Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH2:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:16][CH:15]=2)=[O:8])[CH:2]=1.Br.C(O)(=O)C.CS(C)=O.C(OC(C)C)(C)C>C(O)(=O)C.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:16][CH:15]=2)=[O:8])[CH:2]=1
Reactant: O=C1CCC(c2ccc(CCCCNC(=O)c3cccnc3)cc2)=NN1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: O=C(NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
In acetic acid (100 ml) was dissolved 10.0 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butyl)phenyl]-4,5-dihydropyridazin-3(2H)-one. 25% hydrogen bromide-acetic acid (100 ml) was added to the solution, and the mixture was stirred at room temperature for 5 minutes. 2.9 g of dimethylsulfoxide was added to the mixture at room temperature, and the resulting mixture was stirred at the same temperature for 1 hour. Ethanol (150 ml) was added to the reaction mixture, and the mixture was stirred for 2 hours. Diisopropyl ether (150 ml) was further added to the mixture, and the resulting mixture was stirred for 2 hours. Precipitated crystal was collected by filtration, washed with diisopropyl ether and then dissolved in hydrated ethanol, and the solution was neutralized with aqueous ammonia. Precipitated crystal was collected by filtration, washed with water and then recrystallized from methanol to obtain 8.9 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butyl)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]>S(=O)(=O)(O)O>[I:1][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[C:4]=1[CH3:3])[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: II
Agent: O=S(=O)(O)O
Product: Cc1c(I)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 94.8 %

Procedure:
To a mixture of iodine (19.6 g, 77.3 mmol) in fuming sulfuric acid (35 mL) was added 4-methyl-3-nitro-benzoic acid (10.0 g, 55.2 mmol). The mixture was stirred at 85° C. over night, then cooled to room temperature and poured over ice. The mixture was partitioned between ethyl acetate and aqueous sodium bisulfite, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give 16.06 g (95%) of 3-iodo-4-methyl-5-nitro-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](/[CH:24]=[CH:25]\[CH2:26][O:27][CH3:28])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].O1CCCC1.C(N(CC)CC)C>C(#N)C.O.FC(F)(F)C(O)=O.[C].[Pd]>[NH2:1][C:2]1[N:23]=[C:22]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: COC/C=C\c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: COCCCc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
To a mixture of 2-amino-6-(3-methoxy-1-(Z)-propenyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-90 (3.0 mg, 0.0059 mmol) and tetrahydrofuran (1 mL) were added triethylamine (3.6 mg, 0.036 mmol) and 10% palladium-carbon (50% water wet, 5 mg), and the solution was stirred under hydrogen atmosphere at room temperature for 15 minutes. The interior of the reaction system was exchanged with nitrogen, then, filtration was carried out through Celite pad, the solvent was evaporated in vacuo. The residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (0.48 mg, 0.00094 mmol, 16%) was obtained.
Reaction SMILES: C([O:8][C:9]1[C@@H:14]([C@H:15]([CH2:17][OH:18])[OH:16])[O:13][C:11](=[O:12])[C:10]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:20]([O:19][C:10]1[C:11]([O:13][C@H:14]([C@H:15]([CH2:17][OH:18])[OH:16])[C:9]=1[OH:8])=[O:12])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCOC1=C(OCc2ccccc2)[C@@H]([C@@H](O)CO)OC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O
Yield: 86.4 %

Procedure:
3-O-Benzyl-2-O-octadecylascorbic acid (2.1 g) was dissolved in ethyl acetate (25 ml), and 5% Pd-C (0.5 g) was added to the solution to conduct catalytic reduction under atmospheric pressure. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure. The reaction product was recrystallized from isopropyl ether-ethyl acetate to give 2-O-octadecylascorbic acid [compound (1-12)](1.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[NH:34][C:35]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22])=[O:36]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1N
Product: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene, to afford the title compound was obtained as a white solid (5 mg, 12%).
Reaction SMILES: C(OOC(C)(C)C)(C)(C)C.[C:11]([O:20][O:21][C:22]([C:25]1C=CC=C[CH:26]=1)([CH3:24])[CH3:23])([C:14]1C=CC=C[CH:15]=1)([CH3:13])[CH3:12]>>[C:22]([O:21][O:20][C:11]([CH2:14][CH3:15])([CH3:13])[CH3:12])([CH2:25][CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Product: CCC(C)(C)OOC(C)(C)CC

