O)=O>CO>[CH3:18][O:19][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[CH3:11])[CH:4]=[C:5]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1Cc2c(C)ccc(C)c2N1
Agent: OO
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: COC(=O)c1cc2c(C)ccc(C)c2n1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A flask was charged with 1.0 g (4.9 mmol) of methyl 4,7-dimethylindoline-2-carboxylate and 64 mg (0.193 mmol) of sodium tungstate-dihydrate, and the air in the reaction system was substituted with nitrogen. After 15 ml of methanol was added and the reaction mixture was cooled to 0° C., 1.25 g of 30% aqueous hydrogen peroxide solution was added and the reaction mixture was stirred for 3 hours. Then 1.1 g of potassium carbonate and 0.68 g of dimethyl sulfate were added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to ice water and extracted with 15 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals thus obtained were purified by silica gel column chromatography to provide 400 mg of white crystals. Yield: 36% m.p.: 90°-91° C.; 1H-NMR (300 MHz, CDCl3 /TMS; δppm): 7.16 (s, 1H), 7.00 (d, 1H), 6.82 (d, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 2.68 (s, 3H), 2.48 (s,3H)
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.C(O)C>[C:10]1(=[O:11])[N:6]([CH2:5][CH2:4][C:3]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[CH:2]=2)[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: Nc1ccccn1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCc1cn2ccccc2n1
Yield: 57.7 %

Procedure:
1-Bromo-4-phthalimidobutan-2-one (23.6 g.) was added to a solution of 2-aminopyridine (7.6 g.) and sodium bicarbonate (6.8 g.) in dimethylformamide (100 ml.) and the mixture was heated at 100° for 1 hour. Cooling followed by addition to water and recrystallisation from ethanol afforded 2-(2-phthalimidoethyl)imidazo [1,2-a]-pyridine (13.4 g.) m.p. 181° - 181.5°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:11])=[CH:5][NH:6]2.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:11])=[CH:5][N:6]2[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c[nH]c2cccc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C)c3c(Br)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
4-Bromo-3-methyl-1H-indole (1.33 g) was dissolved in dimethylformamide (20 mL), and sodium hydride (0.33 g) was added thereto under ice-cooling. After stirring at 0° C. for 15 minutes, p-methoxybenzyl chloride (0.95 mL) was added thereto. The reaction solution was stirred under heating at 70° C. for 30 minutes and partitioned between ethyl acetate and 1M HCl aqueous solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (45a) (2.09 g, 99%) as a colorless oily substance.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:44][C:45]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=1)[CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[N:17][C:18]=2[NH:22][O:23][CH3:24])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH:10]([O:44][C:45]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=1)[CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[N:17][C:18]=2[NH:22][O:23][CH3:24]
Reactant: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1ncn2CCC(CO[Si](C)(C)C(C)(C)C)OC(c1ccccc1)(c1ccccc1)c1cccc(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1ncn2CCC(CO)OC(c1ccccc1)(c1ccccc1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 15 (10.6 g, 12.02 mmol) in THF (120 mL) is treated with tetrabutyl ammonium fluoride (1M in THF, 12.1 mL) and the reaction mixture stirred at room temperature for 2 h followed by concentration. The residue is purified on a silica gel column using ethyl acetate:hexanes:methanol (1:1:0 to 1:1:0.1) to give 8.87 g (96%) of 16 as a white solid: 1H NMR (DMSO-d6): δ 8.21 (s, 1H), 7.92 (s, 1H), 7.38-7.05 (m, 25H), 6.89 (d, J=9.1 Hz, 2H), 6.82 (d, J=9.0 Hz, 2H), 5.09 (t, J=5.4 Hz, 1H), 4.88-4.77 (m, 1H), 3.77-3.70 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 2.96-2.76 (m, 2H), 2.44-2.27 (m, 1H), 2.27-2.11 (m, 1H). IR (KBr, cm−1) 3412, 2932, 1734, 1606, 1509, 1251 and 1033. Anal. Calcd for C49H45N5O4.0.25 H2O.0.4 EtOAc: C, 75.25; H, 6.08; N, 8.67. Found: C, 75.35; H, 6.04; N, 8.50.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9].Br[C:18]([F:25])([F:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C([Zn]CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:16][C:13]([CH3:14])([S@:11]([NH:10][C@@:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:9])[C:18]([F:25])([F:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])[CH3:15]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(=N[S@](=O)C(C)(C)C)c1ccccc1F
Agent: [Rh]
Agent: CC[Zn]CC
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
Tris(triphenylphosphine)rhodium(I) chloride (1.50 g, 1.62 mmol) was placed in a dry round bottom flask. The flask was evacuated and filled with argon (×3). (R)—N-(1-(2-Fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (15.6 g, 64.6 mmol) was dissolved in tetrahydrofuran (265 ml) (dried over 4 Å MS) and added to the reaction flask followed by ethyl bromodifluoroacetate (26.2 g, 16.6 ml, 129 mmol). The dark red/orange reaction mixture was cooled to 0° C. using an ice/water bath. Diethyl zinc (126 ml, 126 mmol, 1 M in hexane) was added in a dropwise manner. Upon complete addition the reaction was stirred at 0° C. for an additional 1 h, the cooling was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (250 mL) and quenched with saturated aqueous NaHCO3 (100 mL). The resulting suspension was filtered through a plug of celite, the phases were separated, and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified using a CombiFlash system (330 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40) to afford (R)-ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluorophenyl)butanoate (14.1 g, 59.7% yield). The stereochemistry was assigned based on literature precedence (WO2012110459) 1H NMR (600 MHz, CDCl3) δ 7.46 (t, J=8.0 Hz, 1H), 7.41-7.35 (m, 1H), 7.19-7.14 (m, 1H), 7.07 (dd, J=13.0, 8.2 Hz, 1H), 4.65 (d, J=2.6 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.07 (s, 3H), 1.30-1.21 (m, 12H).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27]C(N)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:3]([NH:2]/[CH:4]=[C:5]3\[C:6](=[O:15])[NH:7][CH2:8][C:9]4[C:14]\3=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NCc4ccccc43)cc2)CC1
Temperature: 110 °C
Yield: 25.2 %

