Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:17])[NH:11][CH2:12][CH2:13][C:14](=[NH:16])[NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[N:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])=[N:22][CH:21]=1>C(O)C>[CH2:2]([O:9][C:10](=[O:17])[NH:11][CH2:12][CH2:13][C:14]1[NH:15][C:28](=[O:29])[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][N:22]=2)[N:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCc1nc(-c2ccncn2)cc(=O)[nH]1)OCc1ccccc1
Yield: 33 %

Procedure:
To a suspension of 6 g (23.3 mmol) of (2-Carbamimidoyl-ethyl)-carbamic acid benzyl ester hydrochloride (1:1) in 60 ml of ethanol were added 0.93 g (23.3 mmol) of sodium hydroxide and 4.5 g (23.3 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE2705582). The resulting mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The resulting mixture was treated with water and the precipitate was filtered, washed with diethyl ether to afford 2.7 g (33%) of the desired compound as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:14][CH2:15][C:16](Br)=[O:17]>C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:1][C:16](=[O:17])[CH2:15][Br:14]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CBr)Nc1cccc(O)c1
Temperature: 10 °C

Procedure:
m-Aminophenol, 66.5 g. (0.61 mole), is dissolved in 500 ml. of a 50/50 (v/v) mixture of glacial acetic acid and saturated sodium acetate solution. The mixture is cooled to approximately 10° C. and 200 g. (0.99 mole) of bromoacetyl bromide is added dropwise. The temperature is maintained between 15° and 20° C. When addition is complete, the mixture is stirred while cooling until the temperature is about 5° C. The product is filtered off, washed successively with cold water, saturated sodium bicarbonate solution and finally two portions of water. The product is dried under vacuum. The yield of the title compound is 121 g. (86 percent of theory), m.p. 167°-170° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(C)=O.[I-:14].[Na+]>C(Cl)Cl>[I:14][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)CCCI
Yield: 69.2 %

Procedure:
Mix ethyl 4-chlorobutyrate (80 g), acetone (400 mL) and sodium iodide (100 g). Reflux for 8 hours, cool and add methylene chloride (400 mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200 mL) and water (200 mL). Separate the organic phase, dry (MgSO4) and evaporate to an oil. Purify by distillation to give the title compound (89 g); bp 64° C.@0.5 mm Hg.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:13]([Cl:27])[C:12]2=[O:28])=[C:6]([F:29])[CH:5]=1.C(N(CC)CC)C.[NH:37]1[CH:41]=[C:40]([C:42](O)=[O:43])[N:39]=[CH:38]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:27][C:13]1[C:12](=[O:28])[N:11]([C:7]2[C:6]([F:29])=[CH:5][C:4]([CH2:3][NH:2][C:42]([C:40]3[N:39]=[CH:38][NH:37][CH:41]=3)=[O:43])=[CH:9][C:8]=2[F:10])[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Reactant: O=C(O)c1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1)c1c[nH]cn1
Reaction time: 8 h