Procedure:
tert-butyl peroxide and cumyl peroxide;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.S([C:27]#[N:28])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([C:27]#[N:28])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2ccsc12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2cc(C#N)sc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
To a solution of 1-benzothien-7-yl methyl ether (1 g, 6.1 mmol) in THF (12 mL) at −78° C. was added a solution of 2.5 M n-butyllithium in hexanes (2.9 mL, 7.3 mmol). After stirring for 1.5 hr this solution was added dropwise to a solution of tosyl cyanide (1.66 g, 9.1 mmol) in THF (8 mL), this was left stirring at −78° C. for 0.5 hr and then warmed to room temperature. After 16 h this was poured onto ice-water and extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, dried (MgSO4) and the solvent removed in vacuo to give an oil. This was purified by flash chromatography with a gradient of 0–30% ethyl acetate in hexane to give the title compound (0.31 g, 27%); δH (300 MHz, CDCl3) 7.79 (1H, s, 3-ArH), 7.46–7.38 (1H, m, 4-ArH), 7.37–7.31 (1H, m, 5-ArH), 6.88–6.82 (1H, m, 6-ArH) and 3.94 (3H, s, OCH3). Starting material 1-benzothien-7-yl methyl ether was recovered from the reaction (0.56 g, 56%); δH (300 MHz, CDCl3) 7.45–7.29 (4H, m, ArH), 6.75 (1H, m, ArH), 4.00 (3H, s, OCH3).
Reaction SMILES: Cl[CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH3:34][NH:35][CH3:36].CN1CCCN(C)C1=O.C(OCC)(=O)C.CCCCCC>CO>[CH3:34][N:35]([CH3:36])[CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: CNC
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN1CCCN(C)C1=O
Product: CN(C)C(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
A partial solution of ??g of α-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide in 1 ml of methanol is treated with 0.5 ml of dimethylamine and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirring continued for 20 hours. The methanol is evaporated and the residue diluted with water. The resulting solid is washed with water, dissolved in ethyl acetate and the organic layer washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated vacuo to give a residue which is stirred with ethyl acetate-hexane to give 0.15 g of a beige solid. MS(CI): 465(M+H).
Reaction SMILES: [CH:1]([O:3][C@H:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C@@H:5]([CH:19]=[O:20])[CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:2].P([O-])(O)(O)=[O:34].[Na+].Cl([O-])=O.[Na+].OO>O.C(OCC)(=O)C.C(#N)C>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:7][CH2:6][C@@H:5]([C@H:4]([O:3][CH:1]=[O:2])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=1)[C:19]([OH:34])=[O:20]
Reactant: O=CO[C@H](CCc1ccc(C(F)(F)F)cc1)[C@@H](C=O)CCN1C(=O)c2ccccc2C1=O
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=CO[C@H](CCc1ccc(C(F)(F)F)cc1)[C@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound obtained from step g above (0.22 g) in a solvent mixture of acetonitrile:water (3 mL:1 mL) at 0° C., sodium dihydrogenphosphate (0.021 g), sodium chlorite (0.081 g) and hydrogen peroxide (1 mL, 30% in water) were added. The reaction mixture was stirred for 2 hours at room temperature. The solvents were evaporated under reduced pressure to obtain a residue. Ethyl acetate and water were added to the resulting residue. The organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to afford the title compound (0.2 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][N:44]=[CH:43]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:45]3[C:46]4[C:42](=[CH:41][C:40]([Cl:39])=[CH:48][CH:47]=4)[CH:43]=[N:44]3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Clc1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Temperature: 110 °C
Reaction time: 15 h
Yield: 73.4 %

Procedure:
2-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (145 mg, 328 μmol) was dissolved in toluene (3 mL) and copper (I) iodide (3.29 mg, 36.7 μmol), sodium iodide (98.2 mg, 655 μmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (11.9 mg, 83.6 μmol) added. The mixture was degassed with bubbling nitrogen, then sealed and the mixture heated at to 110° C. After 15 h, 5-chloro-1H-indazole (50 mg, 328 μmol) and potassium phosphate tribasic (146 mg, 688 μmol) were added, the mixture degassed again, and the mixture sealed and the mixture heated at for an additional 24 h. The mixture was cooled, filtered the filtrates concentrated and purified by chromatography (silica, 24 g Analogix column, 0-40% ethyl Acetate in hexanes to give 2-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (124 mg, 74%) as a solid. MS (M+H)+=515; 1H NMR (CDCl3) d: 9.19 (s, 1H), 8.52 (d, J=8.9 Hz, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.81-7.85 (m, 1H), 7.47 (dd, J=8.9, 1.9 Hz, 1H), 5.73 (s, 2H), 3.81 (s, 2H), 3.60 (dd, J=8.8, 7.6 Hz, 2H), 1.54 (s, 6H), 0.91-1.01 (m, 2H), −0.02 (s, 9H)
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]3[CH2:23][N:22]([C:24](=[O:44])[C@@H:25]([NH:30][C:31](=[O:43])[C@@H:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:21]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][C@@H:19]1[CH2:23][N:22]([C:24](=[O:44])[C@@H:25]([NH:30][C:31](=[O:43])[C@@H:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH3:33])[C:26]([CH3:28])([CH3:29])[CH3:27])[C@H:21]([C:45](=[O:57])[NH:46][C@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][CH2:49][CH2:48]2)[CH2:20]1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (6.14 g, 7.87 mmol) in CH2Cl2 (40 mL) was added piperidine (4.67 mL, 47.2 mmol) dropwise. The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was washed with methanol and the resulting solid was removed by filtration. The filtrate was concentrated in vacuo and purified by flash column chromatography (gradient elution from 0 to 10% MeOH/CH2Cl2) to give the title compound (3.48 g, 79%) as a light tan solid. MS(ESI+) m/z 558.4 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[Cl:14][C@H:15]1[C@H:19]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@@H:18]([CH2:29][O:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)[C@H:17]([OH:39])[CH2:16]1.O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[N:43]1([CH2:42][CH2:41][O:27][C:26](=[O:28])[CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:21]\[CH2:20][C@H:19]2[C@H:15]([Cl:14])[CH2:16][C@@H:17]([OH:39])[C@@H:18]2[CH2:29][O:30][C:31]2[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1
Reactant: OCCN1CCOCC1
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](COc2cc(Cl)cc(Cl)c2)[C@H](O)C[C@H]1Cl
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCC/C=C\C[C@@H]1[C@@H](COc2cc(Cl)cc(Cl)c2)[C@H](O)C[C@H]1Cl)OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.3 %

