Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[CH2:13](N(CC)CC)C.[Cl:20]/[C:21](/[CH3:27])=[C:22](\C)/[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[Cl:20][C:21]([CH3:27])=[C:22](/[N:8]=[C:4](/[O:5][CH2:6][CH3:7])\[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])[C:23]([CH3:13])=[O:24]
Reactant: CCN(CC)CC
Reactant: C/C(Cl)=C(/C)C(=O)Cl
Reactant: CCOC(=N)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: CCO/C(=N/C(C(C)=O)=C(C)Cl)c1ccccc1Cl
Reaction time: 4 h

Procedure:
Ethyl 2-chlorobenzimidate (2.80 g) and triethylamine (1.70 g) are dissolved in toluene (50 ml), to which is added dropwise (E)-3-chloro-2-methyl-2-butenoyl chloride at 5° C.-10° C. with stirring, and the stirring is continued at room temperature for 4 hours after the completion of the addition. After the completion of the reaction, the reaction mixture is added with toluene (150 ml), washed with a saline solution, dried on anhydrous magnesium sulfate and concentrated under a reduced pressure. The concentrate is purified through a silica gel column chromatography (Wakogel C-200: made by Wako Junyaku Kabushiki Kaisha) using a mixed solution of hexane-ethyl acetate (10:1) as a developing medium to obtain an oily ethyl (E)-N-(3-chloro-1-methyl-2-butenoyl)-2-chlorobenzimidate (2.37 g).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([NH2:9])=[N:7][N:8]=1)[CH2:2][CH3:3].[CH3:10][N:11]=[C:12]=[O:13]>CN(C)C=O>[CH2:1]([C:4]1[S:5][C:6]([NH:9][C:12]([NH:11][CH3:10])=[O:13])=[N:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nnc(N)s1
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CCCc1nnc(NC(=O)NC)s1
Reaction time: 1 h

Procedure:
To 14.9 g (0.1 mol) 2-n-propyl-5-amino-1,3,4-thiadiazole dissolved in 100 ml dimethyl formamide there are added dropwise, at 20° C., 5.7 g (0.1 mol) methyl isocyanate. After the subsidence of the heat effect, stirring is continued for 1 hour at 50° C., and distillation to one half of the original volume is then effected in a vacuum, followed by pouring into 400 ml of water. The crude N-(2-n-propyl-1,3,4-thiadiazol-5-yl)-N'-methyl urea (13) is obtained in solid form and is filtered off with suction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Cl.CC1[CH:14]=[C:15]([O:24]CC(O)CNC(C)(C)C)C2NC(=S)NC=2C=1C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(OCC)(=O)C.N1C=CC=CC=1>[C:15]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:34](=[O:36])[CH3:35])(=[O:24])[CH3:14]
Reactant: Cc1cc(N)c(O)cc1C
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(OCC(O)CNC(C)(C)C)c2[nH]c(=S)[nH]c2c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C)c(C)cc1OC(C)=O