Procedure:
1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one hydrochloride (150 mg, 0.334 mmol) is dissolved in a solution of 4 ml tetrahydrofuran and triethylamine (35 mg, 0.35 mmol). 4-imidazolecarboxylic acid (62 mg, 0.56 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 0.67 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (128 mg, 0.668 mmol), and triethylamine (100. mg, 0.989 mmol) were combined in 5 ml tetrahydrofuran and stirred under nitrogen. The solution containing 1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one hydrochloride was added in one portion, rinsing with 2 ml tetrahydrofuran. Stirring was continued at room temperature overnight, then the reaction was poured into 90 ml of icewater, and the product collected by filtration and dried in vacuo (254 mg, 94%). 1H-NMR (400 MHz, DMSO-d6) δ 12.55 (br s, 1H), 8.73 (t, J=6.57 Hz, 1H), 7.90 (d, J=7.87 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 2H), 7.35, (dt, J=10.04, 2.54 Hz, 1H), 7.21 (m, 3H), 6.78 (d, J=8.04 Hz, 1H), 5.39 (s, 2H), 4.47 (m, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.26 (quintet, J=7.87 Hz, 1F), −113.52 (quartet, J=9.30 Hz, 1F), −120.59 (d, J=9.21 Hz, 2F). LC/MS tr=4.48 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0818 (M−H calcd for C23H16ClF4N4O3 requires 507.0842).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]1=[O:13].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1C(=O)N([I:41])C(=O)C1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH3:12])=[C:4]([I:41])[C:3]1=[O:13]
Reactant: Cc1cc(C(F)(F)F)n(C)c(=O)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(F)(F)F)n(C)c(=O)c1I
Temperature: 77.5 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1,4-dimethyl-6-(trifluoromethyl)-1H-pyridin-2-one (1.44 g, 7.23 mmol), trifluoroacetic acid (9 mL) and trifluoroacetic anhydride (1.53 mL, 10.85 mmol) was added NIS (2.569 g, 10.85 mmol) at room temperature. Then, the mixture was heated to 70-85° C. and was stirred for 2 h. The reaction mixture was cooled to room temperature and saturated sodium carbonate solution was added slowly to neutralize the solution. Then, the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed successively with saturated sodium thiosulfate solution (100 mL) and brine solution (100 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the solvent gave a crude product, which was purified by silica gel chromatography on a Biotage (40 m) column to afford 1.02 g (45% yield) of 1,4-dimethyl-3-iodo-6-(trifluoromethyl)-1H-pyridin-2-one as an amorphous white solid. ES-LRMS: m/z 318.1 (M+H), 381.2 (M+Na+ CH3CN). f) Preparation of N-[(1,1-dimethylethoxyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].CS(C)=O.[OH-].[Na+].Cl[CH2:20][CH2:21][CH2:22][Si:23]([O:28][CH3:29])([O:26][CH3:27])[O:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:20][CH2:21][CH2:22][Si:23]([O:28][CH3:29])([O:26][CH3:27])[O:24][CH3:25])[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCN(CC)c1cccc(OCCC[Si](OC)(OC)OC)c1
Temperature: 88 °C

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 90.75 g (0.55 mole) m-diethylaminophenol, 112 cc dimethylsulfoxide, 120 cc toluene and 43.28 g of a 50% aqueous sodium hydroxide solution. All of the water present in the reactor was removed by azeotropic distillation. The reaction mixture was allowed to cool to 80° C., at which time 109 g (0.55 mole) of chloropropyl trimethoxysilane were gradually added over a period of 2 hours. The temperature of the reaction mixture increased to 88° C. during the addition. Following completion of the addition, external heating was applied to maintain the temperature of the reaction mixture at 80° C. for 16 hours. The reaction mixture was then allowed to cool and was filtered. The liquid phase was recovered and evaporated under a pressure of 5 mm of mercury to remove the toluene and dimethylsulfoxide. The pressure inside the reactor was reduced to 2 mm and the product, 3(m-diethylaminophenoxy)propyl trimethoxysilane, distilled at a temperature of 185°-187° C. Analysis by vapor phase chromatography demonstrated that the product was 97% pure.
Reaction SMILES: [C-:1]1([C:6]([NH:8][NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].C(=O)([O-])[O-].[K+].[K+].[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1(C)C=CC=CC=1.O>[C-:1]1([C:6]([NH:8][N:9]([C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[Br:26])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5]1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: CC(C)(C)NNC(=O)[c-]1cccc1
Reactant: O=C(Cl)c1ccccc1Br
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)[c-]1cccc1)C(=O)c1ccccc1Br
Reaction time: 2 h

Procedure:
To a stirred mixture of N-ferrocenoyl-N'-tert-butylhydrazine (0.5 g, 1.65 mmoL) in toluene (10 mL), and potassium carbonate (0.5 g, 3.62 mmoL) in water (5 ml) was added a solution of 2-bromobenzoyl chloride (0.5 g, 1.82 mmoL) in toluene (5 mL) dropwise in 15 minutes. The resulting mixture was stirred vigorously for two hours and the solid was filtered, washed with water, ethyl ether and dried to afford product as a bright yellow solid, melting point 175° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:32]2[CH:37]=[CH:36][C:35]([O:38]CC3C=CC=CC=3)=[CH:34][CH:33]=2)[C:16]2[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=2[CH2:18][NH:19][CH:20]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Br.C(O)(=O)C.C(=O)([O-])O.[Na+]>>[CH:20]1([NH:19][CH2:18][C:17]2[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=2[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: c1ccc(COc2ccc(C(c3ccc(OCc4ccccc4)cc3)c3ccccc3CNC3CCCCCCC3)cc2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CNC2CCCCCCC2)cc1
Reaction time: 2 h
Yield: 54.5 %

