Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:11][N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=1.[C:45]([O:51][CH2:52]Cl)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:52][O:51][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:16])=[CH:11][N:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2/C=C/C(=O)OCOC(=O)C(C)(C)C)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A mixture of (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoic acid (0.303 g), chloromethyl pivalate (0.075 g), potassium carbonate (0.138 g) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from hexane-ethyl acetate gave [(2,2-dimethylpropanoyl)oxy]methyl (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoate as a colorless powder (0.271 g, yield 75%). melting point: 131-132° C.
Reaction SMILES: FC1C(S)=CC=CC=1C(OCC)=O.C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:49]=3[F:59])=[C:28](C3CC3)[N:29]2C2C=NN(CCCC(O)=O)C=2)=[CH:25][CH:24]=1>C(Cl)Cl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:47][C:48]3[C:49]([F:59])=[C:50]([CH:51]=[CH:52][CH:53]=3)[C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:28][NH:29]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)O)c3)c3c(F)c(Cl)ccc23)c1F
Agent: CCOC(=O)c1cccc(S)c1F
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Sc2c[nH]c3c(F)c(Cl)ccc23)c1F
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a stirred solution of Intermediate A (1.18 g, 5.91 mmol) in CH2Cl2 (30 mL) under inert atmosphere was added NCS (792 mg, 5.91 mmol) at RT and stirred for 1 h. To this, indole 1 (Example 4, Step 1; 1.0 g, 5.91 mmol) in CH2Cl2 (20 mL) was added at RT and stirred for 4 h. After completion of the reaction by TLC, the reaction mixture was diluted with water (40 mL) and extracted with CH2Cl2 (2×60 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 10% EtOAc/Hexanes) to afford compound 2 (1.2 g, 55%) as a light brown solid. 1H NMR (500 MHz, DMSO-d6): δ 12.60 (br s, 1H), 8.00 (d, J=4.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.24-7.17 (m, 2H), 7.09 (t, J=8.0 Hz, 1H), 6.90-6.86 (m, 1H), 4.34 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H); MS: m/z 368.6 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9]>C(O)(=O)CC>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]1[C:5]2[NH:1][C:2]([C:6]([C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[OH:9])=[C:2]3[N:1]=[C:5]([C:6]([C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[OH:9])=[C:2]4[NH:1][C:5](=[C:6]([C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[OH:9])[C:2]5[CH:3]=[CH:4][C:5]=1[N:1]=5)[CH:4]=[CH:3]4)[CH:4]=[CH:3]3)=[CH:3][CH:4]=2
Reactant: c1cc[nH]c1
Reactant: O=Cc1ccccc1O
Solvent: CCC(=O)O
Product: Oc1ccccc1-c1c2nc(c(-c3ccccc3O)c3ccc([nH]3)c(-c3ccccc3O)c3nc(c(-c4ccccc4O)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyrrole (1.0 equivalents) and salicylaldehyde (1.2 equivalents) are dissolved in propionic acid (1 liter/20 ml pyrrole) and the solution is refluxed for 30 minutes. The reaction mixture is allowed to cool to room temperature and stand for one day. The mixture is filtered and the product is recrystallized to yield 5,10,15,20-tetrakis(2'-hydroxyphenyl)porphyrin.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([O:3][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCc3cccnc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An oily suspension (50% by weight; 1.2 g) of sodium hydride is added in small portions at a temperature in the region of 0° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (6.2 g) in anhydrous dimethylformamide (100 cc). The suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. and a 1.4M solution (16 cc) of 3-chloromethylpyridine in toluene is then added. The reaction mixture is heated with stirring to a temperature of 70° C. for 1 hour, then cooled to a temperature in the region of 10° C., poured into distilled water (600 cc) and extracted with dichloromethane (3×200 cc). The organic phases are combined, washed with distilled water (4×50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 1N aqueous hydrochloric acid solution (30 cc) is added to the residue obtained. After removal of a solid by filtration, the filtrate is alkalinized with 10N aqueous sodium hydroxide solution to a pH in the region of 11, and extracted with dichloromethane (3×150 cc). The organic phases are combined, washed with distilled water (3×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-[(3-pyridyl)methoxy]-1-isoindolinone (3.7 g), m.p. 175° C., is obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][O-:15].[Na+].O>CO>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:15][CH3:14])[CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(I)cc([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 52 h
Yield: 99 %