Procedure:
The diamino compound required as intermediate is synthesised in the following manner from 2-amino-4,5-dimethylphenol (see E. Diepolder, Chem. Ber., 42, 2916/1909). This phenol compound is acetylated with acetic anhydride in ethyl acetate/pyridine to give 2-acetamido-1-acetoxy-4,5-dimethylbenzene (m.p. 156°-158° C.) which is nitrated in acetic anhydride with 100% nitric acid in acetic anhydride at 20° C. From the nitration mixture there is isolated, in 43% yield, 2-acetamido-1-acetoxy-4,5-dimethyl-3-nitrobenzene; m.p. 209°-211° C. After saponification of this compound in 2 N hydrochloric acid, there is isolated 2-amino-4,5-dimethyl-3-nitrophenol; m.p. 176°-178° C. This compound is converted into the sodium salt with a methanolic solution of sodium methylate. This salt is reacted in dioxan/dimethylformamide with excess 3-chloro-1,2-epoxypropane at 75° C. After evaporation, the residue is taken up in chloroform, treated with water and active charcoal and freed from solvent. The amorphous residue of 2-amino-4,5-dimethyl-1-(2,3-epoxypropoxy)-3-nitrobenzene is reacted in boiling ethanol with tert.-butylamine to give 2-amino-4,5-dimethyl-1-(2-hydroxy-3-tert.-butylaminopropoxy)-3-nitrobenzene. This compound is then quantitatively hydrogenated in ethanol over platinum dioxide to give 2,3-diamino-4,5-dimethyl-1-(2-hydroxy-3-tert.-butylaminopropoxy)-benzene, which is isolated as its trihydrochloride.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21]>CN(C=O)C.O>[ClH:1].[NH2:21][CH2:20][CH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([NH:9][C:2](=[O:3])[O:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH:11]=2)[NH:15][CH:14]=1
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)Nc1ccc2[nH]cc(CCN)c2c1
Product: Cl
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (1.5 ml) was added dropwise to a stirred solution of 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry DMF (20 ml). After 10 min the solution was diluted with water (150 ml) and stirring continued for 30 min. The resulting solution was extracted with ethyl acetate (2×100 ml) and the combined extracts washed with brine (10%, 100 ml), water (100 ml), dried (Na2SO4) and evaporated in vacuo to yield the crude product as a brown oil. This was purified by column chromatography (Kieselgel 60, 100 g) using ether as the eluent, to give the title compound as a colourless gum (1.08 g) which darkened to a brown gum on storage. This material failed to crystallise from common organic solvents.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14](Cl)=[C:13]([CH:17]=[O:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.C(N(CC)CC)C.[Pd].C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)c(Cl)s1
Reactant: [H][H]
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)cs1

Procedure:
5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chlorothiophene-3-carbaldehyde (0.8 g) (example 278, step b) in a mixture of ethanol (50 mL) and triethylamine (0.91 mL) with 10% palladium on carbon catalyst (0.28 g) was stirred vigorously under 4 bar pressure of hydrogen for 18 hours. The mixture was filtered through celite and the filter pad washed with ethanol (50 mL). The combined filtrate and washings were evaporated and azeotroped with toluene (20 mL) to give a yellow oil. The oil was dissolved in DCM (100 mL), manganese dioxide (2.3 g) was added and the resulting suspension refluxed overnight. The mixture was filtered through celite and the filter pad washed with DCM (50 mL). The combined filtrate and washings were evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.6 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O.[N+:29]([C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccc([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 40 %

Procedure:
A 2.25 g (1.2 mmol) sample of (R)-1-t-butoxycarbonyl-2-azetidinemethanol (prepared as in Example 1b above, except replacing the N-BOC-L-proline thereof with N-BOC-S-azetidinecarboxylic acid) and 2.25 g (18 mmol) of 3-nitrophenol (Aldrich) were added to a complex of TPP and DEAD (prepared as in Example 1 above, 18.1 mmol of each)in 80 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform:hexane to give 1.5 g (40%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][C:19]([F:22])([F:21])[F:20])[CH:13]=1)(=[O:10])=[O:9].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].C(N(CC)CC)C>CN(C=O)C>[F:20][C:19]([S:18][C:14]1[CH:13]=[C:12]([N:11]2[C:23](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=1)([F:22])[F:21]
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc(SC(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2S(=O)(=O)N1c1cccc(SC(F)(F)F)c1
Temperature: 100 °C
Yield: 140 %

