Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH2:9][C:10]([N:12]1[CH2:16][C@H:15]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C@H:13]1[C:26]([OH:28])=[O:27])=[O:11]>C(O)=O>[C:18]([NH:17][C@H:15]1[CH2:16][N:12]([C:10](=[O:11])[CH2:9][NH:8][CH:1]=[O:3])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:14]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Solvent: O=CO
Product: O=CNCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.6 %

Procedure:
Acetic anhydride (Acros) (0.32 mL, 3.4 mmol, 10 equivalents) was added dropwise to a solution of (2S,4R) 1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (Compound 2, 0.1 g, 0.34 mmol, 1 equivalent) in formic acid (J. T. Baker) (1 mL) at 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred an additional 24 hours. The reaction mixture was monitored by TLC and LCMS. An additional amount of acetic anhydride (0.32 mL, 3.4 mmol, 10 equivalents) was added and the reaction mixture stirred for 24 hours at room temperature. Ice-water (1 mL) was added and the volatiles were removed in vacuo to yield an oily crude product that was further purified by HPLC (column:Waters Atlantis 19×150 mm) using 0.1% formic acid in H20/MeOH 20-40% MeOH over 15 minute gradient to afford 0.031 g (29%) of the desired product.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[N:22]=1>C1(C)C=CC=CC=1.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>[CH:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:22]=1)=[O:28]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2cccc3ccccc23)n1
Temperature: 70 °C
Yield: 87 %

Procedure:
Inside of a dry box, naphthylboronic acid (9.12 g, 53.0 mmol) and Na2CO3 (11.64 g, 110 mmol) are dissolved in 290 mL of degassed 4:1H2O/MeOH. This solution is added to a solution of 8 g (43 mmol) of 2-bromo-6-formylpyridine and 810 mg (0.7 mmol) of Pd(PPh3)4 in 290 mL of degassed toluene. The charged reactor is removed from the dry box, while under a blanket of N2 and is connected to the house N2 line. The biphasic solution is vigorously stirred and heated to 70° C. for 4 h. On cooling to RT, the organic phase is separated. The aqueous layer is washed with 3×75 mL of Et2O. The combined organic extracts are washed with 3×100 mL of H2O and 1×100 mL of brine and dried over Na2SO4. After removing the volatiles in vacuo, the resultant light yellow oil is purified via trituration with hexanes. The isolated material is recrystallized from a hot hexane solution and ultimately yielded 8.75 g, 87% yield. mp 65–66° C.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(F)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-fluorophenylboronic acid (140 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (64 mg, yield 82%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(OC1CCCC=1)(=O)=O.N[C:18]1[N:26]=[C:25]2[C:21]([NH:22][CH:23]=[N:24]2)=[C:20](Cl)[N:19]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CS(C)=O>[N:19]1[CH:20]=[C:21]2[C:25]([N:24]=[CH:23][NH:22]2)=[N:26][CH:18]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cc1ccc(S(=O)(=O)OC2=CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of the cyclopentenyl tosylate 2 (0.25 g, 0.58 mmol), 2-amino-6-chloropurine (0.212 g, 1.25 mmol, 2.2 eq), and K2CO3 (1 g) was suspended in 2 mL of DMSO and stirred at room temperature for 42 h. The suspension was then poured into CH2Cl2 and washed with dilute NaCl. Evaporation of the CH2Cl2 gave an oil which was further dried under high vacuum to remove residual DMSO. Purification by preparative TLC (silica, 3:2 EtOAc:Hexane) gave two major purine containing products of which the faster moving and predominant was the desired N-9 alkylated purine 18 (0.117 g, 47%), mp 137°-140°; 1H-NMR (CDCl3) δ 1.35 (s, 3H, CH3), 1.46 (s, 3H, CH3), 4.27 (s, 2H, H-6'a,b), 4.61 and 4.62 (2H, PhCH2 ), 4.67 (d, J=5.3 Hz, 1H, H-2'), 5.10 (br s, 2H, NH2, exchangeable), 5.36 (d, J=5.3 Hz, 1H, H-3'), 5.43 (br s, 1H, H-1'), 5.78 (br s, 1H, H-5'), 7.34 (m, 5H, Ph), 7.65 (s, 1H, H-8); 13C-NMR (CDCl3) δ 25.8 (CH3), 27.2 (CH3), 64.3 (C-1'), 66.2 (C-6'), 72.8 (PhCH2), 83.7 (C-2'), 83.9 (C-3'), 112.4 (methylethylidene C), 122.7 (C-5'), 125.2 (d, J=12.6 Hz, C-5), 127.3 (Ph), 127.5 (Ph), 128.1 (Ph), 128.2 (Ph), 137.6 (Ph), 140.1 (dd, J=210 Hz, J'=4.4 Hz, C-8), 149.2 (C-4'), 151.0 (s, C-6), 153.2 (dd, J=4.7 Hz, J'=3.1 Hz, C-4), 159.1 (s, C-2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:23]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Product: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 100.3 %

