Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1
Reactant: Cc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(OCc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Temperature: 0 °C
Yield: 56.2 %

Procedure:
A solution of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoic acid (460 mg, 1.42 mmol, 1.00 equiv), EDCI (320 mg, 1.68 mmol, 1.18 equiv), HOBT (240 mg, 1.78 mmol, 1.25 equiv), pyridin-3-ylmethanamine (180 mg, 1.67 mmol, 1.17 equiv) and triethylamine (440 mg, 4.36 mmol, 3.06 equiv) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of ice/water. The solid was collected by filtration and washed with 3×10 mL of hexane. The crude product was purified on a silica gel column eluted with chloroform/methanol (50:1-20:1) to give 0.33 g (56%) of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a gray solid. LC-MS: (ES, m/z): 414 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.16 (s, 2H), 8.56 (s, 1H), 8.46 (s, 1H), 8.00-7.95 (m, 3H), 7.75 (d, 1H), 7.34 (m, 1H), 6.86-6.81 (m, 2H), 6.68 (d, 1H), 4.50 (d, 2H), 3.78 (s, 2H), 2.50 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH2:1]([C@@:3]1([CH3:18])[NH:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[N:11][C:12](F)=[C:13]([CH3:15])[CH:14]=2)[C:4]1=[O:17])[CH3:2].[CH3:19][C:20]1([CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[CH2:22][O:21]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:19][C:20]1([CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:12]3[N:11]=[CH:10][C:9]([N:5]4[C:4](=[O:17])[C@:3]([CH2:1][CH3:2])([CH3:18])[NH:7][C:6]4=[O:8])=[CH:14][C:13]=3[CH3:15])[CH:27]=2)[CH2:22][O:21]1
Reactant: CC1(C)OCc2ccc(O)cc21
Reactant: CC[C@@]1(C)NC(=O)N(c2cnc(F)c(C)c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC[C@@]1(C)NC(=O)N(c2cnc(Oc3ccc4c(c3)C(C)(C)OC4)c(C)c2)C1=O
Temperature: 110 °C
Reaction time: 10 h
Yield: 26.6 %

Procedure:
To a solution of (5R)-5-ethyl-3-(6-fluoro-5-methyl-3-pyridyl)-5-methyl-imidazolidine-2,4-dione (Intermediate 5, 48 mg, 0.19 mmol) in DMF (1 ml) 3,3-dimethyl-1H-isobenzofuran-5-ol (Intermediate 18, 45 mg, 0.27 mmol) and dipotassium carbonate (75.7 mg, 0.55 mmol) were added and the reaction mixture was stirred at 110° C. for 10 hours. The reaction was quenched with an aqueous saturated solution of ammonium chloride (5 ml) and extracted with ethyl acetate (10 ml). The organic layer was washed with brine (3×10 ml) dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 10 g as column and cyclohexane/ethyl acetate from 85:15 to 20:80 as eluent to afford the title compound (20 mg) as white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][F:20])[CH2:14]3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2].[CH:26]([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:26])[CH:15]([CH2:19][F:20])[CH2:14]3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2]
Reactant: O=C[O-]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)cc21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(CF)C3)cc21

Procedure:
A 100 mg portion of 1-ethyl-6-fluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 300 mg of sodium formate were dissolved in a mixture of 3 ml of glacial acetic acid and 3 ml of 37% formaldehyde and refluxed overnight. The mixture was cooled, basified with sodium hydroxide, acidified with glacial acetic acid and evaporated. The residue was triturated with hot chloroform and the solid crystallized from methanol, giving 91 mg of the desired product, mp 230°-235° C. (dec.).
Reaction SMILES: [OH-:1].[Na+].[C:3]([NH:6][C@@H:7]([CH3:20])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13](C(OC)=O)=[CH:12][CH:11]=1)(=[O:5])[CH3:4].Cl.[CH3:22][OH:23]>>[C:3]([NH:6][C@@H:7]([CH3:20])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:18][C:19]=1[C:22]([OH:23])=[O:1])(=[O:5])[CH3:4]
Reactant: CO
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(C)=O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(=O)N[C@@H](C)COc1ccccc1C(=O)O
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
1M Aqueous sodium hydroxide solution (23 mL) was added to a solution (7 mL) of methyl 4-{[(2S)-2-(acetylamino)propyl]oxy}benzoate (3.80 g) in methanol, and the mixture was stirred at 60° C. for 40 min. The reaction mixture was neutralized with 6M hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether, and the precipitated solid was collected by filtration to give the title compound (3.33 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=4)[CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=4)[CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nccc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Yield: 107.4 %