Procedure:
A toluene (3 mL) solution containing (4E)-4-[(dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone (300 mg, 1.48 mmol) and 4-(4-methyl-piperazin-1-yl) -phenylamine (318 mg, 1.66 mmol) is heated at 110° C. for 4 h. Using the same workup as example 1, 0.13 g (25%) orange solid is obtained: mp 186-187° C. (dec.); HRMS (ESI) m/z calcd for C21H24N4O 349.20229. found 349.20180 (M+H)+1.
Reaction SMILES: O[CH:2]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[O:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH:3]=[CH:2][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[O:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CC2OC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CC=Cc1ccc(CC2OC(=O)NC2=O)cc1
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A mixture of 5-[4-[1-hydroxy-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]benzyl]-2,4-oxazolidinedione (0.21 g), p-toluenesulfonic acid monohydrate (p-TsOH.H2O) (0.1 g) and toluene (40 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate and water, dried (MgSO4) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:2), 5-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-propenyl]benzyl]-2,4-oxazolidinedione (0.14 g, 70%) was obtained, which was then recrystallized from dichloromethane-isopropyl ether to yield colorless needles having a melting point of 168°-169° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:6]([CH2:8][CH2:9]Cl)[N:7]=1.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:24]=[N:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C>CO>[CH3:1][S:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:22]4[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=4[N:25]=[N:24]3)[CH2:31][CH2:30]2)=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:4]=1
Reactant: Fc1ccc2c(c1)nnn2C1CCNCC1
Reactant: CSc1nc(CCCl)c(-c2ccc(F)cc2)[nH]1
Agent: CSc1nc(-c2ccc(F)cc2)c(CCCl)[nH]1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(-c2ccc(F)cc2)c(CCN2CCC(n3nnc4cc(F)ccc43)CC2)[nH]1
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 0.141 g of 2-methylthio-4-(2-chloroethyl)-5-(4-fluorophenyl)imidazole, 2-methylthio-5-(2-chloroethyl)-4-(4-fluorophenyl)imidazole, 0.095 g of 4-(5-fluoro-1H-benzotriazol-1-yl)piperidine, 0.19 ml of diisopropylethylamine and 0.6 ml of methanol was stirred with heating under reflux for 17 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Chromatorex NHDM1020, eluent: hexane-ethyl acetate=1:3). The purified product was recrystallized from ethanol-hexane to obtain 0.104 g of 2-methylthio-4-(4-fluorophenyl)-5-[2-[4-(5-fluoro-1H-benzotriazol-1-yl)piperidin-1-yl]ethyl]imidazole {2-methylthio-5-(4-fluorophenyl)-4-[2-[4-(5-fluoro-1H-benzotriazol-1-yl)piperidin-1-yl]ethyl]imidazole}.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:24]([F:27])([F:26])[F:25])([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>C(OCC)C>[F:16][C:12]1[C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([C:24]([F:26])([F:27])[F:25])([O:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[CH2:4][OH:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(CC(C)(C)c1cccc(F)c1OC)(O[Si](C)(C)C)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1c(F)cccc1C(C)(C)CC(CO)(O[Si](C)(C)C)C(F)(F)F
Temperature: 25 °C

