Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[OH-].[K+].[C:11](#[N:14])[CH:12]=[CH2:13].Cl>O1CCOCC1>[NH2:7][C:2]([CH2:5][O:6][CH2:13][CH2:12][C:11]#[N:14])([CH2:3][O:4][CH2:13][CH2:12][C:11]#[N:14])[CH2:1][O:8][CH2:13][CH2:12][C:11]#[N:14]
Reactant: NC(CO)(CO)CO
Reactant: C=CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCCOCC(N)(COCCC#N)COCCC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Tris(hydroxymethyl)aminomethane (24.2 g, 0.2 mol) was added to a mixture of dioxane (25 ml) and aqueous potassium hydroxide (1.2 g KOH in 3 ml water). Acrylonitrile (40 ml, 0.61 mol) was added dropwise. After 2 h the solution was stood in a cold water bath to moderate any exothermic reaction and stirred for 16 h at RT. The solution was neutralized with dil. HCl and filtered. The oil was dissolved in DCE, dried (MgSO4), filtered and concentrated. The brown oil was purified by chromatography (SiO2, CH2Cl2/MeOH 1% to 4%) to give the title product (26.9 g, 0.096 mol, 48%) as a colourless oil. δH (400 MHz, CDCl3) 3.71 (6H, t, J 6.0), 3.47 (6H, s), 2.63 (6H, t, J 6.0); TLC (CH2Cl2/MeOH 10%) 0.55.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20]Br.Cl.[CH3:24][NH:25][CH3:26].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][N:25]([CH3:26])[CH3:24]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.102 g (0.273 mmol) of the above (example 45A]) prepared 2-bromomethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester was dissolved in 1.5 ml of acetonitrile and treated with 0.027 g (0.331 mmol) of dimethylamine hydrochloride and 0.080 ml (2 eq.) of triethylamine. After stirring for 2 h at ambient temperature, the reaction mixture was poured onto crashed ice/KHSO4-solution and extracted twice with AcOEt. Washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, AcOEt/MeOH/NEt3=9/1/0.05), produced 0.047 g of pure title compound as off-white crystals.
Reaction SMILES: O[CH:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([CH3:17])=[CH:3]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH3:17][C:4]1[CH:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2([CH2:11][CH2:2][CH:3]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)C1C(C)=CC(O)CC12CCCC2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1C(C)=CCCC12CCCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
At −20° C., a solution of ethyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (1.5 g, 6.3 mmol, cis/trans 34:66, prepared as described in example 16) in dichloromethane was treated with successively with triethylsilane (3.66 g, 31.5 mmol) and with BF3.OEt2 (1.34 g, 9.4 mmol). The resulting solution was stirred for 45 min., poured into an ice-cold 2M aqueous NaOH solution (50 ml), and extracted twice with MTBE (40 ml). The organic phases were washed with water (40 ml), with a saturated aqueous solution of NaCl (40 ml), dried (MgSO4) and concentrated. FC (100 g SiO2, hexane/MTBE 25:1) of the crude product (1.28 g) gave ethyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (0.98 g, 70%).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](Cl)=[O:6])[CH:3]=1.[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[C:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[C:2]2[CH:10]=[CH:9][CH:8]=[CH:4][CH:3]=2)[CH:3]=1)(=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Yield: 75 %

Procedure:
According to the general mode of operation described above, 203 g (1 mole) of isophthaloyl dichloride in 500 ml of THF is reacted with 274 g (2 moles) of phenyl magnesium chloride. The subsequent hydrolysis is effected with the aid of a dilute hydrochloric acid solution. By cooling, the diketone crystalises. 1,3-dibenzoyl-benzene is obtained in a yield of 75%. The product is recrystallised from ethanol. White crystals are obtained, the melting point of which is 100° C., which corresponds to the formula: ##STR5##
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[S:7])=[O:4].[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:14][C:9]1[C:8]([NH2:15])=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:7])=[O:4]
Reactant: Nc1ccccc1N
Reactant: COC(=O)N=C=S
Solvent: c1ccccc1
Product: COC(=O)NC(=S)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(o-aminophenyl)-3thioallophanate is prepared by dissolving 11.7 parts of methoxycarbonyl isothiocyanate in 50 parts of benzene and adding this to 10.8 parts of o-phenylenediamine in 200 parts of benzene at 10°-15° C. After stirring for 1 hour at room temperature, 13.7 parts of methyl 4-(o-aminophenyl)-3-thioallophanate is recovered by filtration, m.p. 187° C.(D).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])[CH2:2]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])[N:14]=1.C(N(CC)CC)C>C(Cl)Cl>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])[N:14]=[C:13]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([CH:9]2[CH2:10][CH2:11]2)=[O:8])[CH2:2]1
Reactant: O=C(N[C@@H]1CCNC1)C1CC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A mixture of N—((R)-pyrrolidin-3-yl)cyclopropanecarboxamide (250 mg, 0.86 mmol), 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.86 mmol) and triethylamine (0.240 mL, 1.72 mmol) in CH2Cl2 (10 mL) was stirred at room temperature. The reaction was complete after one hour. The reaction was quenched with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried-over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 gave N—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide (230 mg, 68%). LC/MS: m/z 393.3 (M+H)+ at 2.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.42-8.46 (m, 2H), 8.03 (dd, J=10.5, 2.6 Hz, 1H), 7.88-7.92 (m, 1H), 7.74-7.79 (m, 1H), 7.35-7.39 (m, 1H), 6.92-6.96 (m, 2H), 4.44-4.47 (m, 1H), 4.01-4.28 (m, 3H), 3.83-3.87 (m, 1H), 2.20-2.28 (m, 1H), 1.99-2.06 (m, 1H), 1.51-1.57 (m, 1H), 0.63-0.73 (m, 4H) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:24])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)cc(F)c4C)ccc32)cc1