Procedure:
1-(2-(Methylthio)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (91 mg, 0.251 mmol) was dissolved in methylene chloride (1 mL). At 0° C., 3-chloroperoxybenzoic acid (87 mg, 0.502 mmol) was added. 1 hour later, the reaction mixture was added to sodium bicarbonate aqueous solution and extracted with methylene chloride. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. 1-(2-(Methylsulfinyl)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (102 mg) was yielded.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1(=O)[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13]1.C(OC(=O)C)(=O)C.C([O-])(=O)C>O1CCCC1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]2=[O:18])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCCC(=O)O1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(=O)N1Nc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C

Procedure:
3 g of p-nitrophenylhydrazine and 2 g of glutaric anhydride in 20 ml THF ("tetrahydrofuran") were stirred for 15 min at room temperature. Analysis by infrared spectroscopy showed high conversion to amide-acid. To the reaction mixture was added 2 g of acetic anhydride, 1 ml of triethylamine which as then heated to near reflux. 50 mg of colbalt(II) acetate was added which induced an exothermic reaction. Analysis (IR) after a few minutes showed high conversion to imide. The mixture was evaporated under nitrogen and then slurried with ethanol. The ethanol soluble fraction (main product) was removed and concentrated to 3.4 g of brown solid. This solid was washed twice with benzene to remove 0.2 g and then crystalized from methanol to yield yellow needles, mp=197-198° C. The structure was confirmed by elemental analysis, IR and NMR. DSC analysis showed no crystallization when the melt was cooled at 20° C./min. On reheating a Tg was detected at 65° C., a Tc was detected at 120° C. and a Tm was detected at 204° C. Thin films cast from THF were glassy (noncrystalline) with Tg of 65° C. and were shown, by IR, to contain hydrogen bonds involving the carbonyl and N-H groups. On heating to 120° C., crystallization occured and the H-bonding was lost. High viscosity above Tg was observed by the resistance to sliding of two glass plates sandwiching a thin film of the compound. The μβ, determined by EFISH in dioxane, was 26×10-48 esu. Thin films were prepared on a conducting glass by spin coating using Film Forming Procedure 1 and were poled using Poling Procedure 1. The resulting material retained a substantial portion of the induced molecular ordering for more than 6 months. The induced d33 determined from SHG Measurements was ≈4×10-12 m/V.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+]>O>[OH:14][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccccc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 123.5 %

