Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4](I)[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OO>CS(C)=O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][CH2:6][N:7]2[C:8]([C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=[C:11]12)=[O:21]
Reactant: COC(=O)C(I)CCn1cccc1C(=O)c1ccccc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1CCn2c(C(=O)c3ccccc3)ccc21

Procedure:
As set out in Scheme 1, 2-benzoylpyrrole (II, prepared according to known procedures, e.g., J. Org. Chem. 1977, 42, 4248) is N-alkylated in step 1 with gamma-butyrolactone to provide, after esterification, 4-(2-benzoylpyrrol-1-yl)butyric acid methyl ester (III). 4-(2-Benzoylpyrrol-1-yl)butyric acid methyl ester (III) is then iodinated in step 2 with lithium diisopropylamide and a source of electrophilic iodine, such as iodine, iodine monochloride, or N-iodosuccinimide, to yield 4-(2-benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV). 4-(2-Benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV) is then cyclized in step 3 via a free radical ring closure reaction, for example, with hydrogen peroxide and iron (II) sulfate heptahydrate in dimethylsulfoxide, to yield 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid methyl ester (V). 5-Benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid methyl ester (V) is then hydrolyzed in step 4 to the corresponding acid (I, ketorolac) by known procedures, e.g., U.S. Pat. No. 4,089,969.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1)=[O:13])[CH3:10].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)#[N:24]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([Br:22])[N:17]([CH:19]([CH3:21])[CH3:20])[C:18]=1[CH:29]([C:28]1[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1)[OH:30])=[O:13])[CH3:10]
Reactant: CCOC(=O)c1cn(C(C)C)c(Br)n1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(C#N)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
LDA (2 M in THF, 53.6 mL, 107 mmol) was added slowly (over 30 min) to a cold (−78° C.) solution of intermediate A (20 g, 77 mmol) in THF (400 mL) (during the addition, the temperature raised to −70° C.). The mixture was stirred for 1 h at −78° C. A solution of 4-cyanobenzaldehyde (14 g, 107 mmol) in THF (100 mL) was added slowly. The reaction mixture was stirred for 30 min at −78° C., allowed to warm to −20° C. over 1 h, quenched by addition of acetic acid (10 mL), diluted with EtOAc/water, and extracted with EtOAc. The organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 1:1), followed by trituration in EtOAc, to provide 20.1 g of the title compound. tR: 0.99 min (LC-MS 2); ESI-MS: 392.2/394.1 [M+H]+ (LC-MS 2); Rf=0.29 (hexane/EtOAc, 1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=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[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Reactant: C#Cc1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A dried pressure tube was charged with (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (250 mg, 622 μmol) and dimethylformamide (2 ml). The solution was flushed with argon, thereafter, successively bis(triphenylphosphin)palladium(II)chloride (31.2 mg, 43.5 μmol), triphenylphoshine (3.26 mg, 12.4 μmol), triethylamine (126 mg, 1.24 mmol), 1-chloro-3-ethynylbenzene (175 mg, 1.24 mmol), and copper(i) iodide (3.6 mg, 18.7 μmol) were added. The tube was sealed and the reaction mixture stirred at room temperature for 10 minutes, then it was heated at 60° C. for 16 hours. For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 60:10 as the eluent. The (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 90% yield) was obtained as a green foam. MS (ISP): m/z=422.1 [M+2+H]+ and 424.2 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB(/[CH:33]=[CH:34]/[C:35]2[CH:48]=[CH:47][C:38]([CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH:33]=[CH:34][C:35]3[CH:36]=[CH:37][C:38]([CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:47][CH:48]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CC1(C)OB(/C=C/c2ccc(CCN3CCOCC3)cc2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(C=Cc4ccc(CCN5CCOCC5)cc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a mixture of (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (172 mg, 0.4 mmol) and (E)-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenethyl)morpholine (138 mg, 0.4 mmol) in PhCH3/EtOH (8 mL/4 mL) in a 20 mL microwave vial was added 1 M Na2CO3 (0.8 mL, 0.8 mmol), followed by Pd(PPh3)4 (23 mg, 0.02 mmol, 5 mol %). The resulting mixture was purged with argon, then microwaved for 2 h at 125° C. After cooling to rt, the mixture was diluted with H2O (20 mL), extracted with EtOAc (30 mL×2) and dried (Na2SO4). After removal of solvents, the residue was redissolved in DMF (4 mL) and purified by preparatory HPLC to give the title compound (TFA salt, 115 mg, 45%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.90 (d, J=8.4 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.43 (s, 1H), 7.37 (d, J=6.4 Hz, 2H), 7.28 (d, J=7.2 Hz, 2H), 6.95 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.06 (d, J=11.2 Hz, 2H), 3.80 (t, J=11.2 Hz, 2H), 3.56 (d, J=11.2 Hz, 2H), 3.38 (t, J=7.6 Hz, 2H), 3.27-3.12 (m, 5H), 3.07 (t, 2H), 2.20-2.10 (m, 2H); MS ESI 521.4 [M+H]+, calcd for [C32H32N4O3+H]+ 521.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc2c(=O)c(-c3ccccc3)coc2c1
Yield: 62.1 %

