Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26]>C1COCC1>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:18]2([OH:26])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17]2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C1Cc2ccccc2C1
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2(O)Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A suspension of anhydrous cerium chloride (40.60 g, 164.7 mmol) in THF(250 mL) was stirred at room temperature for 2 hours under nitrogen. 4-t-Butylphenylmagnesium bromide (70.0 mL of 2.0M solution in diethyl ether, 140.0 mmol) was added at 0 ° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature overnight (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. 2-Indanone (1.34 g) was distilled off at 80° C/0.3 mm Hg. The residue was washed with pentane (50 mL) and subject to Kugelrohr distillation (185° C./0.3 mm Hg). 2-(4-t-Butyl-phenyl)-2-indanol (23.43 g) was obtained in pure form. 1H-N.M.R. (CDCl3) d 1.32 ( s, 9H), d 1.36 (s, 1H), d 3.25 (d, J=16.2 Hz, 2H), d 3.50 (d, J=16.2 Hz, 2H), d 7.15-7.45 (m, 8H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[C:30]([CH:32]=O)[N:29]=[C:28]2[N:34]=[CH:35][CH:36]=[CH:37][C:27]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][N:22]([CH2:32][C:30]5[N:29]=[C:28]6[N:34]=[CH:35][CH:36]=[CH:37][C:27]6=[N:26][CH:31]=5)[CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cnc2cccnc2n1
Reactant: CC(C)(C)c1ccc(-c2cn3c(N4CCNCC4)cccc3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(-c2cn3c(N4CCN(Cc5cnc6cccnc6n5)CC4)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Crude 2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine (0.100 g, 0.298 mmol) and pyrido[2,3-b]pyrazine-3-carbaldehyde (0.062 g, 0.378 mmol) was dissolved in NMP (5 mL). The mixture was treated with 3 drops of glacial acetic acid, followed by sodium triacetoxyborohydride (0.126 g, 0.596 mmol.) The mixture was stirred at room temperature overnight and then purified by semipreparative RP-HPLC (Method C) followed by basification as in example 18 to obtain 0.0155 g of the title compound (11%). HPLC (Method B): r.t.=9.0 min., purity 85.2% at 210-370 nm, 81.1% at 252 nm. HRMS: calcd for C29H31N7+H+, 478.27137; found (ESI, [M+H]+), 478.271.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](=[CH:11][C:12]([O:14][C:15]1([CH3:24])[CH2:20][CH2:19][CH:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1)=[O:13])=[N-]>ClCCl>[C:3]1([CH:2]2[CH2:1][CH:11]2[C:12]([O:14][C:15]2([CH3:24])[CH2:20][CH2:19][CH:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C1CCC(C)(OC(=O)C=[N+]=[N-])CC1
Reactant: C=Cc1ccccc1
Solvent: ClCCl
Product: CC(C)C1CCC(C)(OC(=O)C2CC2c2ccccc2)CC1

Procedure:
To a mixture of styrene (1.063 g, 10.2 mmol) and Rh2 (4R-BNOX)4 (0.0050 g, 0.0058 mmol) in 3.0 mL of refluxing anhydrous dichloromethane was added, by syringe at room temperature, 1-menthyl diazoacetate (0.109 g, 0.485 mmol) in 3.0 mL of dichloromethane under nitrogen and at an addition rate of 0.8 mL/h (syringe pump). After addition was complete, the dichloromethane solution was passed through a plug of neutral alumina, and solvent was removed under reduced pressure. The residue was analyzed by capillary gas chromatography (SPB-5 column) for diastereomeric separation and enantiomeric purity. Similar procedures were followed for the cyclopropanation of 3,3-dimethyl-1-butene, ethyl vinyl ether, and dihydropyran.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([N:11]([C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:21]=[C:20]([CH3:34])[CH:19]=1)[CH2:12][CH2:13][C:14](O)=[O:15])([CH3:10])[CH3:9].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:69]([NH2:73])([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:69]([NH:73][C:14]([CH2:13][CH2:12][N:11]([CH:8]([CH3:9])[CH3:10])[C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[CH:21]=[C:20]([CH3:34])[CH:19]=1)=[O:15])([CH3:72])([CH3:71])[CH3:70]
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(=O)O)C(C)C)c1
Reactant: CC(C)(C)N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(=O)NC(C)(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(isopropyl-{3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-amino)-propionic acid trifluoroacetate (0.018 g) and PyBroP® (0.017 g) in DMF (1 ml) was added DIPEA (0.012 ml) followed by tert-butylamine (0.005 ml), after 1 min. The reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.009 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:8][C:7]([NH2:9])=[N:6][N:5]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[I-].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:10]1([CH2:2][CH2:3][C:4]2[S:8][C:7]([NH2:9])=[N:6][N:5]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: Nc1nnc(CCCl)s1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nnc(CCN2CCOCC2)s1
Reaction time: 4 h