Procedure:
Example 134 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 4-methoxybenzylamine to give the title compound (0.012 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH3:12])[CH:7]=[CH:8][CH:9]=1.Cl.[OH-:19].[Na+]>[Fe]>[F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:19])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: CC(=Cc1cccc(SC(F)(F)F)c1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Product: CC(=O)Cc1cccc(SC(F)(F)F)c1
Reaction time: 7 h
Yield: 60.5 %

Procedure:
13.2 g. (50 mmols) of 1-(3'-trifluoromethylthiophenyl)-2-nitro-propene, 19.6 g. (0.35 g. atom) of iron powder and 0.25 g. of ferric chloride are introduced into a 250 ml. three-necked flask equipped with a mechanical stirrer, a condenser and a dropping funnel, and this mixture is heated on an oil bath at 80°-90°C. 13.5 ml. of concentrated hydrochloric acid are added dropwise, via the dropping funnel, with stirring, over the course of 7 hours, while the temperature is kept at 90°C. The reaction mixture is allowed to cool and rendered alkaline with sodium hydroxide solution. The ketone is then steam distilled. The distillate is extracted twice in succession with 100 ml. of diethyl ether each time. The two ether extracts are combined, dried over sodium sulphate and filtered. The solvent is evaporated from the filtrate in vacuo on a water bath, and the residue is rectified. 7.1 g. (60.5% yield) of 1-(3'-trifluoromethylthiophenyl)-2-propanone are thus obtained as a colourless oil, b.p. 138°-146°C./25-30 mm. Hg., nD23 ° = 1.489.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19].O>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([NH:8][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCCCI
Reactant: Nc1cncnc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCNc1cncnc1Br
Temperature: 60 °C
Yield: 22.7 %

Procedure:
A mixture of 4-bromopyrimidin-5-amine (1 g, 5.75 mmol), sodium tert-butoxide (1.11 g, 11.5 mmol) and 1-iodobutane (1.11 g, 6.03 mmol) in DMA (15 mL) was heated at 60° C. for 15 hours. The mixture was poured into water and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexanes-EtOAc 3:1) to afford 300 mg of the title compound. MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: NCCC[N:5]1[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][N:7]([C@@H:8]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([N:15]=[N+:16]=[N-:17])[CH2:9]2)[C:6]1=[O:23].CCN(CC)CC>CO>[CH3:22][C:19]1[C:20](=[O:21])[NH:5][C:6](=[O:23])[N:7]([C@@H:8]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([N:15]=[N+:16]=[N-:17])[CH2:9]2)[CH:18]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN)c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
A solution of 10 mg MTAF (Example 31), 10 mg of 3-AP-AZT (Example 28) and 2.5 ul Et3N in 250 ul MeOH was incubated 90 minutes at 56° C., then 24 hours at room temperature and chromatographed twice over RPF 250 um using the solvent system MeOH/H2O/HOAr: (50+50+3). The product (Rf =0.25) was homogeneous on TLC and was found to provide a satisfactory tracer for quantitation of AZT by FPIA.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][C:17]3=[O:18])=[CH:12][CH:11]=2)=[O:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:31](Br)[CH3:32]>CN(C)C=O>[CH2:31]([N:7]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][C:17]2=[O:18])=[CH:12][CH:11]=1)=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)[CH3:32]
Reactant: COc1ccc(NC(=O)c2ccc(N3C(=O)CCc4ccccc43)cc2)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(N2C(=O)CCc3ccccc32)cc1)c1ccc(OC)cc1
Yield: 55.8 %