Procedure:
Using 4-(benzyloxy)-2-fluoro-1-nitrobenzene (10.3 g, 41.6 mmol) and 2-ethylhexyl 3-sulfanylpropanoate (10.0 g, 45.8 mmol) and in the same manner as in Reference Example 81, the title compound (18.6 g, quantitative) was obtained as an oil.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[CH2:12][CH2:13][CH2:14][OH:15]>CN(C=O)C>[C:1]([O:9][CH2:12][CH2:13][CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: OCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCCO)c1ccccc1
Temperature: 135 °C
Yield: 70.9 %

Procedure:
Sodium benzoate (96.32 g) in DMF (690 ml) was heated to 80° C., and 1-chloro-3-hydroxypropane (63.06 g) was added over 15 minutes. The temperature increased to 135° C., and the reaction mixture was heated at 135°-175° C. for 3 hours. Filtration removed 38 g of sodium chloride (97% of theory). The filtration was partially evaporated at reduced pressure at <40° C. The concentrated filtrate was poured into ice water and extracted well with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. The residual oil was distilled through a Vigreux column to give 3-benzoyloxy-1-propanol (85.2 g), b.p. 124°-132° C. at 0.055 mm Hg.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:6]([CH3:23])=[N:5][CH:4]=1.CC(C)([O-])C.[K+].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K]>O1CCCC1>[CH3:23][C:6]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:3]([CH2:2][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])=[CH:4][N:5]=1
Reactant: Cc1ncc(CCl)n1-c1ccc(Cl)cc1Cc1ccccc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1Cc1ccccc1F
Temperature: 10 °C

Procedure:
To a suspension of 89.4 g (0.232 mole) of 5-(chloromethyl)-2-methyl-1-[4-chloro-2-(2-fluorobenzyl)phenyl]-1H-imidazole in 900 ml of tetrahydrofuran cooled to 10° C. was added 26.2 g (0.232 mole) of potassium t-butoxide. The temperature was maintained at 20° C. by means of an ice water bath during this addition. The bath was removed. To this mixture was added 51.5 g (0.278 mole) of potassium phthalimide. The reaction mixture was stirred under reflux for 2 hr. The mixture was cooled to room temperature and poured onto 1.2 l. of ice-water and extracted with 3×600 ml of methylene chloride. The organic phases were combined and dried over sodium sulfate. The solution was filtered free of drying agent and the filtrate concentrated to dryness giving an oil. The oil was crystallized from 180 ml of ether. The resulting crystals were collected and dried to give end product of m.p. 152°-156° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7]1[O:14]C(=O)C[O:10][C:8]1=[O:9]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:8]([OH:10])(=[O:9])[CH2:7][OH:14]
Reactant: O=C1COC(=O)CO1
Agent: CC(O)C(=O)O
Product: O=C(O)CO
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The lactide obtained in Example 2 (19 g) and glycolide (1 g) were put into a 100-ml reaction vessel equipped with a stirrer and a nitrogen-introducing tube. After substitution of nitrogen gas was carried out three times, the mixture was stirred at 150° C. for 3 hours in a stream of nitrogen. To the resulting mixture was added 0.4 g of Baylith 5A [synthetic zeolite (Kurita Water Industries Ltd.) ]*2, and the temperature was raised to 195°±5° C. The pressure was reduced gradually to 20 mmHg over 30 minutes, followed by stirring for one hour. After the pressure was reduced gradually to 1 mmHg over 30 minutes, the mixture was stirred at 195°±5° C. for 9 hours to give lactic acid-glycolic acid copolymer in the molten state. The product was cooled to room temperature to give 14.64 g of white copolymer. The weight-average molecular weight of this copolymer was 73,000.
Reaction SMILES: [OH-].[Na+].Cl.C([O:6][C:7]([CH2:9][C:10]1([C:16]([C:18]2[CH:37]=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([CH2:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[NH:31])=[CH:28][CH:27]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])C>O.C(O)C>[C:7]([CH2:9][C:10]1([C:16]([C:18]2[CH:37]=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([NH2:32])=[NH:31])=[CH:33][CH:34]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([OH:8])=[O:6]
Reactant: CCOC(=O)CC1(C(=O)c2ccc3c(c2)nc(Cc2ccc(C(=N)N)cc2)n3C)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(Cc2ccc(C(=N)N)cc2)nc2cc(C(=O)C3(CC(=O)O)CCCCC3)ccc21