Procedure:
A mixture of 5-(2-chloro-ethyl)-[1,3,4]thiadiazol-2-ylamine (54a) (2.5 g, 15.3 mmol), morpholine (2.67 g, 30 mmol) and sodium iodide (0.15 g) is heated with stirring in toluene at 80° C. After adding triethylamine (2.13 ml, 15.3 mmol) heating is continued for an additional 4 hours. The solvent is removed and the residue is partitioned between water (pH 13) and n-butanol. The organic extract is dried (MgSO4) and the solid is removed to afford the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:11]=1.C([Li])CCC.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=[O:22].O>O1CCCC1.CCCCCC>[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:11][C:7]=2[N:8]=1)[OH:22]
Reactant: FC(F)(F)c1ccc2scnc2c1
Reactant: CC(C)(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)C(O)c1nc2cc(C(F)(F)F)ccc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a stirred solution of 3.8 g (19.0 mmol) of 5-(trifluoromethyl)-1,3-benzothiazole in 30 mL of tetrahydrofuran at −78° C. was added 13.1 mL (21.0 mmol) of a 1.6 M solution of n-butyllithium in hexane over 45 min. Then, 1.8 g (21.0 mmol) of trimethylacetaldehyde in 10 mL of tetrahydrofuran was added dropwise over 30 min. The reaction mixture was stirred for 1 h at −78° C., and then allowed to warm to 0° C. Then, 25 mL of water was added and the mixture was extracted with 80 mL of ether. The ether was washed with 40 mL of water (3×), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (1:9) to afford 1.8 g (33%) of 2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]-1-propanol as an off-white solid. The enantiomers were separated in 98.8% ee using a Chiralpak AD, 10 micron column with a mobile phase of 90% carbon dioxide: 10% methanol and a flow rate of 2.0 mL/minute. 1H-NMR (400MHz, DMSO-d6): δ 8.33–8.29 (m, 2H), 7.71 (d, J=8 Hz, 1H), 6.61 (d, J=5 Hz, 1H), 4.60 (d, J=5 Hz, 1H), 0.97 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:10])[CH2:4][CH2:3][CH:2]=[CH2:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCOCC
Product: C=CCCC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 156.1 %

Procedure:
To a suspension of 14.6 g (80 mmol) of CdCl2 in 200 mL of ether cooled to 0° C. was added 115 mL of 1.3M solution of 3-butene-1-magnesium bromide dropwise. The mixture was refluxed for 1 h and ether was then removed by distillation. Benzene (500 mL) was introduced, followed by a solution of 17.5 g (100 mmol) 4-fluorophenylacetyl chloride. After refluxing for 1 h, the reaction mixture was quenched with 200 mL of saturated aqueous NH4Cl, 50 mL of 1N HCl, and extracted with 200 mL of 1:1 hexane/EtOAC. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluted with 4:1 hexane/EtOAc to give 15 g of the title product.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.O.[OH-].[Na+].Cl>C(O)C>[C:15]1([C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][OH:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
34.2 g of 4-acetoxy-1,1,2-triphenyl-1-butene are dissolved in 200 ml of 94% ethanol, after which 20 ml of water and 45 ml of a 20% sodium hydroxide solution are added. The mixture is refluxed for 1 h. The solution is neutralized with 2 M hydrochloric acid, after which the ethanol is evaporated. Water is added into the residue. The product is extracted in ethyl acetate, the ethyl acetate solution is dried over sodium sulfate and the solvent is evaporated. The product is recrystallized from a mixture of water and methanol and then has m.p. 117°-9° C. The yield is 23.7 g (79%).
Reaction SMILES: [N:1]1[C:6](C=O)=[CH:5][CH:4]=[CH:3][C:2]=1C=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)=O>C(O)C>[C:12]1([N:11]=[C:6]2[CH2:5][CH:4]=[CH:3][C:2](=[N:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(C=O)n1
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: O=CO
Product: C1=CC(=Nc2ccccc2)NC(=Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
2,6-pyridine dicarboxaldehyde (0.3071 g, 2.3 mmol) was added to a solution of aniline (0.5292 g, 5.7 mmol) in absolute ethanol (20 mL) at room temperature. 0.5 mL of formic acid was then added to the above solution. The mixture was stirred at room temperature for 65 hours. The product was filtered, washed with cold ethanol and dried in a vacuum oven (50° C.) overnight. Yield 0.2245 g (34.2%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:17]([NH2:21])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:21][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)C

