Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:28][CH2:29][CH3:30])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:6]=1[C:7](O)=[O:8].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1.Cl>O1CCCC1.O.CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH2:28][CH2:29][CH3:30])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1)=[O:8]
Reactant: CCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCc1nc(Cl)c(C(=O)NCCc2ccc(O)cc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a solution of 4.86 g of 4-chloro-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid in 115 mL of tetrahydrofuran at 25° C. is added 2.25 g of carbonyl diimidazole, and the resulting solution is stirred at 25° C. for 3 hours. To the solution is added 3.94 g of tyramine and 23 mL of 2-propanol, and the mixture was stirred at 25° C. for an additional 3 hours. The reaction mixture is poured into water, and the resulting emulsion is adjusted to pH 3 employing hydrochloric acid and then extracted with chloroform. The combined extracts are washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (elution: 10% 2- propanol/chloroform) affords 3.15 g of the product as an amorphous solid. NMR (300 MHz, DMSO-d6) δ 8.07 (t, 1H, J=8 Hz), 7.69-7.50 (m, 4H), 7.07-6.99 (m, 6H), 6.65 (d, 2H, J=8 Hz), 5.42 (s, 2H), 3.36 (quart., 2H, J=7 Hz), 2.63 (t, 2H, J=7 Hz), 2.50 (t, 2H, J=7 Hz), 1.51 (sext., 2H, J=7 Hz), 0.82 (t, 3H, J=7 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:3][CH:2]=1.[Br:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=1)=[O:16]>ClCCl>[Br-:13].[CH2:10]([O:9][C:8]([NH:7][C:4]1[CH:3]=[CH:2][N+:1]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=2)=[O:16])=[CH:6][CH:5]=1)=[O:12])[CH3:11]
Reactant: COc1cc(C(=O)CBr)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)Nc1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cc[n+](CC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1
Product: [Br-]
Yield: 100 %

Procedure:
This compound is prepared according to the same method as that described in Example 47, Step A by quaternization of 1.21 g (7.33 mmol) of ethyl 4-pyridinylcarbamate [described in J. Chem. Soc.; (1962), 2379-2381] with 2-bromo-1-(3-methoxy-4-nitrophenyl)-1-ethanone in dichloromethane. 3.24 g of a white precipitate are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C1COCC1>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)c2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A solution 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyridin-2-amine (11 mg, 0.035 mmol) in THF (1 mL) was cooled in an ice bath and treated with a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 250 μL, 0.070 mmol) and stirred at RT for 2 h. The mixture was concentrated in vacuo and the residue triturated with isopropyl ether to give the title compound (11 mg, 65%) as a white solid. 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.56 (s, 1H), 9.01 (s, 1H), 8.03 (d, 1H, J=5.6 Hz), 7.77 (dd, 1H, J=13.3, 2.0 Hz), 7.63-7.60 (m, 2H), 7.41-7.31 (m, 5H), 7.19-7.14 (m, 2H), 7.05 (dd, 1H, J=9.1, 8.5 Hz), 6.43 (dd, 1H, J=6.2, 2.1 Hz), 6.10 (d, 1H, J=2.1 Hz), 3.74 (s, 2H); MS(ESI+) m/z 493.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:28][OH:29]>C(O)C.O>[C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2([OH:21])[CH2:19][CH2:18][C:17](=[N:28][OH:29])[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Yield: 93 %