Procedure:
1-Iodo-3,5-dinitrobenzene (1.8 g, 6.1 mmol) are dissolved in methanol (12 ml) and treated with a solution of sodium methoxide in methanol (5.4M, 1.2 ml). The mixture is then stirred at 65° C. for 52 h. After cooling to ambient temperature, water (50 ml) is added and the mixture extracted three times with ethyl acetate (50 ml). The combined organic layers are extracted with brine (100 ml), dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1) affords the product (1.7 g, 99%) as light yellow solid. MS: m/e=279 (M+).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:15][O:14][C:10]1[N:11]=[CH:12][CH:13]=[C:8]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:17][NH:16][C:9]=12
Reactant: O=N[O-]
Reactant: COc1nccc(Cc2ccccc2)c1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1nccc2c(-c3ccccc3)n[nH]c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a solution of 4-benzyl-2-methoxypyridin-3-amine (8.8 g) in acetic acid (310 mL) was added an aqueous solution prepared by dissolving sodium nitrite (2.83 g) in water (15.5 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min, and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethanol and hexane to give the title compound (5.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10]
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1nc(-c2ccc(Sc3ccccc3)nc2)oc1C
Yield: 73.4 %

Procedure:
[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (4.8 g, 17.98 mmol) is dissolved in anhydrous dimethylformamide (100 mL) and allowed to stir under nitrogen. Benzenethiol (2.78 mL, 27 mmol) is added by syringe, followed by anhydrous cesium carbonate (12.6 g, 36 mmol). The mixture is allowed to stir under nitrogen 50° C. and monitored by HPLC. After complete consumption of strating material, the solution is quenched with 1N sodium hydroxide solution, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure (5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester (4.51 g, 13.2 mmol) is isolated in 74% yield after column chromatography.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)=O.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:1][CH:3]2[C:12]3[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=3)[O:6][CH2:5][CH2:4]2)[CH2:30][CH2:29]1
Reactant: N#Cc1ccc2c(c1)OCCC2C=O
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CCN2CCN(CC3CCOc4cc(C#N)ccc43)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol) in DCM (3 mL) was added 4-methyl-5-[2-(piperazine-1-yl)ethyl]-2-benzofuran-1(3H)-one (57 mg, 0.27 mmol), sodium triacetoxyborohydride (27.0 mg, 0.267 mmol) and DIPEA (57 mg, 0.27 mmol). The reaction was stirred under nitrogen at room temperature for 16 hours when LC-MS indicated product formation. The mixture was diluted with DCM and the product was isolated by flash chromatography. LC-MS (IE, m/z): 432 [M+1]+. (0.18 μM)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C.[NH4+].[Cl-].C(Cl)Cl>[C:10]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([CH2:7][CH2:8][O:9][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[N:5]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(N)n(CCO)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(N)n(CCO[Si](C)(C)C(C)(C)C)n1
Reaction time: 6 h
Yield: 70.8 %

Procedure:
A solution of Intermediate 10a (1.00 g, 5.46 mmol), tert-butyl-dimethyl-chlorosilane (823 mg. 5.46 mmol), and imidazole (774 mg, 11.38 mmol) in DMF (9 mL) was stirred at RT under a nitrogen atmosphere for 18 h. Additional tert-butyl-dimethyl-chlorosilane (823 mg. 5.46 mmol) and imidazole (774 mg, 11.38 mmol) were added to the reaction mixture and stirred for 6 h. The reaction mixture was diluted with NH4Cl saturated aqueous solution (10 mL) and DCM (10 mL). The layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (1.15 g, 70%). LCMS (Method 3): Rt 3.06, 3.23 min, m/z 298 [MH+].
Reaction SMILES: [OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][CH2:11][C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:26])([C@@:5]([OH:25])([C:21](=[O:24])CO)[CH2:6][CH2:7]2)[CH2:3]1.I(O)(O)(O)(O)(O)=[O:28]>CO.O>[OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][CH2:11][C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:26])([C@@:5]([OH:25])([C:21]([OH:28])=[O:24])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)O
Yield: 81 %