Procedure:
In a DMF solution containing 2.0 g of Boc-Ile-OH, 0.82 ml of isobutylamine, 1.27 g of HOBt and 2.06 g of DCC were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture, after filtration, was treated similarly to that in Example 50 (Process 2), except for the crystallization solvent (hexane) to give 1.44 g of the title compound.
Reaction SMILES: S(O[CH:12]1[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14][CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:25][NH2:26].C(OCCO)C.C(=O)(O)[O-].[Na+]>>[CH3:25][NH:26][CH:12]1[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC2CCc3[nH]c4ccccc4c3C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Product: CNC1CCc2[nH]c3ccccc3c2C1
Reaction time: 8 h

Procedure:
A mixture of 17 g. of 3-tosyloxy-1,2,3,4-tetrahydrocarbazole and 25 g. of 40% methylamine in 200 ml. of 2-ethoxyethanol containing 5 g. of sodium bicarbonate was heated on a steam bath for 1 hour then left standing overnight at room temperature. The solvent was removed by distillation and the residue taken up in ether and the mixture filtered. Evaporation of the filtrate gave a residue which crystallized upon trituration with ether. The 3-(methylamino)-1,2,3,4-tetrahydrocarbazole thus obtained melted at 134°-136° C. (corr.).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:53][C:54]1[CH:55]=[CH:56][C:57]2[O:61][C:60]([C:62](O)=[O:63])=[CH:59][C:58]=2[CH:65]=1>CN(C=O)C.O>[Cl:53][C:54]1[CH:55]=[CH:56][C:57]2[O:61][C:60]([C:62]([N:16]3[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]4/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/4)[CH2:14][CH2:15]3)=[O:63])=[CH:59][C:58]=2[CH:65]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2cc3cc(Cl)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (0.56 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (283 mg), and 5-chlorobenzofuran-2-carboxylic acid (151 mg). The reaction mixture was stirred at room temperature overnight, water was added, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (57 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH2:21]([N:24]([CH2:33][CH2:34][CH3:35])[C:25]1[N:30]=[C:29](Cl)[N:28]=[C:27](Cl)[N:26]=1)[CH2:22][CH3:23].[OH2:36]>CC(N(C)C)=O>[CH2:21]([N:24]([CH2:33][CH2:34][CH3:35])[C:25]1[N:30]=[C:29]([NH:7][NH:6][C:4](=[O:5])[C:3]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][C:2]=2[OH:1])[N:28]=[C:27]([NH:7][NH:6][C:4](=[O:5])[C:3]2[CH:8]=[CH:9][C:10]([O:36][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][C:2]=2[OH:1])[N:26]=1)[CH2:22][CH3:23]
Reactant: CCCN(CCC)c1nc(Cl)nc(Cl)n1
Reactant: O
Reactant: CCCCCCCCOc1ccc(C(=O)NN)c(O)c1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOc1ccc(C(=O)NNc2nc(NNC(=O)c3ccc(OCCCCCCCC)cc3O)nc(N(CCC)CCC)n2)c(O)c1
Temperature: 120 °C

