Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH:12]([F:14])[F:13])[CH:3]=1.[CH2:15](O)[CH:16]([OH:19])[CH2:17][CH3:18]>>[F:14][CH:12]([F:13])[O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH3:9])[O:19][CH:16]([CH2:17][CH3:18])[CH2:15][O:10]1
Reactant: CCC(O)CO
Reactant: CC(=O)c1ccc(Cl)cc1OC(F)F
Product: CCC1COC(C)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C

Procedure:
12.8 parts of 1-(4-chloro-2-difluoromethoxyphenyl)ethan-1-one and 10.4 parts of 1,2-butanediol are heated under reflux for 12 hours in 100 ml of abs. toluene in the presence of 0.2 part of p-toluenesulfonic acid as catalyst, while removing the water of reaction with a water separator. The reaction mixture is cooled to room temperature and then washed with 2×100 ml of water, dried over sodium sulfate and filtered. The solvent is removed by evaporation and the residual oil is purified by high-vacuum distillation; b.p. 78°-80° C./0.04 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([NH:28][OH:29])=[NH:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[C:35](OC(=O)C)(=O)[CH3:36]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]5[N:27]=[C:35]([CH3:36])[O:29][N:28]=5)=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:15][CH:16]=2)=[O:30])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(NO)c1ccc2c(ccn2-c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc3c(ccn3-c3ccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)c2)no1
Temperature: 80 °C
Reaction time: 14 h
Yield: 36.4 %

Procedure:
In 0.2 mL of pyridine, 10.5 mg (0.022 mmol) of 1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-N-hydroxy-1H-indole-5-carboxamidine was dissolved, and 10 mg (0.098 mmol) of acetic anhydride was added thereto, and the mixture solution was stirred at 80° C. for 14 hours. The reaction solution was concentrated under reduced pressure, and then the obtained residue was purified by Megabond Elute Silica Gel (a product of Varian, 1 g, methylene chloride:methanol=20:1) to obtain 4.1 mg (37%) of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-{4-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)indol-1-yl]phenyl}urea (Table 1, Compound No. 26).
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:6](=[O:25])[N:5]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:4]=2[N:3]=1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C12CCCCC1CCCNN=2>CN1CCCC1=O>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:2]2[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]3[C:8](=[O:16])[N:7]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[C:6](=[O:25])[N:5]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:4]=3[N:3]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C1CCC2CCCNN=C2C1
Solvent: CN1CCCC1=O
Product: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 150 °C
Reaction time: 6.5 h
Yield: 45 %

Procedure:
2,2-Dimethylpropionic acid [8-chloro-3-(2,2-dimethylpropionyloxymethyl)-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (470 mg) and 1-piperazinecarboxylic acid tert-butyl ester (218 mg) were dissolved in N-methylpyrrolidone (4 ml), and diazabicyclo[5.4.0]undecene (160 μl) was added to the solution. The mixture was stirred at 150° C. for 6.5 hours. The reaction mixture was filtered through Celite, diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After the solvent was removed by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 277 mg of the title compound from the elution fraction of hexane-ethyl acetate (2:1)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C-:31]#[N:32].O>CS(C)=O>[C:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:32]
Reactant: [C-]#N
Reactant: BrCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
1-(6-Bromohexyl)-2,4,5-triphenylimidazole (27.6 g) in dry dimethyisulphoxide (70 ml) was added over 10 minutes to a mixture of sodi-m cyanide (3.68 g) in dimethyl-sulphoxide (50 ml) and the reaction was stirred at room temperature for 20 h. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The extracts were combined, washed with water, dried over anhydrous magnesinm sulphate and evaporated to dryness in vacuo. Recrystallisation from diethyl ether and hexane gave 1-(6-cyanohexyl)-2,4,5-triphenylimidazole (24.19 g, 99%) as a white solid, m.p. 104°-6°.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(#N)C>[C:24]([O:23][C:21]([NH:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@H]2CC[C@@H]1O2
Temperature: 80 °C
Yield: 92.1 %

Procedure:
A solution of (1S,2R,3S,4R)-methyl 3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate (11) (500 mg, 2.4 mmol), Et3N (0.85 ml, 6 mmol) and BOC2O (0.66 ml, 2.88 mmol) in acetonitrile was stirred at rt for 2 h and then heated at 80° C. for 30 min when TLC confirmed completion of reaction. Acetonitrile was removed and the crude product was purified by column chromatography using silica gel (100-200 mesh) to afford the desired compound (600 mg, 92%) as a colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:17][C:18]([O:20]C)=O)([CH2:13][N+:14]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].O.C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][NH:14][C:18](=[O:20])[CH2:17]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(C[N+](=O)[O-])CCN(Cc2ccccc2)C1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: O=C1CC2(CCN(Cc3ccccc3)C2)CN1