Procedure:
5.24 g (12.34 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 45 ml of diethyl ether and mixed at 0 to 5° C. in portions with 936.9 mg (24.69 mmol) of LiAlH4. After four and one-half hours of stirring at room temperature, the reaction mixture is carefully mixed with saturated NaHCO3 while being cooled in an ice bath, stirred for one hour under cold conditions and overnight at room temperature. After the usual working-up, 4.11 g (87.1%) of a mixture that consists of the desired compound and the compound in which the silyl ether has migrated is obtained. The mixture is incorporated in crude form into the next stage.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:53]1[CH2:58][CH2:57][O:56][CH2:55][CH:54]1[C:59]1[C:67]2[S:66][C:65]([NH2:68])=[N:64][C:63]=2[C:62]([O:69][CH3:70])=[CH:61][CH:60]=1>C1COCC1.C(Cl)(Cl)Cl>[O:53]1[CH2:58][CH2:57][O:56][CH2:55][CH:54]1[C:59]1[C:67]2[S:66][C:65]([NH:68][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][N:19]=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[CH:12]=3)=[N:64][C:63]=2[C:62]([O:69][CH3:70])=[CH:61][CH:60]=1
Reactant: O=C(O)c1ccnc(COCCN2CCCC2=O)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COCCN4CCCC4=O)c3)nc12

Procedure:
From 2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxymethyl]-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+84.1° (c=1.02, CHCl3), ES-MS m/e (%): 513 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].[CH3:14][NH2:15]>O>[CH3:14][N:15]1[C:1](=[NH:2])[C:3]2[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=2[S:10]1(=[O:12])=[O:11]
Reactant: CN
Reactant: N#Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: O
Product: CN1C(=N)c2c(Cl)cccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7.1 g of 2-cyano-3-chlorobenzenesulphonylchloride were added to a solution of 9 ml of methylamine in approx. 15 ml of water cooled at 0° C. After stirring at 0°-10° C. for 1 hour, the solid was sucked off, washed with water and dried in air. The desired product was obtained in a yield of 5,5 g; melting-point 140°-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc(C#N)cn1
Yield: 44.2 %

Procedure:
(S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g), 6-chloronicotinonitrile (0.21 g), potassium carbonate (0.41 g) and diisopropylethylamine (0.78 ml) were heated in xylene at 130° C. for 26 h, cooled and the mixture filtered through kieselguhr. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title compound (0.2 g). Mass Spectrum (API+): Found 303 (MH+). C16H22N4O2 requires 302.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[O:5]([C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18](=[N:20][OH:21])[CH3:19])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1(C2CCCCCCC2)CCCCCCN1>C(#N)C>[CH3:1][NH:2][C:3](=[O:5])[OH:4].[O:5]([C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18](=[N:20][OH:21])[CH3:19])=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN=C=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Agent: CC(COc1ccc(Oc2ccccc2)cc1)=NO
Solvent: CC#N
Product: CNC(=O)O