Procedure:
Triethylamine (6.5 μL, 0.047 mmol) and ethyl chloroformate (7 μL, 0.073 mmol) were added sequentially to a solution of (Z)-7-[(1R,2S,3R,5R)-5-chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic acid (see U.S. 60/644,069, 20 mg, 0.047 mmol) in CH2Cl2 (0.47 mL) at room temperature. After 2.5 h, triethylamine (6.5 μL, 0.047 mmol) and 4-(2-hydroxyethyl)-morpholine (58 μL, 0.47 mmol) were added. After stirring overnight at room temperature, the reaction mixture was partitioned between H2O (5 mL) and CH2Cl2 (5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×5 mL). The combined organic phase was washed with 1 N HCl (5 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5% MeOH/CH2Cl2) afforded 5.1 mg (20%) of the title compound (2).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[C:13]([CH2:17][CH3:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[CH2:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[C:19]([F:22])([F:20])[F:21])[CH2:9][NH:8][CH2:16]2)[CH3:18]
Reactant: CCc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCc1cc2c(cc1C(F)(F)F)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-ethyl-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): 216.4 ([M+H]+, 100%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:36]>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:24]=[C:23]([C:25]([NH2:36])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(C(N)=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCN1CCCCC1
Reactant: Oc1ccc2c(C3CCCCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: c1cc2c(C3CCCCC3)noc2cc1OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 3-cyclohexyl-1,2-benzisoxazol-6-ol (2.69 g, 12 mmol), 1-(2-chloroethyl)-piperidine hydrochloride (2.39 g, 13 mmol) and K2CO3 (3.59 g, 26 mmol) in CH3CN (30 ml) was heated at reflux for 3 h and stirred at room temperature overnight. The reaction mixture was poured into H2O and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4) and concentrated to give a residue (3.78 g). This residue was purified by flash chromatography (toluene/1,4-dioxane 8/2). Crystallisation from EtOH gave white crystals (0.53 g, 13.4%). mp 69° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.N.[NH2:21]C1C2N=C(C3C=CC(F)=CC=3)C=CC=2N=CN=1>CO>[CH3:1][C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1ncnc2ccc(-c3ccc(F)cc3)nc12
Reactant: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Agent: N
Solvent: CO
Product: Cc1nc(N)c2nc(-c3ccc(F)cc3)ccc2n1
Yield: 99 %

Procedure:
This compound was synthesized from 2-methyl-4-chloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine and a ammonia solution in methanol in 99% yield, using the procedure described for the synthesis of 4-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine. The mass spectrum was as follows: MS (m/z): 255 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:47][Cl:48]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:47][Cl:48])=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)O)CC1
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)OCCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(N-benzyloxycarbonyl-L-valyloxy)cyclohexanoic acid (6.6 g, 20 mmole) in 1,4-dioxane (70 ml) was added a 40% solution of tetrabutylammonium hydroxide (11.34 g, 17.5 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 60 ml dichloromethane and iodochloromethane (30.9 g, 175 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. About 100 ml ethyl actate was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 4.1 g=55%.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15](I)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH2:37][CH:38]4[CH2:40][CH2:39]4)[CH:27]=3)[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[C:61]1(B(O)O)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH2:37][CH:38]4[CH2:40][CH2:39]4)[CH:27]=3)[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OCC3CC3)c2)c(I)c2c(=O)n(Cc3ccccc3)ncc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OCC3CC3)c2)c(-c2ccccc2)c2c(=O)n(Cc3ccccc3)ncc21
Yield: 92.9 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 383 mg (0.552 mmol) of 5-benzyl-2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 38-(c) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, using 84 mg (0.69 mmol) of phenylboronic acid in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, and using 55 μl of tetrahydrofuran solution containing 100 mM palladium complex prepared previously from 231 mg (1.03 mmol) of palladium acetate and 846 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl in place of tetrakis(triphenylphosphine)palladium, whereby 330 mg of the title compound was obtained as a pale brownish foam. (Yield: 93%)