Procedure:
To a solution of 160 mg (4 mmol) of sodium hydroxide in 5 ml water and 20 ml ethanol are added 400 mg (0.8 mmol) of 4-[(5-(1-ethoxycarbonylmethyl-cyclohexan-1-yl-carbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride. After two hours at ambient temperature the solution is evaporated down, the residue is dissolved in water and acidified with glacial acetic acid. The precipitate is suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1I.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ccc(Cl)c(I)c1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cc(F)ccc1Cl
Temperature: 90 °C
Yield: 55.1 %

Procedure:
A mixture of 1-chloro-4-fluoro-2-iodobenzene (10 g, 40 mmol), (trimethylsilyl)acetylene (28 mL, 190 mmol), copper(I) iodide (740 mg, 3.9 mmol), (triphenylphosphine)palladium(0) (2.5 g, 2.2 mmol), and N,N-diisopropylethylamine (14 mL, 78 mmol) in 1,4-dioxane (100 mL) was heated at 90° C. for 2 hours. The cooled reaction mixture was then diluted with diethyl ether (200 mL) and washed with water (300 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 220 g, ISCO, heptane) to afford the title compound as a pale yellow oil (5 g, 60%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[N+]([NH:22][C:23](N)=[O:24])([O-])=O.O>C(O)C>[NH2:22][C:23]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1)=[O:24]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 65 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 4.0 g 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 100 ml of 95% ethanol was treated with 1.73 g of nitrourea and then stirred at 65° C. for five hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvents afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The resultant solid was recrystallized from hot isopropanol to yield 3.41 g (73.3%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 170°-172° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Product: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 6 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and trimethylsilylacetylene: MS (m/z) 363.2 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)[CH:55]=[N:56][CH:57]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)[CH:55]=[N:56][CH:57]=1
Reactant: COc1cncc(-c2cccc(N)c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(5-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 79% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[CH2:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.CO.[H][H]>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH3:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: C=C(c1ccc([N+](=O)[O-])cc1)c1ccnc2cc(OC)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(C(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 3 h

Procedure:
A mixture of 7-methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline (0.146 g, 0.477 mmol) and Palladium on carbon, 10% (0.152 g, 1.43 mmol) in EtOAc (10 mL) and MeOH (1 mL) at RT was exposed to an atmosphere of Hydrogen (balloon). After 3 hrs, the mixture was filtered through celite and concentrated in vacuo to afford 4-(1-(7-methoxyquinolin-4-yl)ethyl)benzenamine as a white foam. MH+=279.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=O)=[CH:11][C:10]=2[O:19][CH3:20])=[N:6][CH:7]=1.N1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P([N:70]=[N+:71]=[N-:72])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]3[N:15]([CH3:16])[N:72]=[N:71][N:70]=3)=[CH:11][C:10]=2[O:19][CH3:20])=[N:6][CH:7]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)c1ccc(Nc2ncc(Cl)c(NC)n2)c(OC)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: CCOC(C)=O
Product: CNc1nc(Nc2ccc(-c3nnnn3C)cc2OC)ncc1Cl
Temperature: 45 °C
Yield: 37.1 %