Procedure:
Two grams of 2-[bis(4-benzyloxyphenyl)methyl]-N-(cyclooctyl)benzylamine obtained by Example 82 was dissolved in 120 ml of a mixture of ice-cooled hydrogen bromide-acetic acid solution. The solution was stirred for 2 hours, and the mixture was added to a mixture of ice and a saturated aqueous sodium hydrogencarbonate, stirred and then neutralized with sodium hydrogencarbonate. Thereafter, it was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to recrystallization to afford 0.76 g of the desired compound (Compound 85).
Reaction SMILES: [C:1]([NH:6][C:7]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH3:18])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Se](=O)=[O:21]>O>[C:1]([NH:6][C:7]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH:18]=[O:21])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[CH:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Reactant: O=[Se]=O
Solvent: O
Product: CCCC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Reaction time: 33.5 h
Yield: 65 %

Procedure:
In a 25 ml. round-bottomed flask equipped with a magnetic bar, water-cooled reflux condenser, and an argon filled balloon, 7-butyramido-2-methylquinoline-5,8-dione (30) (prepared as described in Example 30) (0.516 g., 2 mmol), selenium dioxide (0.255 g., 2.3 mmol), 12 ml. of dried, distilled 1,4-dioxane, and 0.25 ml. of water were stirred and slowly heated to reflux over a two-hour period. The reaction was monitored by TLC and found to be complete after 33.5 hours. The selenium metal was allowed to settle, and the supernatant solution was pipetted off and filtered. 1,4-Dioxane (10 ml.) was added to the residue, stirred and refluxed for five minutes. The entire mixture was filtered and the selenium was washed with dichloromethane (10 ml.). All filtrates were combined and stored at 4EC overnight. This solution was diluted with 50 ml of dichloromethane and washed with a 3% sodium bicarbonate solution (2×50 ml.). The organic layer was dried with magnesium sulfate and rotoevaporated to give a pale yellow product. The solid was dried under vacuum overnight and weighed 0.356 g. (yield of 65%). The product was recrystallized from ethyl acetate: mp. 208-210E C; 1H NMR (CDCl3) * 1.02 (3H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3),1.70 -1.89 (2H, m, 7NHCOCH2CH2CH3), 2.52 (2H, t, J=7.4 Hz, 7NHCOCH2CH2CH3), 8.06 (1 H, s, C-6H), 8.31 (1 H, d, J=8.0 Hz, C-3H), 8.39 (1H, br. s, C-7NH), 8.61 (1H, d, J=8.0 Hz, C4H), 10.28 (1H, s, C-2CHO); IR (KBr) vmax 3299, 3081, 2966, 2935, 2876, 1723, 1694, 1638, 1606, 1505 cm-1 ; EIMS, m/e (relative intensity) 272 (54), 202 (36), 175 (9); HRMS, m/e for C14H12N2O4 calculated 272.079707, found 272.078696; analysis for C14H12N2O4 calculated C, 61.76; H, 4.44; N, 10.29; found C, 61.31; H, 4.36; N, 9.94.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)[CH:7]=1)CCC.[I:29]I>C1COCC1>[I:29][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccc3cnccc3c2)no1
Reactant: II
Solvent: C1CCOC1
Product: Ic1cc(-c2ccc3cnccc3c2)no1
Temperature: 80 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
To a solution of 6-(5-(tributylstannyl)isoxazol-3-yl)isoquinoline (1.00 g, 2.1 mmol) in 20 mL of THF in a sealable tube was added iodine (0.52 g, 2.1 mmol). The tube was sealed and heated to 80° C. by immersion in an oil bath. After 12 hours, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 2.5% MeOH/DCM), affording 6-(5-iodoisoxazol-3-yl)isoquinoline (0.60 g, 90% yield) as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.52 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.12 (dd, J=1.6 Hz, 8.6 Hz, 1H), 7.92 (d, J=5.7 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[NH2:48][CH2:49][CH2:50][O:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[C:55]#[N:56]>Cl.O>[C:55]([C:54]1[CH:53]=[C:52]([CH:59]=[CH:58][CH:57]=1)[O:51][CH2:50][CH2:49][NH:48][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:17][CH:16]=1)#[N:56]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: COC(=O)c1ccc(Cc2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OCCNC(=O)c2ccc(Cc3ccncc3)cc2)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