Procedure:
A mixture of 2-amino-N-{3-[(trifluoromethyl)sulfanyl]phenyl}benzenesulfonamide (52 mg, 0.15 mmol), 1,1′-carbonyldiimidazole (97 mg, 0.60 mmol) and triethylamine (41 μL, 0.30 mmol) in DMF (0.75 mL) was heated in a sealed tube for 5 h at 100° C. After concentration in vacuo, DCM and 1M aqueous HCl were added, the phases were separated, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography, eluting with 3% MeOH in DCM yielded the title compound (45 mg, 0.21 mmol).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C([O-])=O.[Na+]>CN(C=O)C.O.CCOCC.[Cu]I>[F:16][C:12]([F:17])([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]([F:19])([F:18])[F:10]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
4-Bromobenzonitrile (10 g, 54.9 mmol), sodium pentafluoropropionate (26.5 g, 0.143 mol) and copper (I) iodide (27.1 g, 0.142 mol) were heated to 150° C. in dry DMF (130 ml) for 4 h. The reaction mixture was diluted with water and Et2O and kieselgur filter aid was added. This bi-phasic mixture was stirred for 5 min, filtered and separated. The aqueous phase was extracted with Et2O. The combined organic phases were washed with water and aq. NH3, then dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product as a brown oil. This was purified by flash chromatography (silica gel, 20-30% DCM in iso-hexanes) to give the title compound, 7.5 g (62%). 1H NMR (500 MHz, CDCl3): δ 7.75 (2H, d, J 8.3), 7.83 (2H, d, J 8.6), 19F NMR (470 MHz, CDCl3): δ −84.5, −116.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35].CCOCC>C(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:24])[C:18]=1[CH3:23])=[O:35]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3C)c2cc1OC
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethyl-aniline (710 mg) was dissolved in chloroform (7 ml), and 2,4-difluorophenyl isocyanate (310 μl) was then added to the solution. The mixture was heated under reflux for one hr, and a large amount of ether was added to the reaction solution. The resultant precipitate was collected by suction filtration to give 735 mg (yield 70%) of the title compound.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:30](=[O:39])[C:29]2=[O:40].C(C1C=CC=CN=1)(=O)C>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:30](=[O:39])[C:29]2([OH:40])[CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Reactant: CC(C)CN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CC(=O)c1ccccn1
Product: CC(C)CN1C(=O)C(O)(CC(=O)c2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-isobutylindoline-2,3-dione and commercially available 2-acetyl pyridine (purchased from Fisher Scientific). 1H-NMR δ 8.71 (ddd, 1H), 8.13 (dd, 1H), 7.93 (dd, 1H), 7.56 (ddd, 1H), 7.31 (d, 1H), 7.28-7.26 (m, 2H), 6.78 (d, 1H), 3.74 (dd, 1H), 3.56-3.40 (m, 3H), 2.13 (m, 1H), 0.96 (d, 6H). calculated mass for C19H19ClN2O3, 358.11, observed, 359.1 (M+1).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[OH2:12].O=[C:14]1[O:20][C@H:19]([C@H:21]([CH2:23]O)O)[C:17](O)=[C:15]1O.Cl[CH2:26]Cl>FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O>[C-:1]1([C:19]([C-:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)([CH2:17][CH2:15][CH2:14][OH:20])[CH2:21][CH2:23][CH2:26][OH:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:11].[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:11]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O
Reactant: ClCCl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: OCCCC(CCCO)([c-]1cccc1)[c-]1cccc1
Reaction time: 16 h
Yield: 59 %

Procedure:
Ten grams of ferrocene and 2.0 g. of I were dissolved in 40 ml of dichloromethane. To this was added a mixture of 6.6 g of trifluoroacetic anhydride and 8.0 g of trifluoroacetic acid as catalyst. The solution was mixed and allowed to stand at 25°C. A nitrogen atmosphere was maintained in the reaction vessel during mixing and during the subsequent reaction. After 16 hours, 100 ml of water was stirred with the brown colored reaction mixture and enough ascorbic acid was added to discharge the green color of the aqueous phase and to turn the organic phase orange in color. The phases were separated and the organic phase was stirred with another 100 ml of water and separated. Dichloromethane was removed from the organic phase under reduced pressure and the residue was dissolved in 100 ml of methanol containing 2 ml of water and 2.0 g of potassium hydroxide. The solution was stirred for 30 minutes and then the methanol and water were removed under reduced pressure. The residue was extracted with (dissolved in) 700 ml of hot ethylene dichloride and filtered. The cooled filtrate was poured onto a dry 36 mm by 240 mm alumina column. Unreacted ferrocene, 5.0 g, was eluted from the column with ethylene dichloride. Using 2% methanol in ethylene dichloride, 5.8 g of a mixture of IV, V and other byproducts were eluted. Recrystallization of this mixture from ethylene dichloride gave 4.6 g (59% yield) of 4,4-diferrocenylheptane-1,7-diol, mp 166°-168°C. Another recrystallization raised the mp to 168°-170°C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][C@H:9]([CH3:22])[C:8]1=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2.O(C[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2)[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[O:1]([CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][C@H:9]([CH3:22])[C:8]1=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2)[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Reactant: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO[Si](C)(C)C(C)(C)C)CCC(=O)C=C12