Procedure:
To a solution of 2.00 g of 1-[2-(phenylmethyl)phenyl]-4-oxocyclohexanol of Example 4 in 100 ml of 95% ethanol is added a solution of 1.2 g of sodium acetate in 10 ml of H2O and a solution of 1.0 g of hydroxylamine hydrochloride in 4 ml of H2O and the mixture is refluxed for 90 minutes. The solvents are removed under reduced pressure and the product is crystallized from ethanol-H2O (20 ml-100 ml) and dried (P2O5 --40°) in vacuo to provide 1.96 g of 1-[2-(phenylmethyl)phenyl]-4-oxocyclohexanol oxime, m.p. 137°-138° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=[CH:30][C:31](O)=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[CH:30]/[C:31]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:21][CH:20]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c2ccccc12
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c4ccccc34)nc2n(CCC)c1=O
Yield: 56.1 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.33 g (14.6 mmol) of 3-(4-methoxynaphthyl)acrylic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.12 g (yield 56%) of Compound 62 as yellow needles.
Reaction SMILES: C(C1C=C([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=[O:20])N(C2C=CC(C)=CC=2)N=1)(C)(C)C.COC(=O)C(C1C2C(=CC=CC=2)C(OCCN2CCOCC2)=CC=1)=O.N[C:67]1[C:68]([O:82][CH3:83])=[C:69]([NH:77][S:78]([CH3:81])(=[O:80])=[O:79])[CH:70]=[C:71]([C:73]([CH3:76])([CH3:75])[CH3:74])[CH:72]=1>>[C:73]([C:71]1[CH:70]=[C:69]([NH:77][S:78]([CH3:81])(=[O:80])=[O:79])[C:68]([O:82][CH3:83])=[C:67]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=[O:20])[CH:72]=1)([CH3:76])([CH3:74])[CH3:75]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: COC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Product: COc1c(NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
The title compound was prepared by the same method described for compound 13 starting from compound 12 and compound 14. Calculated mass=583. Observed mass=584.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2C1C=NC=CC=1)=[O:4].COC1C=CC=CC=1O[C:24]1[CH:25]=[C:26](C=[CH:29][CH:30]=1)[NH2:27].C([N:37](CC)CC)C.C>O1CCOCC1.C(#N)C>[N:27]1[CH:29]=[CH:30][CH:24]=[C:25]([CH:11]2[S:10][CH2:9][N:8]3[CH:7]=[CH:6][C:5]([C:3]([NH2:37])=[O:4])=[C:12]23)[CH:26]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1Oc1cccc(N)c1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: NC(=O)c1ccn2c1C(c1cccnc1)SC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 48.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (10 g) is added, at a temperature between 61° and 65° C., to a solution of 3-(2-methoxyphenoxy)aniline (7.1 g) and triethylamine (6.7 g) in dioxane (160 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 30 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (400 cc). The solution obtained is washed with distilled water (100 cc), twice with an aqueous 1N sodium hydroxide solution (200 cc in total), and 6 times with distilled water (600 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (7.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (15 cc in total) and twice with diethyl ether (30 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-methoxyphenoxy)phenyl]-3-(3-pyridyl-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.9 g) in the form of white crystals, m.p. 163° C. is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br-].[CH2:16]([C:19]1[C:27]2[O:26][N:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23]=2[CH:22]=[CH:21][C:20]=1[O:34][CH2:35][CH2:36][CH2:37]Br)[CH2:17][CH3:18].C(C1C2ON=C(C3C=CC=CC=3)C=2C=CC=1O)CC>>[CH3:1][C:2]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:37][CH2:36][CH2:35][O:34][C:20]2[CH:21]=[CH:22][C:23]3[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:25][O:26][C:27]=3[C:19]=2[CH2:16][CH2:17][CH3:18])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCBr)ccc2c(-c3ccccc3)noc12
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Agent: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Agent: [Br-]
Product: CCCc1c(OCCCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(-c3ccccc3)noc12

Procedure:
rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5-methyl-5-phenylimidazolidine-2,4-dione and the appropriate bromide. The bromide, 7-propyl-3-phenyl-6-(3-bromopropyloxy)-1,2-benzisoxazole, was prepared as for Example 7 using the 7-propyl-3-phenyl-6-hydroxy-1,2-benzisoxazole prepared in Example 6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([Sn](CCCC)CCCC)[CH2:13][CH2:14]C.O>CN(C=O)C>[CH2:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:13]=[CH2:12]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cccc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-bromobenzoate (10.0 g, 46.5 mmol) in DMF (50 mL) was added ally tributyltin (23.1 g, 69.8 mmol) followed by tetrakis(triphenylphoshine) palladium(0) (1.08 g, 0.93 mmol). After stirring 80° C. overnight the reaction mixture was poured into H2O (500 mL), extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum to afford the desired product.
Reaction SMILES: Cl.COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N.COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N[P:43]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44].C(N(CC)CC)C.C(Cl)(Cl)(Cl)[Cl:74]>C(Cl)Cl>[CH2:45]([P:43]([Cl:74])([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)NP(=O)(Cc1ccccc1)Cc1ccccc1
Agent: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=P(Cl)(Cc1ccccc1)Cc1ccccc1
Temperature: -30 °C

Procedure:
Dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester L-methionyl-L-prolyl-L-proline methylester hydrochloride (2.0 g, 5.1 m mole) was dissolved in methylene chloride (20 ml), and triethyl amine (1.54 g, 15.2 m mole) was added thereto. The solution was cooled at -30° C., and to the cooled solution, a carbon tetrachloride solution (10 ml) of dibenzylphosphorylchloride produced from dibenzylhydrogen phosphite (1.41 g, 5.1 m mole) was added dropwise, and the mixture was further stirred overnight at room temperature. To the reaction solution, methylene chloride (100 ml) was added, and the mixture was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate and water in this order. The mixture was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a candy-like residue (3.23 g). The residue was purified by column chromatography (silica gel, developing solvent; ethyl acetate:methanol=20:1) to obtain dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester (1.87 g, yield: 59.6%). A single spot with Rf =0.1 was obtained by thin layer chromatography (developing solvent, ethyl acetate:methanol32 20:1, Colour forming method, spraying of 25% hydrobromic acid and 0.1 ninhydrin, and heating).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(O[CH2:13][CH3:14])(=O)C.[CH3:15][CH:16](O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:13]([CH3:14])=[C:15]([CH3:16])[N:8]=2)[CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)O
Reactant: Nc1ncc(Br)cn1
Solvent: CN(C)C=O
Product: Cc1nc2ncc(Br)cn2c1C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of 5-bromopyrimidin-2-amine (400 g, 2.2 mol) in i-PrOH (2 L) and DMF (500 mL) was added compound B-9-2 (400 g, 2.6 mol), the resulting mixture was stirred at 100° C. for 20 hrs. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete, the reaction mixture was quenched by addition of aqueous Na2CO3 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to afford compound B-9-4 (12.0 g, 2.4%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].Cl([O-])=[O:39].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:24])[F:25])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:39])=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:15])[F:16]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: [Na+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 2, 4-{3-chloro-4-[2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-3-trifluoromethyl-benzaldehyde was oxidized with sodium chlorite to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=562.0 [M−H+].
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[C:15]([C:22]([O:24]C)=O)=[C:16]([CH3:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=O)=[CH:7][C:6]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1)=[O:27]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:14]3[C:15](=[C:16]([CH3:21])[N:17]([CH3:20])[C:18]=3[CH3:19])[C:22](=[O:24])[NH:2][N:3]=2)=[CH:7][C:6]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1)=[O:27]
Reactant: NN
Reactant: COC(=O)c1c(C(=O)Cc2ccc(F)c(C(=O)N3CCC(OC)CC3)c2)c(C)n(C)c1C
Solvent: CC(=O)O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)n(C)c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.5 %