Procedure:
With stirring, a solution of 3.42 g of methyl isocyanate in 10 ml of acetonitrile is added dropwise over 30 minutes at room temperature to a solution of 12.85 g (0.05 mole) of 4-phenoxyphenoxyacetone oxime and 0.05 g of diazabicyclooctane in 90 ml of acetonitrile. After stirring for 7 hours at 40° C., the solvent is distilled off by rotary evaporation and the residue is purified by chromatography over 200 g of silica gel (eluant: a 3:1 mixture of diethyl ether and hexane). The main fraction is subsequently recrystallised in diethyl ether, affording 4-phenoxyphenoxyacetone oxime N-methyl carbamate (compound 5) of the formula ##STR20## with a melting point of 60°-62° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[N:29]([C@@H:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C@H:31]2[OH:43])[C:28](=[O:44])[CH2:27][S:26]1>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:27]4/[C:28](=[O:44])[N:29]([C@@H:30]5[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]5[OH:43])[C:25](=[O:24])[S:26]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)CSC2=O)[C@H](O)C1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1O

Procedure:
(5Z)-5-({1-[4-Fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-hydroxypiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from [4-fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 5) and 1,1-dimethylethyl trans-4-(2,4-dioxo-1,3-thiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (from Example 270) following General Procedure F.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][OH:11])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:13][O:14][C:15]([C:17]1[O:21][NH:20][C:19](=O)[CH:18]=1)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[O:21][N:20]=[C:19]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:12])[CH:18]=1)=[O:16]
Reactant: CCCCc1noc(C)c1CO
Reactant: COC(=O)c1cc(=O)[nH]o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 3-butyl-5-methyl-4-isoxazolyl-methanol (1.5 g, 8.9 mmol) in THF (30 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (1.27 g, 8.9 mmol) and triphenylphosphine (2.79 g, 10.6 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 4.25 mL, 9.8 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) afforded the title compound (1.44 g, 55%) as a colourless liquid. MS: m/e=295.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[O:15])[CH:12]=2)[NH:7][CH:6]=1>CO>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccc(CO)cc12
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A 50 ml hydrogenation bomb is charged with 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Example 13) (1.0 g, 4.62 mmol) and methanol (10 mL). The bomb is purged with hydrogen (three times to 200 psi and release to atmospheric pressure), and then pressurised to 200 psi. After stirring for one hour, the pressure is released, and a solution of [Rh DiPFc (COD)]BF4 (6.6 mg, S/C=500) in methanol (1 ml) is added through a septum port. The bomb is pressurized with hydrogen to 200 psi, and left stirring at ambient temperature for 18 hours. Removal of the solvent from the hydrogenation mixture gives the title product (1.05 g, quant.) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:16][NH:17][O:18][CH3:19].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([N:17]([O:18][CH3:19])[CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)acetic acid (1 g, 5.1 mmol), N,O-dimethylhydroxylamine hydrochloride (480 mg, 5.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (978 mg, 5.1 mmol), hydroxybenzotriazole (690 mg, 5.1 mmol) and triethylamine (2.57 g, 25.5 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=8:1) to afford 2-(3,4-dimethoxyphenyl)-N-methoxy-N-methylacetamide (370 mg, yield 30.3%).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:18][CH2:19][OH:20].[ClH:21]>>[ClH:21].[OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[NH:5])[O:20][CH2:19][CH3:18]
Reactant: COCCOCCOc1cccc(C#N)c1O
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cccc(OCCOCCOC)c1O

Procedure:
A solution of 2-hydroxy-3-(2-(2-methoxyethoxy)ethoxy)benzonitrile (6 g) in EtOH/HCl (g) (150 mL) was heated to 40° C. overnight in a sealed tube. The solvent was evaporated under vacuum and the residue (7 g, crude) was used for the next step without further purification.