Procedure:
23.8 g of 7-hydroxy-isoflavone in 200 ml of anhydrous acetone are boiled, under stirring, with 18 g of n-hexyl bromide, 18 g of potassium carbonate and 1 g of potassium iodide for 72 hours under reflux condenser. The inorganic salts are removed by filtration, the filtrate is subjected to steam distillation in order to remove acetone and excess reagent, the precipitate is filtered and recrystallized from acetone, yielding 20 g of 7-n-hexyloxy-isoflavone, m.p. 120°-122° C. In a similar way, also 7-isopropyloxy-isoflavone, 7-n-butyloxy-isoflavone, and 7-n-amyloxy-isoflavone already characterized in Example 1, 7-isopropyloxy-2-methyl-isoflavone, 7-n-butyloxy-isoflavone and 7-n-amyloxy-isoflavone already characterized in Example 5, and
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([F:25])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:37])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([F:25])[CH:3]=1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.54 mmol) of the compound from Example 38 were introduced into 30 ml of dichloromethane at 0° C., 132 mg (0.54 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 107 mg (51% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([N:22]([CH2:23][CH3:24])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CCCCNCC
Product: CCCCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Various portions of the 1-chloro-2,6-dinitro-4-(trifluoromethyl)benzene (treated as described above) were aminated with N-n-butyl-N-ethylamine, to produce N-n-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline, or with N-ethyl-N-methallylamine, to produce N-ethyl-N-methallyl-2,6-dinitro-4-(trifluoromethyl)aniline. Each product was analyzed for nitrosamine content. The N-n-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline was found to contain 7 or 20 ppm of N-nitroso-N-n-butyl-N-ethylamine (two different analytical laboratories) and the N-ethyl-N-methallyl-2,6-dinitro-4-(trifluoromethyl)aniline was found to contain 16 ppm of N-nitroso-N-ethyl-N-methallylamine.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:3][CH:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCC(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(C)NS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a solution of 10 g (50 mmol) 2-aminotridecane and 5 g triethylamine in 100 ml methylene chloride is added 6 g methanesulfonyl chloride while cooling and stirring for a period of 10 minutes. After one hour of additional stirring, it was allowed to stand over night. The reaction mixture was subsequently transferred to a separatory funnel, washed three times with water, dried over Na2SO4, evaporated to a white solid and dried in a vacuum oven.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:18][C:12]=3[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:37][CH:36]=[CH:35][CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[C:10](=[O:38])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:41](N(CC)CC)[CH3:42]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:41][CH3:42])=[O:22])=[CH:18][C:12]=3[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:37][CH:36]=[CH:35][CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[C:10](=[O:38])[CH2:9]2)=[O:7])=[CH:39][CH:40]=1
Reactant: O=C(O)CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
10 mg (0.018 mmol) of 3[4-(4-chlorobenzoyl)-2-oxo-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepin-8-propionic acid was dissolved in 2 ml of dichloro-methane. 4 mg (0.02 1 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 nil (0.036 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2([CH2:16][CH2:15][N:14]([C:12]([NH:11][CH:2]3[CH:3]4[CH2:9][CH:7]5[CH2:6][CH:5]([CH2:10][CH:1]3[CH2:8]5)[CH2:4]4)=[O:13])[CH2:19][CH2:18]2)[CH2:20]1)(=[O:39])[CH3:38]
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a solution N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (50 mg, 0.108 mmol) and DIEA (27.86 g, 0.22 mmol) in dry CH2Cl2 (2-mL) at 0° C. under nitrogen was added dropwise a solution of acetyl chloride (9.28 mg, 0.12 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred overnight at rt and evaporated to give a residue, which was purified by preparative HPLC to provide a white solid 1-acetyl-N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (5.2 mg, 12%). 1H NMR (400 MHz, CD3OD): δ=1.61 (s, 1H), 1.653 (d, 2H), 1.72 (s, 1H), 1.88 (m, 10H), 2.015 (d, 5H), 2.286 (s, 3H), 3.027 (t, 2H), 3.867 (s, 1H), 4.088 (d, 4H), 7.044 (t, 1H), 7.191 (t, 2H), 8.082 (d, 1H); LC-MS (4 min) tR=1.59 min, m/z=408(M++1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1[CH:14]=[CH:15][CH:16]([S:26]([CH:29]([CH:39]=[CH:40][C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>O1CCCC1>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccccc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccccc3)c2)c(OC)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of benzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-benzamido-4-methoxybenzylsulfone in 76% yield. m.p. 163-166° C. NMR (DMSO-d6) δ 3.82(s, 3H), 3.83(s, 6H), 3.86(s, 3H), 4.2(s, 2H), 6.14(s, 2H), 7.10-7.18(d,1 H vinylic), 7.00-7.86(m, aromatic), 8.90(s,1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2)#[N:2].Cl.C(N(CC)CC)C.[N-:27]=[N+:28]=[N-:29].[Na+]>COCCOC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([C:1]4[NH:29][N:28]=[N:27][N:2]=4)=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Fc1ccc(-n2ccc3cc(-c4nnn[nH]4)ccc32)cc1