Procedure:
L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of 4.15 g (42.4 mmol) of concentrated sulfuric acid in 110 g of water and then, at an inside temperature of 20° C., a mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water was added over 5 hours. After addition, the mixture was further stirred at 20° C. for 20 hours and, thereafter, the same work-up procedure as in Example 1 was followed. The combined extract (115.8 g) obtained contained 8.7 g of (2S)-2-hydroxy-3-phenylpropionic acid (yield 87%, optical purity 92.0% ee). The proton concentration (normality) in the reaction of this example was 0.8 mol/kg, the amount of the protonic acid was 1.4 equivalents (relative to L-phenylalanine), and the reaction temperature was 20° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CCOCC.C1(C)C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:7]=2[C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
1.02 g (0.026 mol) of 60% oil-dispersed sodium hydride were dissolved in 20 mL of ether and cooled to 5° C. 20 mL of an ether solution containing 5.00 g (0.024 mol) of 2,4-di-tert-butylphenol were dropped in over the course of 15 minutes at 5° C. and stirred for 30 minutes followed by dropping in 20 mL of a toluene solution containing 4.16 g (0.022 mol) of p-toluenesulfonyl chloride over the course of 20 minutes, stirring for 30 minutes at 25° C. and confirming the 2,4-di-tert-butylphenol to no longer be present. Following completion of the reaction, water was added and the organic layer was extracted with ethyl acetate followed by washing twice with saturated aqueous NaHCO3 solution and once with saturated brine, drying with MgSO4 and concentrating. The resulting crystals were purified by crystallizing with n-hexane to obtain 3.0 g (yield: 38%) of 2,4-di-tert-butylphenyl p-toluenesulfonate (white crystals, melting point: 81° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:18]([O:26][C@@H:27]1[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([C:41]([NH:43][CH2:44][CH3:45])=[O:42])[O:29][C@H:28]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([I:56])=[N:50][C:51]=2Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(C)C>[C:18]([O:26][C@@H:27]1[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:30]([C:41]([NH:43][CH2:44][CH3:45])=[O:42])[O:29][C@H:28]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([I:56])=[N:50][C:51]=2[NH:10][CH2:9][CH:8]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
2,2-Bis(4-chlorophenyl)ethanamine (426 mg, 1.51 mmol) (J. Am. Chem. Soc., 1983, 105(10), 3138) was added to a stirred solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (500 mg, 0.755 mmol) (Preparation 47) in isopropyl alcohol (20 ml) at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure to give a residue that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:(99:1 by volume). The solvent was removed under reduced pressure to give the title compound (329 mg) as a foam.
Reaction SMILES: Br[C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:10])[C:4]=2[CH:3]=1.[O:12]1C[CH2:15][CH2:14][CH2:13]1.C(O)C#C.C(N(CC)C(C)C)(C)C>[Cu]I.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.O>[Cl:10][C:9]1[C:4]2[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:12])[NH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C1CCOC1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OCC#Cc1cc2c(Cl)ncnc2[nH]1
Yield: 31 %

Procedure:
A mixture comprising 3.00 g (12.9 mmol) 6-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No: 784150-41-0), 90 mL tetrahydrofuran, 3.0 mL prop-2-yn-1-ol, 246 mg copper(I) iodide, 746 mg tetrakis(triphenylphosphine)palladium(0) and 3.93 mL N,N-diisopropylethylamine was heated at 80° C. for 4 hours. Water was added and the mixture extracted with ethylacetate/methanol (8:2). The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvents the residue was purified by chromatography to give 833 mg (31%) of the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O.[C:14](#[N:16])[CH3:15].Cl>C1COCC1.C(OCC)(=O)C>[O:11]=[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: CCOC(=O)c1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a mixture of sodium hydride (15 g, 60% in oil, 375 mmol) and ethyl 2-picolinate (50 g. 331 mmol) in anhydrous THF (250 mL) was added dropwise a solution of anhydrous acetonitrile (20 g, 487 mmol) in anhydrous THF (200 mL), at about 65° C. After complete addition the reaction mixture was heated at about 65° C., for about 5 h. After cooling to rt, ethyl acetate (500 mL) was added, followed by 1 M aqueous HCl (360 mL). The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layers were washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give crude 3-oxo-3-(2-pyridyl)propanenitrile (48.6 g, 331 mmol, 100%), which was used as such in the next step. 1H-NMR (CDCl3, Bruker 400 MHz) δ 4.39 (2H, s); 7.58 (1H, m); 7.91 (1H, dt, J=2 Hz, 10 Hz); 8.11 (1H, dt, J=2 Hz, 10 Hz); 8.70 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[CH:4][C:3]=1[F:22].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[CH:4][C:3]=1[F:22]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
5.00 g (16.3 mmol) of Compound 26 obtained in Example 26 was dissolved in 50 ml of pyridine, 2.2 ml of pivaloyl chloride was added under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 6.35 g (100%) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1(Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([NH:4][CH2:3][CH2:2][OH:1])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrC1CCCCCC1
Product: OCCNC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give N-cycloheptyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cycloheptyl-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[NH:8][CH2:7][C:6]=2[CH:12]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:10])(=[O:11])[N:8]([CH3:13])[CH2:7][C:6]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=S1(=O)NCc2cc(Br)ccc21
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CN1Cc2cc(Br)ccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 725.7 %