Procedure:
22.6 g of 2-hydroxy-4-octoxy-benzhydrazide are dissolved in 200 ml of dimethylacetamide at 60° C and treated with a solution of 10 g of 2-(di-n-propylamino)-4,6-dichloro-s-triazine in 50 ml of dimethylacetamide whilst keeping the temperature constant. The reaction mixture is heated to 120° C over the course of 3 hours. After cooling, it is poured into one litre of water, whereupon the product precipitates as a white solid. After filtration, it is dried and recrystallised from ethylene glycol-monomethyl ether. 2-(Di-n-propylamino)-4,6-di-(2-hydroxy-4-octoxybenzoylhydrazino)-s-triazine (Stabiliser No. 21) is thus obtained in the form of a white powder of melting point 195° - 196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=C.C1C[O:41]CC1.O.I([O-])(=O)(=O)=O.[Na+]>CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:41]
Reactant: C1CCOC1
Reactant: C=Cc1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(C=O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 50 %

Procedure:
A suspension of 6-(N-(3-chloro-4-vinylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (890 mg, 1.65 mmol) in 1:1 THF/water (36 mL) was treated with a solution of osmium tetroxide (2.5% in t-butanol, 0.415 mL, 0.033 mmol) and stirred for a few minutes. The resulting solution was treated with sodium periodate (883 mg, 4.13 mmol) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with EtOAc and washed with 1:1 water/brine (1×), then brine (1×). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane, filtered and the filtrate was purified by flash chromatography (silica gel, gradient of 0 to 50% EtOAc in hexanes) to afford the title compound (0.45 g, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.23 (s, 1H), 8.45-8.53 (m, 1H), 8.04 (s, 1H), 7.94-8.01 (m, 2H), 7.86 (d, 1H), 7.35-7.46 (m, 3H), 7.31 (dd, 1H), 7.24-7.29 (m, 1H), 3.57 (s, 3H), 2.84 (d, 3H), 1.89-1.98 (m, 1H), 0.68-1.02 (m, 3H), 0.42-0.58 (m, 1H). LCMS (m/z, ES+)=541 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].CCCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:39]3[CH2:38][CH2:37][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:35])[CH2:41][CH:40]=3)[CH:3]=[CH:4][C:5]=2[F:28])[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 88 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 1.06 mmol) prepared in Step 5 of Preparation 8, 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (26.7 mg, 1.59 mmol), Pd(PPh3)4 (123.0 mg, cat.) and a 2N sodium carbonate solution (5.0 mL) were added to a mixed solvent of ethanol (5.0 mL) and 1,2-dimethylethane (20.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give 360.0 mg of the titled compound as a white liquid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccccc1C#CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2-bromobenzaldehyde (10 g, 54 mmol) in anhydrous N,N-dimethylformamide (150 ml) was added 3-butyn-1-ol (6.13 ml, 81 mmol) and triethylamine (11.3 ml, 81 mmol), followed by copper (I) iodide (490 mg, 5.4 mmol) and Pd(PPh3)2Cl2 (1.9 g, 2.7 mmol), and the mixture degassed three times and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with EtOAc (3×150 ml); the combined EtOAc layers were washed with water (2×250 ml), sat NaCl (100 ml), then dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 50% Et2O in isohexanes to give the title compound (8.5 g, 90%) as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].COC1C=CC(/C=[C:31]2/[C:32]([NH:34][C:35]([S:37]/2)=[NH:36])=[O:33])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:36][C:35]1[S:37]/[C:31](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][N:5]=[C:4]3[O:3][CH2:1][CH3:2])/[C:32](=[O:33])[N:34]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCOc1ncnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ncnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 25 °C

Procedure:
The suspension of 4-ethoxy-quinazoline-6-carbaldehyde (example 10b) (1 equiv.), pseudothiohydantoin (1 equiv.), and sodium acetate (4 equiv.) in acetic acid was stirred under reflux for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried to 2-amino-5-[1-(4-ethoxy-quinazolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 301 (MH+) as a slight yellow solid. LC-MS m/e 256 (MH+).