Procedure:
A suspension of 5-cyano-1-(4-fluorophenyl)-1H-indole (20 g) (prepared according to the method in Perregaard et al. J. Med. Chem. 1992 (35), 1092-1101), triethylamine hydrochloride (35 g) and sodium azide (20 g) in DME (250 mL) was boiled at reflux for 16 hours. Inorganic salts were filtered off and the solvent evaporated in vacuo. The remaining solid material was dissolved in ethyl acetate (500 mL) and water (500 mL) and glacial acetic acid was added. The organic phase was worked-up according to the general procedure above yielding 19 g of crystalline title compound 8a, mp 224-225° C. (washed with diethyl ether).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[N:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[N:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:20][CH:19]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccncc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound A (400 mg, 1.63 mmol), 2-(pyridin-4-yloxy)ethylamine (540 μl) and sodium hydrogencarbonate (1.32 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(pyridin-4-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (23 mg).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.CO>O1CCCC1.[C].[Pd]>[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[O:32])=[CH:28][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1N
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.2 %

Procedure:
After dissolving (4-{4-[3-(4-fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (100 mg) in a mixture of tetrahydrofuran (10 ml)-methanol (10 ml), 10% palladium carbon (10 mg) was added and the mixture was stirred for 7 hours at room temperature under hydrogen gas at 1 atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated to obtain the title compound (60 mg) as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[Br:21][CH2:22][C:23](Br)=[O:24]>ClCCl>[Br:21][CH2:22][C:23]([N:6]1[CH2:5][CH2:4][N:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]1=[O:1])=[O:24]
Reactant: CC(C)(C)OC(=O)NN1CCNC1=O
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1CCN(C(=O)CBr)C1=O
Temperature: 0 °C

Procedure:
N-(2-Oxo-1-imidazolidinyl)carbamic acid, 1,1-dimethylethyl ester (12.0 g, 0.06 mmol) was dissolved in dichloromethane (75 ml) containing pyridine (5.2 g, 0.066 mol). The solution was cooled to 0° C. and treated slowly with bromoacetyl bromide (13.3 g, 0.066 mol). The solution was evaporated in vacuo to give a yellow oil. The oil was chromatographed on silica gel (~300 g) eluting with 10% ethyl acetate/dichloromethane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid, 16.7 g.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.CN(C)[CH:18]=[O:19].[Cl-].[Na+]>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:18]=[O:19])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C=O
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-bromo-3-methylbenzonitrile (4 g, 20 mmol) in tetrahydrofuran (100 ml), cooled to -100° C. under a nitrogen atmosphere, was added dropwise a solution of n-butyllithium in hexanes (1.6M, 12.8 ml). After addition, the pale red solution was stirred for 5 minutes at -100° C. and dry dimethylformamide (2.2 ml) then added dropwise. After 20 minutes, during which the temperature reached -60° C., the reaction mixture was poured onto a saturated solution of sodium chloride (100 ml). The organic phase was separated and combined with a diethyl ether (100 ml) wash of the aqueous phase, dried, filtered and evaporated. Crystallised from diethyl ether-hexane to give 4-cyano-2-methylbenzaldehyde as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A solution of 4-bromophenylacetic acid (502 mg, 2.33 mmol), m-toluidine (0.25 mL, 2.33 mmol), HOBT (350 mg, 2.59 mmol), and N-methylmorpholine (0.51 mL, 4.64 mmol) in DMF (10 mL) was treated with EDCI (496 mg, 2.59 mmol), stirred overnight at room temperature, and poured into ice water. The resulting white precipitate was collected by filtration to give 672 mg of the desired product. MS (ESI(+)) m/e 304, 306 (M+H)+.