Procedure:
Hydrazine hydrate (0.014 mL, 0.19 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate (59) (0.076 g, 0.17 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (4.00 mg, 5.49% yield); m/z (LC-MS, ESI+), RT=1.60 min (M+H=427.11).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]2[CH:8]([CH:9]3[O:14][CH:12]2[CH2:11][CH2:10]3)[C:7](=[O:15])[CH:6]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:6]1[C:7](=[O:15])[CH:8]2[CH:13]([C:5]=1[O:4][CH3:3])[CH:12]1[O:14][CH:9]2[CH2:10][CH2:11]1
Reactant: COC1=CC(=O)C2C3CCC(O3)C12
Reactant: BrBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(Br)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (0.14 ml, 2.8 mmol) in dichloromethane (5 ml) is added dropwise to a solution of the enol ether (0.48 g, 2.6 mmol) prepared in step 1 in dichloromethane (40 ml) at 0° C. and the reaction mixture is stirred for 1 hour. Triethylamine (0.64 ml, 4.6 mmol) is then added and the reaction mixture is allowed to warm to room temperature and then stirred for 3 hours. The reaction mixture is washed with 2M aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-bromo-5-methoxy-10-oxatricyclo[5.2.1.02,6]dec-4-en-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].CN(C)C=O.[CH3:17][C:18]([CH3:20])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][CH:18]([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)Nc1cc(C(=O)O)ccc1N

Procedure:
To a stirred mixture of 3,4-diaminobenzoic acid (15.2 g), in 200 mL of tetrahydrofuran, 30 mL of dimethyl formamide, 7.3 mL of acetone, and 5.7 mL of acetic acid, was added 31.8 9 of sodium triacetoxyborohydride in portions. After 3 hours the mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The filtrate was concentrated to dryness. Crystallization of the residue with ethyl acetate/hexanes gave 11 grams of 4-amino-3-isopropylamino-benzoic acid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl.[CH:10]12[CH2:15][CH:14]1[CH2:13][NH:12][CH2:11]2.CCN(CC)CC>O>[CH:10]12[CH2:15][CH:14]1[CH2:13][N:12]([C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1)[CH2:11]2
Reactant: Nc1cccc(F)n1
Reactant: C1NCC2CC12
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cccc(N2CC3CC3C2)n1
Temperature: 205 °C
Yield: 76.3 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (448 mg, 4 mmol), 3-aza-bicyclo[3.1.0]hexane hydrochloride (576 mg, 4.8 mmol) and Et3N (808 mg, 8 mmol) in water (0.5 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=10:1) to give 6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridin-2-amine (535 mg, 76%) as a colorless oil. LC-MS: [M+H]+, 176.2, tR=1.042 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(C(=O)O)ccc43)ncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(C(=O)O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 19b (65 mg, 0.37 mmol) in 1.5 mL of DCM, was added TFA (1.5 mL, 19.5 mmol) and the reaction was stirred at room temperature for 2 h. The mixture was concentrated to give 19c.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[OH:32])=[CH:21][C:20]=3[OH:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](Cl)(=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[O:32][C:34](=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:21][C:20]=3[OH:33])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cc(OC2CCCCC2O)ccc1-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)OC1CCCCC1Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Reaction time: 20 h

Procedure:
A mixture of 5.0 g (11.3 mmol) of 2,4-diphenyl-6-(2'-hydroxy-4'-(2"- hydroxycyclohexyloxy)phenyl)-1,3,5-triazine, 5.7 g (26 mmol) of dodecanoyl chloride (Fluka, 98%) and 0.1 g (1.3 mmol) of pyridine in 60 ml of toluene is stirred under nitrogen and kept at 50° C. for 20 h.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH2:7].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28]([NH:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ncco1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ncco1
Yield: 62 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use oxazol-2-ylmethanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 62% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 7.45-7.30 (m, 5H), 7.13 (s, 1H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.49 (d, J=5.7 Hz, 2H), 2.54 (m, 3H); MS (ES+) m/z 423.2 (M+1).