262 mg (1.15 mmol) of methyl 4-[(pyridine-4-yl)methyl]benzoate was dissolved in 5 ml of concentrated hydrochloric acid. The solution was stirred at 70° C. for 15 hours. The solvent was evaporated, and the residue was dissolved in 5 ml of dichloromethane. 0.24 ml (1.73 mmol) of triethylamine, 243 mg (1.27 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 172 mg (1.27 mmol) of 1-hydroxybenzotriazole and 308 mg (1.27 mmol) of 3-(2-aminoethoxy)benzonitrile hydrochloride were added to the solution, and they were stirred for 15 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water, 1 N sodium hydroxide and saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]([NH:9][C@H:10]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:11][CH2:12][CH2:13][NH:14]C(=O)OCC2C=CC=CC=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1>[Pd].CO>[N:1]1([CH2:6][C:7]([NH:9][C@@H:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)=[O:26])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(Cn1cncn1)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: NCCC[C@H](NC(=O)Cn1cncn1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
Step (a) A flask was charged with (S)-benzyl 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate (700 mg, 1.25 mmol), prepared as in Example 1, palladium on carbon (10%, 70 mg) and methanol (30 mL) and the mixture was placed under a hydrogen atmosphere (balloon). The mixture was stirred 16 hours at ambient temperature and then concentrated and filtered. Product was purified from the residue by reverse phase HPLC to give (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-amino-N-(4-(4-fluorophenoxy)phenyl)pentanamide (420 mg, 0.985 mmol, 79%) as an off-white solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=3)[C:12]([CH2:22][CH3:23])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[Na+].[NH2:26][C:27]1[C:28]([Cl:34])=[N:29][CH:30]=[N:31][C:32]=1[Cl:33]>C1(C)C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:34][C:28]1[C:27]([NH:26][C:19]([C:16]2[CH:17]=[C:18]3[C:13]([C:12]([CH2:22][CH3:23])=[N:11][N:10]3[CH:5]3[CH2:6][CH2:7][CH2:8][CH2:9]3)=[CH:14][CH:15]=2)=[O:21])=[C:32]([Cl:33])[N:31]=[CH:30][N:29]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3c(Cl)ncnc3Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.7 %

Procedure:
50 μL (0.680 mmol, 1.3 equiv) thionyl chloride were added to a room temperature solution of 135 mg (0.523 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1h-indazole-6-carboxylic acid and 10 μL DMF in 5 mL anhydrous toluene. The reaction mixture was heated to reflux for 2 hours, then cooled to room temperature, concentrated to dryness on a rotary evaporator, and dried at high vacuum, room temperature for several hours. 21 mg (0.523 mmol, 1.0 equiv) sodium hydride, 60% oil dispersion, were added to a separate flask containing a room temperature solution of 86 mg (0.523 mmol, 1.0 equiv) 5-amino-4,6-dichloro-pyrimidine in 5 mL anhydrous DMF. After 10 minutes, a solution of the acid chloride (prepared above) in 5 mL anhydrous DMF was added, and the mixture stirred for 24 hours at room temperature. The reaction mixture was then heated to 70° C. for 1.5 hours, cooled to room temperature, diluted with 75 mL ethyl acetate, washed 2×15 mL H2O, 1×16 mL brine, and dried over MgSO4. The crude product was purified on a silica gel column (20 % ethyl acetate/hexanes) to give 31 mg (15%) of white crystalline solid: mp 171-172° C.; Anal. calcd for C19H19N5OCl2: C, 56.44; H, 4.74; N, 17.32. Found: C, 56.38; H, 4.76; N, 17.33.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([N:33]1[C:37](=[O:38])[C:36](=[CH:39][C:40]2[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=2)[S:35][C:34]1=[S:48])[CH:31]=[CH2:32]>>[CH2:30]([N:33]1[C:37](=[O:38])[C:36](=[CH:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:44][NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]4[C:17]5[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=5)[N:11]=[CH:10][C:9]=4[C:22](=[O:23])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:3]=3)=[CH:46][CH:47]=2)[S:35][C:34]1=[S:48])[CH:31]=[CH2:32]
Reactant: C=CCN1C(=O)C(=Cc2ccc(C=O)cc2)SC1=S
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: C=CCN1C(=O)C(=Cc2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)SC1=S