Procedure:
In a 1000 mL round-bottomed flask was suspended (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (10.4 g, 28.69 mmol) in MeOH (200 mL) and a solution of orthoperiodic acid (9.81 g, 43.04 mmol) in water (200 mL) was added to give a colorless solution. The mixture was stirred for 45 minutes after which an additional 3 g of orthoperiodic acid was added and stirring was continued for another hour. MeOH was removed in vacuo and the residual aqueous mixture was diluted with 200 ml of water. The resulting solid was isolated by filtration and was air-dried on the sinter to yield 8.1 g of the desired compound as a white solid. APCI-MS m/z: 349 [MH+].
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[C:18]([CH3:21])[N:17]=[C:16]([NH2:22])[C:15]=2[N:14]=[C:13]1[CH2:23][O:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:22][C:16]1[C:15]2[N:14]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:20]=2[CH:19]=[C:18]([CH3:21])[N:17]=1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Reactant: CC(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Isobutyryl chloride (181 μL, 1.73 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (0.435 g, 1.57 mmol), triethylamine (280 μL, 2.04 mmol) and chloroform (8 mL). The reaction mixture was allowed to stir at ambient temperature for 4 hours then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel eluting with 1 L of 2% methanol in chloroform containing 0.5% triethylamine) to provide 0.225 g of N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}-2-methylpropanamide as a white powder, m.p. 170.5–172.5° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.Cl[C:17](=[CH2:22])[C:18]([O:20][CH3:21])=[O:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[NH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:7][CH:8]=1
Reactant: FC(F)(F)CN=C(Cl)c1ccc(Cl)cc1
Reactant: C=C(Cl)C(=O)OC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 34.6 %

Procedure:
A solution of N-(2,2,2-trifluoroethyl)-4-chlorobenzimidoyl chloride (10.2 g, 0.04 mol) and methyl 2-chloroacrylate (5.8 g, 0.048 mol) in N,N-dimethylformamide is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 19.5 g, 0.128 mol) over 30 minutes at such a rate that the temperature is kept at 40° C., stirred for two hours, and quenched with water and ethyl acetate. The organic layer is separated, washed sequentially with aqueous HCl and water, and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 20% ethyl acetate in heptane solution and crystallization from heptane gives the title product as white crystals (4.2 g, 34.6% yield, mp 120.0-122.5° C.)
Reaction SMILES: [OH:1]C1C=CC=CC=1C(O)=O.C(OO)(C)(C)C.[CH3:17][CH:18]([C:20](=[CH:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:21]#[N:22])[CH3:19]>C(Cl)Cl.[Se](=O)=O>[OH:1][CH2:34][C:33]([CH3:35])=[CH:32][CH2:31][CH2:30][C:29]([CH3:36])=[CH:28][CH2:27][CH2:26][C:25]([CH3:37])=[CH:24][CH:23]=[C:20]([CH:18]([CH3:17])[CH3:19])[C:21]#[N:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Reactant: O=C(O)c1ccccc1O
Agent: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: ClCCl
Product: CC(=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C)CO
Reaction time: 0.5 h
Yield: 317.6 %

Procedure:
To a suspension of selenium dioxide (58 mg) and 2-hydroxybenzoic acid (365 mg) in methylene chloride (10.5 ml) was gradually added an aqueous solution of 80% t-butyl hydroperoxide (11.6 ml) with stirring on a water bath. After 30 minutes, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.56 g, 26.8 mmol) was added to the mixture, which was then allowed to stand at room temperature for 30 hours. Most of the solvent was removed by evaporation in vacuo, and the residue was dissolved in ether. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated. The resultant residue was subjected to silica gel column chromatography to give the aimed 14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (2.53 g, 31%). The starting material was also recovered (3.10 g, 40%) in the column chromatography. The yield of the aimed product based on the consumed starting material as 52%.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[H-].[Na+].[CH:14](OCC)=[O:15]>C(O)C.O1CCCC1>[OH:15][CH:14]=[C:8]1[C:7](=[O:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9]1
Reactant: CCOC=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CCC2(CC1=CO)OCCO2