Procedure:
A mixture of 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide (112 mg, 0.35 mmol) and 2-pyridyl diphenylphosphine (373 mg, 1.42 mmol) was flushed with N2 for 10 min Anhydrous THF (2 mL) was added followed by dropwise addition of diisopropyl azodicarboxylate (0.28 mL, 1.42 mmol). Diphenylphosphoryl azide (0.31 mL, 1.42 mmol) was added dropwise over 5 min. The mixture was heated at 45° C. under N2 for 18 h. The mixture was diluted with ethyl acetate (20 mL) and washed with saturated sodium hydrogen carbonate solution (2×10 mL). The combined aqueous washes were back-extracted with ethyl acetate (10 mL), and the combined organic extracts filtered through a hydrophobic frit and evaporated. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) followed by trituration with diethyl ether gave 5-chloro-N2-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-N4-methylpyrimidine-2,4-diamine as a white solid (45 mg, 38%). LCMS (10 cm_ESCI_Bicarb_MeCN): [MH+]=347 at 2.67 min. 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J=8.5, 1H); 7.96 (s, 1H); 7.75 (s, 1H); 7.40 (d, J=1.9, 1H); 7.3 (d, J=2.0, 1H); 5.35 (s, 1H); 4.21 (s, 3H); 4.00 (s, 3H); 3.13 (d, J=4.9, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[C@H:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[C:27](Cl)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.C(OC(=O)C)C>[CH3:1][CH:2]([CH3:26])[C@H:3]([N:7]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:22][N:23]=[N:24][N:25]=2)=[CH:13][CH:14]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)O
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: COCCOC
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A suspension of (S)-3-methyl-2-((2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butyric acid (17.6 g; 50.0 mmol) in 1,2-dimethoxyethan (116 g) is cooled to −5° C., and valeroyl-chloride (9.9 ml; 80 mmol) is added, followed by slow addition of pyridine (6.0 ml; 75 mmol) diluted with 1,2-dimethoxyethane (60 ml). [1] After completion of the reaction, the reaction mixture is quenched with methanol (18 ml). Finally water (50 ml) is added at room temperature, and after stirring for 1 h, the mixture is adjusted to pH 7.5 by addition of aqueous sodium carbonate solution 10% (˜116 ml, 120 mmol) at 0° C. The organic solvents are stripped off at 50° C. in vacuo. Ethylacetate (125 ml) is added to the remaining aqueous concentrate, and the two-phase system is adjusted to pH 2 at 0-5° C. by addition of 2.0 M HCl (˜98 ml). The organic phase is separated and concentrated at 45° C. in vacuo (water is azeotropically removed). The crystallization of the product is initiated at 45° C. and—after addition of cyclohexan (102 ml)—completed by cooling to −5° C. The solid is collected by filtration, and after drying at 50° C., (S)-3-methyl-2-{pentanoyl-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid is received as a white powder.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH:13]=1)[CH3:8].O>CS(C)=O>[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]12[CH2:2][CH:13]1[CH2:14][CH2:15][CH2:16][C:17]2=[O:18])[CH3:8]
Reactant: CCOC(=O)CC1=CCCCC1=O
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC12CC1CCCC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
Sodium hydride (18.1 mmol, 543 mg of an 80% dispersion in mineral oil) was washed with 2×5 mL of petroleum ether under nitrogen, then it was dried and trimethylsulfoxonium iodide (3.99 g, 18.1 mmol) was added to the flask followed by 21.6 mL dimethylsulfoxide added dropwise. Next, a solution of 6-oxo-1-cyclohexeneacetic acid ethyl ester (2.90 g, 17.3 mmol) was added dropwise as a solution in 4.5 mL of dimethylsulfoxide as the reaction mixture was cooled with a water bath. After the addition, the reaction mixture was stirred at room temperature for 1.5 hours then poured into 80 mL of cold water and extracted with 4×60 mL of ether. The extracts were combined, washed with 80 mL of brine, dried over magnesium sulfate and concentrated affording 2.4 g (13.2 mmol, 73% yield) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[C:10]([OH:13])(=[S:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[C:10]([S:12][CH:4]([CH3:5])[CH:2]([CH3:3])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:11]
Reactant: CC(O)=S
Reactant: C/C=C(\C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(C)C(C)SC(C)=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
A mixture of 51.27 g (0.40 mol) of ethyl tiglate, 76.12 g (1.00 mol) of thioacetic acid, and 7.60 g (0.04 mol) of para-toluenesulfonic acid was stirred under nitrogen atmosphere at 75° C. for 24 hours. After cooling, diethyl ether and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and washed twice with brine. The solvent in the organic layer was evaporated off, and vacuum distillation (68 to 71° C./2 torr) was performed to give 76.36 g of the objective compound (GC purity: 98.3%, yield: 91.8%, diastereomer ratio: 80.9/19.1).