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(3-allyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 663.8.
Reaction SMILES: [OH:1][C@@:2]12[C:20](=[O:21])[O:19][C@@H:4]([C@H:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH:6]=[CH:7]1)[CH2:3]2.[OH-:22].[Li+]>C1COCC1.O>[OH:1][C@@:2]1([C:20]([OH:19])=[O:21])[CH:7]=[CH:6][C@@H:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C@H:4]([OH:22])[CH2:3]1
Reactant: [OH-]
Reactant: O=C1O[C@@H]2C[C@@]1(O)C=C[C@H]2OCc1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@]1(O)C=C[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](O)C1
Yield: 74 %

Procedure:
A solution of carbolactone VIII (28 mg, 0.10 mmol) in 1 mL of THF and 0.5 mL of a 0.5 M lithium hydroxide aqueous solution was stirred at room temperature for 1 hour. The resulting solution was diluted with milliQ water (5 mL) and treated with Amberlite IR-120 (H+) to pH 6. The resin was filtered and washed with milliQ water (15 mL). The filtrate was concentrated under reduced pressure to give 23 mg of acid IX (74%) in a pale solid yellow form. [α]25D−121° (c 1.1 in CH3OH); 1H-NMR (250 MHz, CD3OD, δ) 8.20 (d, 2H, J 8.8), 7.65 (d, 2H, J 8.8), 5.93 (dd, 1H, J 10.0 and 1.8), 5.73 (d, 1H, J 10.0), 4.84 (s, 2H), 4.04 (m, 1H), 3.93 (dt, 1H, J 7.9 and 1.8) and 2.07 (m, 2H); 13C-NMR (63 MHz, CD3OD, δ) 176.8, 147.6, 147.1, 130.4, 129.3, 128.1, 123.4, 81.1, 73.5, 70.4, 68.2 and 40.2; IR (KBr)/cm−1 3528 and 1596; EM-IQ+ (m/z) 310 (MH+); HRMS calculated for C14H16NO7 (MH+): 310.0928, 310.0928 found.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[C:9]=1[CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)C.O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[N:15]=2)[NH:10][C:9]=1[CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)c(C)n3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cc(-c2cnc3[nH]c(C)c(C(=O)NC(C)(C)C)c3n2)cc(OC)c1OC
Temperature: 60 °C
Yield: 24.9 %

Procedure:
To a solution of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (64 mg) in 0.5 mL of THF was added 400 uL of 1.0 M TBAF in THF. Heated the mixture to 60° C. for 14 h. Diluted with diethyl ether and water and partitioned. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. Flash purification (95:5 methylene chloride:Methanol) afforded 12 mg of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[N:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[N:10]([C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][N:6]=1)[CH2:11][CH2:12]2
Reactant: O=[N+]([O-])c1cnc(N2CCN3CCC2CC3)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(N2CCN3CCC2CC3)nc1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A mixture of 4-(5-nitro-pyrimidin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (0.71 g, 2.85 mmol), palladium (0.25 g, 10% on activated carbon) and methanol (50 ml) was stirred under hydrogen for 10 min. The reaction-mixture was filtered through celite and was washed with ethanol (50 ml). The product was dried and evaporated. Yield 100%.