Procedure:
1,4-Cyclohexanedione monoethylene ketal (5.00 g) was added to a mixture of sodium hydride (1.40 g of a 60% suspension in mineral oil), 10 ml of ethyl formate, 1 drop of ethanol and 200 ml of tetrahydrofuran. The reaction mixture was heated at reflux for 2.5 hours, cooled and partitioned between water and ethyl ether. The ethereal layer was extracted several times with 0.5N sodium hydroxide and the combined aqueous portions were washed once with ether. The aqueous solution was acidified slowly to a pH of 4 with 5N hydrochloric acid and the slurry was exhaustively extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to provide a dark oil. The oil was distilled bulb-to-bulb (120° C./lmm) to afford 7-(hydroxymethylene)-1,4-dioxaspiro-[4.5]decan-8-one as a colorless oil.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31][C:32]([F:42])([F:41])C1C=CC(C=O)=CC=1.COC1C=CC(C=O)=CC=1>>[F:31][C:32]([F:42])([F:41])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Agent: COc1ccc(C=O)cc1
Product: O=C(NCCNCc1ccc(C(F)(F)F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 4-(trifluoromethyl)benzaldehyde lidine instead of 4-methoxy benzaldehyde. LCMS (ESI) 460 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.25 (1H, s) 8.05 (1H, t, J=5.66 Hz) 8.01 (1H, d, J=5.47 Hz) 7.77 (1H, d, J=5.27 Hz) 7.58-7.64 (2H, m) 7.50-7.55 (2H, m) 7.46 (1H, d, J=5.42 Hz) 7.30 (1H, d, J=3.17 Hz) 6.79 (1H, d, J=5.52 Hz) 6.43 (1H, dd, J=3.44, 1.93 Hz) 3.77 (2H, s) 3.35 (2H, q, J=6.23 Hz) 2.63 (2H, t, J=6.52 Hz)
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2ncn(C3CCNCC3)c2-c2ccncn2)cc1
Reaction time: 18 h

Procedure:
TFA (242 mL) was added to a solution of tert-butyl 4-[4-(4-fluorophenyl)-5-pyrimidin-4-yl-1H-imidazol-1-yl]piperidine-1-carboxylate (C14) (30.70 g, 72.49 mmol) in dichloromethane (242 mL). After 18 hours, the reaction was treated with aqueous sodium hydroxide solution (2 N) until the pH of the mixture reached 12.0. {Caution: potential exotherm!} The aqueous layer was extracted with dichloromethane (2×500 mL), and the combined organic layers were concentrated in vacuo to provide the product as a yellowish solid. Yield: 23.90 g, 73.91 mmol, quantitative. 1H NMR (400 MHz, CDCl3) δ 1.82-1.92 (m, 2H), 2.14 (br d, J=12 Hz, 2H), 2.71 (ddd, J=12.3, 12.3, 2.2 Hz, 2H), 3.22 (br d, J=12 Hz, 2H), 4.82 (tt, J=12.0, 3.9 Hz, 1H), 7.03 (dd, J=8.8, 8.8 Hz, 2H), 7.16 (dd, J=5.3, 1.4 Hz, 1H), 7.41 (dd, J=8.9, 5.4 Hz, 2H), 7.83 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[CH:3]=1.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH:15][C:16]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=2)=[O:17])(=[O:14])=[O:13])[CH:3]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: COC(=O)c1ccc(I)cc1S(=O)(=O)N=C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(I)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Under protective gas, a 14.5% strength solution (1465 g) of methyl 4-iodo-2-isocyanatosulfonylbenzoate in xylene is added over 4 hours at a constant rate at 50° C. to a suspension of 84.5 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 670 g of ethyl acetate. After the addition has ended, the mixture is stirred at the same temperature for approximately 4 hours, and the ethyl acetate is then distilled off under reduced pressure (80–60 mbar, T=50° C.). The suspension that remains is filtered off with suction and the solid is washed repeatedly with dilute hydrochloric acid and dried; if appropriate, acetone can be added to the hydrochloric acid. This gives 297 g (content>98%) of the title compound; yield 99.2% of theory.