Procedure:
Following essentially the same procedure and substituting 19-hydroxy-6α-methyl-4-androstene-3,17-dione for the 19-hydroxy-4-androstene-3,17-dione above results in the preparation of 19-t-butyldimethylsiloxy-6α-methyl-4-androstene-3,17-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.O>[Br:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Brc1cc(I)ccn1
Reactant: CCOC(=O)Cc1ccc(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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccnc(Br)c2)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 2-bromo-4-iodopyridine 203-1 (568 mg, 2.0 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate 203-2 (580 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 (636 mg, 6.0 mmol), toluene (4 mL), H2O (4 mL) and ethanol (1 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 80° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give ethyl 2-(4-(2-bromopyridin-4-yl)phenyl)acetate 203-3. MS m/z 320.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>ClCCl>[C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), benzoyl chloride (0.20 ml), triethylamine and dichloromethane (20 ml) is stirred at room temperature for 1 hour. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from ethanol to give 1-{4-[2-(6-benzoylaminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.71 g) as white powder, m.p. 178°-178.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[O-:10][Mn](=O)(=O)=O.[K+].[OH2:16]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[CH:3]=1)[C:8]([OH:10])=[O:16]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
1-bromo-3,5-dimethylbenzene (15 g, 81 mmol, 1.0 eq) in a mixture of pyridine (133 mL) and H2O (83 mL) was heated to 80° C. KMnO4 (25.6 g, 162 mmol, 2.0 eq) was added in portions over 45 min. After the addition was completed, heating was continued at 80° C. for 1.5 h. The hot solution was then filtered, and the filtrate was acidified by addition of concentrated hydrochloric acid. The aqueous solution was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2: MeOH, 80:1 to 40:1) to give the title compound as a white solid (5.2 g, 29%)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([OH:14])=[O:13])#[N:10].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C(O)C>[C:9]([C:11](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: N#CCC(=O)O
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC(=Cc1ccccc1)C(=O)O
Yield: 81.2 %

Procedure:
Benzaldehyde (200 g), cyanoacetic acid (176 g), acetic acid (30 ml) and ammonium acetate (14.5 g) were refluxed for 4 hours in ethyl alcohol (800 ml) with heating. After the reaction, the mixture was concentrated to 400 ml by removing ethyl alcohol under a reduced pressure, followed by pouring into 1 liter of ice water to separate crystals. The resulting crystals were recrystallized from 250 ml of acetonitrile to obtain 265 g of 2-cyano-3-phenylacrylic acid which melted at 184° to 188° C. The resulting compound (150 g) and thionyl chloride (176 g) were dissolved in acetonitrile (100 ml) with heating for 1 hour. After the reaction, the acetonitrile and the thionyl chloride were distilled off under a reduced pressure, and the resulting solid was added to a solution consisting of hydroxyethyl methacrylate (124 g), pyridine (75 g) and acetonitrile (1 l). The reaction was carried out for 2 hours while keeping the reaction temperature below 40° C. After the reaction, the reaction solution was poured into ice water to separate crystals, and the resulting crystals were recrystallized form ethyl alcohol (1 l) to obtain 205 g of the desired compound which melted at 68° to 70° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CC(C)(C)COC(=O)Cl
Product: Cc1c(N2CCN(C(=O)OCC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and neopentyl chloroformate to give neopentyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 0.93 (br s, 9H), 2.09 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.29-3.33 (m, 4H), 3.58 (br s, 4H), 3.69 (t, J=4.4 Hz, 4H), 3.74 (s, 2H), 6.50 (s, 1H), 7.14-7.19 (m, 1H), 7.30-7.28 (m, 1H), 7.51 (d, J=2 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=555.3 (M+1).