Procedure:
To a suspension of 5-bromo-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (200 mg, 0.92 mmol) and potassium carbonate (128 mg, 0.92 mmol) in EtOH (2 mL) was added iodomethane (0.2 mL, 3.2 mmol) and the reaction was stirred at room temperature for 18 hours followed by heating to 50° C. for 2 hours. The reaction was cooled, concentrated in vacuo and diluted with DCM (20 mL). The solution was washed with water (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the title compound as a white solid (1.75 g, 83%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1.F[C:16]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]([NH:30][C:31]2[CH:32]=[N:33][C:34]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35][CH:36]=2)=[O:29])[CH:22]=1)=[O:19]>C1COCC1.C(Cl)Cl>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:17]2[CH:44]=[C:45]([C:48]([F:51])([F:49])[F:50])[CH:46]=[CH:47][C:16]=2[O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)=[O:19])=[CH:22][C:23]=1[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:33][CH:32]=1)=[O:29]
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1C(=O)Nc1cnc(Nc2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2OC2CCN(C)CC2)cc1C(=O)Nc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of potassium t-butoxide (17 mg, 0.151 mmol) in THF (2 mL) was added 1-methylpiperidin-4-ol (15 mg, 0.130 mmol). The mixture was allowed to stir at rt for 15 min, at which time 2-fluoro-N-(4-methyl-3-(((2-(phenylamino)-5-pyrimidinyl)amino)carbonyl)phenyl)-5-(trifluoromethyl)benzamide 40 (55 mg, 0.108 mmol) was added. The reaction mixture was stirred at room temperature for 24 h, at which time the LCMS showed complete conversion. The reaction mixture was diluted with CH2Cl2, washed with water (3×20 mL), dried over Na2SO4 and concentrated. The crude residue was taken up in MeOH/DMSO and purified on the Shimadzu reversed phase HPLC with a 15-85% gradient. Pure fractions were combined, basified with saturated sodium bicarbonate and extracted with CH2Cl2 (4×20 mL). Combined organic extracts were dried over sodium sulfate and concentrated to afford 2-methyl-5-(((2-((1-methyl-4-piperidinyl)oxy)-5-(trifluoromethyl)phenyl)carbonyl)amino)-N-(2-(phenylamino)-5-pyrimidinyl)benzamide 41. MS m/z found 605.3 [MH+]; calc. for C32H31F3N6O3=604.24.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[N:5]=1
Reactant: NCCc1cc2ccccc2cn1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To an ice-bath cooled solution of 3-(2-aminoethyl)isoquinoline (Description 113; 2.70 g, 15.7 mmol) and triethylarnine (2.84 ml, 20.41 mmol) in anhydrous dichloromethane (75 ml) was added slowly ethyl chloroformate (1.65 ml, 17.27 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water, sat NaCl, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica elution with a gradient rising from DCM to 2% MeOH in DCM+0.5% NH4OH to give the title compound (2.27 g, 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[C:6]([CH:5]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 15.0 g (74.1 mmol) of methyl 3-ethoxy-4-methoxybenzoate in 45 mL of acetic acid was treated with 15 mL of conc nitric acid dropwise over 12 min. The reaction was kept at 55° C. for 45 min, cooled to 25° C. and poured into ice water. The product was extracted into methylene chloride and the extracts were washed with water and μl sodium hydroxide, dried and evaporated. The yield was 17.8 g of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate as yellow crystals: mass spectrum (electrospray, m/e): M+H 256.0.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([O-:17])(=O)=[O:15])=[CH:8][CH:7]=1.[Na+].C1C=CC=CC=1>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([Cl:3])(=[O:17])=[O:15])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=S(=O)(Cl)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Thionyl chloride (1.51 mL, 20.8 mmol) was added dropwise at 0° C. to a suspension of sodium 2-(4-bromo-phenyl)-ethanesulfonate (4.33 g, 15.08 mmol) in a mixture of anhydrous benzene (50 mL) and N,N-dimethylformamide (1 mL). The reaction mixture was allowed to warm to room temperature and was then heated at 80° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The solids were washed with benzene and the combined filtrates were concentrated in vacuo. The residue was taken up in hexane (30 mL) and the resulting suspension was heated at 50° C. for 30 min. After cooling to room temperature, the formed precipitate was collected by filtration to give 4.06 g (95% yield) of the title compound.