Temperature: 30 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A suspension of methyl [1-benzyl-3-(nitromethyl)pyrrolidin-3-yl]acetate a46 (3.3 g, 1.1 mmol, 1 eq) and Raney nickel (1 g of a 50% slurry in water) in ethanol (200 ml) is shaken in a Parr bottle at 30° C. for 24 h, under a hydrogen pressure of 40 psi. The reaction mixture is then filtered through Celite and the filtrate is concentrated to afford 1.8 g of 7-benzyl-2,7-diazaspiro[4.4]nonan-3-one a47 as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.Cl.[NH:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1)=[O:12]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCOCC2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 241.4, 150 mg, 0.47 mmol) in N,N-dimethylformamide (3 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 91 mg, 0.47 mmol), EDC.HCl (180 mg, 0.94 mmol), 4-dimethylaminopyridine (114 mg, 0.93 mmol) were added to the reaction. The reaction mixture was stirred for 3 h at 25° C., then diluted with 80 mL of EtOAc. The organic layer was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and ACN (25.0% ACN up to 39.0% in 8 min, hold 39.0% in 1 min, up to 100.0% in 3 min, down to 25.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 133.3 mg (62%) of the title compound as a light yellow solid. m/z (ES+) 461 (M+H)+.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[C:37](=[O:38])[NH:36][N:35]=[CH:34]2)[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:36]2[C:37](=[O:38])[N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[CH:34]=[N:35]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Yield: 84 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.47-7.30 (m, 2H), 7.11-6.97 (m, 2H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 363.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[NH2:25][CH2:26][C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.O.ON1C2C=CC=CC=2N=N1.CN(C)C=O>C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:15])[NH:25][CH2:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: NCc1ncccn1
Reactant: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)O)cc1Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-methoxy-2-methylthiopyrimidine (prepared in the above (2)) 183 mg, 2-aminomethylpyrimidine 70 mg, 1-hydroxybenzotriazole hydrate 67 mg and dimethylformamide 4 ml is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimido hydrochloride 114 mg on an ice bath, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=20:1→10:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder 208 mg. mp 171-172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>O1CCCC1.[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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine (176 mL, 1.26 mol) are dissolved in dry tetrahydrofuran (1.2 L) and nitrogen gas was bubbled through the solution for about 20 min. Copper (I) iodide (1.08 g, 5.7 mmol) and bis(triphenyphosphine)palladium dichloride (2.15 g, 3 mmol) are added and then trimethylsilylacetylene (178 mL, 1.3 mol) was added dropwise over about 40 min with the temperature being maintained at about 23° C. A large amount of precipitate forms which necessitates mechanical stirring. Following complete addition of the trimethylsilylacetylene the mixture was allowed to stir at room temperature for about 18 hours. The mixture was filtered and the solid washed with cyclohexane. The combined filtrates are concentrated under reduce pressure to give a brown oil. Application of this oil to a pad of silica gel followed by elution with cyclohexane gave a yellow solution. Removal of the solvent gave the title compound as a yellow oil; 182.8 g (95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (3.0 g, 0.01 mol) and benzenesulfonyl chloride (1.8 g, 0.01 mol) were dissolved in toluene (14.8 g) and then cooled to 0° C. To the mixture was added dropwise triethylamine (1.0 g, 0.01 mol) at 0° C. over 35 min. The mixture was further kept at 0° C. for 3 hrs. The reaction mass was washed with 5% hydrochloric acid (7.3 g) and 5% aqueous sodium bicarbonate (8.4 g) and then concentrated under reduced pressure with a rotary evaporator to give N-Boc-O-benzenesulfonyl-L-tyrosine methyl ester 5 (4.35 g, yield 100%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([O:30][C:31]1[CH:64]=[CH:63][C:34]([C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:46](=[O:54])[C:47]3[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=3)=[CH:40][CH:39]=2)=[O:36])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CN(C=O)C>[CH2:23]([O:30][C:31]1[CH:64]=[CH:63][C:34]([C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:46](=[O:54])[C:47]3[CH:48]=[CH:49][C:50]([NH:53][C:10](=[O:12])[CH2:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:13]([F:16])([F:15])[F:14])=[CH:51][CH:52]=3)=[CH:40][CH:39]=2)=[O:36])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Prepared using General Procedure 7: To 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (299 mg, 1.28 mmol) in DCM (5 mL) and DMF (20 μL) was added oxalyl chloride (0.117 mL, 1.34 mmol). After stirring at room temperature for 30 min, 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (700 mg, 1.22 mmol) and TEA (0.424 mL, 3.05 mmol) in DCM (10 mL) were added. The reaction was stirred for 1 h then diluted with DCM (100 mL) and washed with NaHCO3 (100 mL). The crude product was purified by chromatography to provide 555 mg (58%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-6. LCMS-ESI (m/z) calculated for C44H49F3N2O8: 791; no m/z observed, tR=3.28 min (Method 4).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1>O.CC(O)=O>[N:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCCCN2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCCCc2ccccc21
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of sodium nitrite (1.35 g, 19.6 mmol) in water (4.0 mL) was added dropwise to a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g, 16.3 mmol) in AcOH (10 mL) at 0-10° C. The mixture was stirred at 5° C. for 10 min, room temperature for 1 h and extracted with CH2Cl2 (3×20 mL). The organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:9) gave 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 91%) as a brown liquid. 1H NMR (CDCl3, 300 MHz) δ 1.70-1.85 (m, 4H), 2.70-2.82 (m, 2H), 3.92 (br, 2H), 7.25-7.32 (m, 1H), 7.32-7.40 (m, 2H), 7.40-7.48 (m, 1H) ppm.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[O:12]1[CH2:14][CH2:13]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[C:11]([CH2:14][CH2:13][OH:12])=[CH:10][CH:9]=[N:8]1
Reactant: Cn1cccn1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nccc1CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
n-Butyl lithium (1.6M in hexanes) (1226 mL, 1961.78 mmol) was added dropwise to 1-methyl-1H-pyrazole (153.4 g, 1868.37 mmol) in THF (3000 mL) cooled to −78° C. over a period of 1 hour under nitrogen. The resulting solution was stirred at −60° C. for 30 minutes, then warmed to −10° C. and stirred for a further 40 minutes. A solution of oxirane (210 mL, 4203.82 mmol) in THF (600 mL) was added slowly at −10° C. followed by further THF (1000 mL) and the resulting slurry was stirred at −10° C. for 30 minutes, then at 0° C. for 30 minutes. The mixture was then allowed to gradually warm to room temp under nitrogen and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl solution (2000 ml), the layers separated and the aqueous phase extracted with n-butanol (3×1000 ml). The combined organics were washed with saturated brine (1500 ml), dried over MgSO4, filtered and evaporated to give an oil, which was azeotroped with toluene (1000 ml) to leave an oil with some solid. The oil was dissolved in DCM and the insoluble solid was filtered off and washed with DCM. The filtrate was purified by chromatography using a silica Novasep prep HPLC column, eluting with a gradient of 5-10% methanol in DCM. Pure fractions were evaporated to dryness to afford 2-(1-methyl-1H-pyrazol-5-yl)ethanol (195 g, 83%) as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:39][N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>ClCCl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:40][CH3:39])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and methylamine (0.185 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (32 mg, 78%). LC-MS m/z 535 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](C(OCC)=O)[C:16]([O:18]CC)=[O:17])=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
To a round-bottom flask containing diethyl 2-(4-benzyloxy-2-nitrophenyl) malonate (4c) (2.00 g, 5.17 mmol) was added EtOH (45 mL) and 10% NaOH (60 mL) producing a dark brown solution. The solution was refluxed for 3 h and checked by TLC (CHCl3), at which time the solution was slightly yellowish and clear. The EtOH was removed under reduced pressure to form a yellow suspension and sufficient THF (30 mL) was added to produce a clear yellow solution which was placed in an ice bath and stirred. 6M HCl (30 mL) was slowly added to the solution to reach pH 1. The light orange solution was refluxed for another hour, at which time two layers formed. The top THF layer was collected, and the aqueous solution was extracted with CHCl3 (100 mL). The organic layers were combined and dried with anhydrous sodium sulfate. The solution was then filtered, and the filtrate was concentrated to produce 4-benzyloxy-2-nitrophenylacetic acid as an orange solid. The solid was then placed on a high vacuum and dried (1.41 g, 4.91 mmol, 95%). Mp 145-152° C.; TLC (CHCl3) Rf=0.15; 1H-NMR (CDCl3, 300 MHz) 7.76 (d, 2.7, 1H), 7.41 (m, 5H), 7.26 (d, 8.7, 1H), 7.21 (dd, 2.7, 8.7, 1H), 5.13 (s, 2H), 4.00 (s, 2H); IR (CHCl3 cast) 3400-2600 (br), 3100, 1698, 1601, 1526, 1523, 1453, 1376, 1349, 1240, 1180, 1022, 848, 815, 760, 712; EI-MS m/z (relative intensity) 287 (M+, 10). Accurate mass (EI-MS) for C15H13NO5: calcd. 287.0794, obsd. 287.0799.