Procedure:
To a solution of 1-[4-(4-methoxyanilinocarbonyl)-phenyl]-3,4-dihydrocarbostyril (0.2 g) in dimethylformamide (15 ml) is added 60% sodium hydride (24 mg) with stirring under ice cooling and the mixture is stirred at room temperature for 0.5 hour. Then, thereto is added a solution of ethyl bromide (64 mg) in dimethylformamide (DMF, 1 ml) and the mixture is refluxed with heating for 1 hour. DMF is distilled off under reduced pressure and water is added to the residue and the mixture is extracted with dichloromethane. The extract is washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give 1-[4-(N-ethyl-4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (0.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH: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][C:10]=2[C:23]([OH:25])=O)[CH:5]=[CH:6][CH:7]=1.[NH3:26]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH: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][C:10]=2[C:23]([NH2:26])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: COc1cc2ncc(C(=O)O)c(Nc3cccc(Br)c3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(Br)c3)c2cc1OC
Temperature: 0 °C

Procedure:
A mixture of 4.03 g of 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-quinolinecarboxylic acid, 3.24 g of carbonyldiimiazole, and 100 ml of dimethylformamide was heated at 55 for 30 m, cooled to 0° C., and saturated with ammonia gas. After warming to 25 the resulting solution was stirred for 45 m, heated at 50, and evaporated to remove dimethylformamide. The residue was stirred with water, and the resulting solid was filtered, washed with water, and dried. Recrystallization from acetone gave a grey solid, mp 239-242° C.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:28][C:29]([F:40])([F:39])[CH:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[C:36]([CH:33]2[CH2:32][CH2:31][CH:30]([C:29]([F:28])([F:39])[F:40])[CH2:35][CH2:34]2)=[O:37])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: O=C(O)C1CCC(C(F)(F)F)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2C(=O)C2CCC(C(F)(F)F)CC2)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was coupled with 4-(trifluoromethyl)-cyclohexane carboxylic acid in analogy to experiment A1 to give (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-1-(4-trifluoromethyl-cyclohexanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a pale yellow oil. MS: 566.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCO)CCC2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4 -sulfonyl)-pyrrolidin-2-yl ]-butyric acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and purification by column chromatography yielded the title compound as a colorless oil, MS: m/e=392.2 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:11])[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[O:6][CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:11])[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)co1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(=O)c(OCc2ccccc2)co1
Yield: 48.2 %

Procedure:
To a stirred solution of 2-azidomethyl-5-benzyloxy-pyran-4-one (4) (30.0 g, 116.7 mmol) in tetrahydrofuran (500 mL) were added triphenyl phosphine (61.16 g, 233.46 mmol) and water (5.2 mL) and the mixture was refluxed for 16 h. After completion of the reaction, solvent was evaporated under reduced pressure, then it was purified by normal column chromatography to get (2-aminomethyl-5-benzyloxy-pyran-4-one (5) (13.0 g, 48.16%) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][C:11]2[C:16]3[C:17]([CH3:21])([CH3:20])[CH2:18][O:19][C:15]=3[C:14]([CH3:22])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O>C1COCC1.[Pd]>[CH3:20][C:17]1([CH3:21])[C:16]2[C:11]([O:10][C:7]3[N:6]=[CH:5][C:4]([NH2:1])=[CH:9][N:8]=3)=[CH:12][CH:13]=[C:14]([CH3:22])[C:15]=2[O:19][CH2:18]1
Reactant: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC2(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
5-nitro-2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyrimidine (Intermediate 32, 243 mg, 0.81 mmol) was dissolved in THF (4 mL) and Palladium on charcoal (5 mol %, 85 mg) was added. The reaction mixture was stirred under hydrogen atmosphere (3 bar) for 1 hour at room temperature. The catalyst was filtered on a pad of celite, washed with THF and the resulting solution was concentrated under vacuum. The residue was diluted with ethyl acetate and water, the organic phase collected, dried over Na2SO4 and evaporated to afford the title compound (220 mg) as colorless oil. The crude product, was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[N:29]=[C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:31][C:32]=3[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])=[O:5])C.[OH-].[Li+]>C(O)C.O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([N:16]4[CH2:17][CH2:18][N:13]([C:11]([CH:7]5[CH2:8][CH2:9][CH2:10][CH:6]5[C:4]([OH:5])=[O:3])=[O:12])[CH2:14][CH2:15]4)=[CH:20][CH:21]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C1CCCC1C(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(N2CCN(C(=O)C3CCCC3C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
To a solution of racemic 2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid ethyl ester (100 mg, 0.171 mmol) in 10 mL ethanol was added a solution of lithium hydroxide (14 mg, 0.342 mmol) in 5 mL water. The reaction mixture was stirred at room temperature for 4 hrs and then heated to 50° C. for 1 hr. The reaction mixture was cooled, diluted with water, and washed with diethyl ether. The pH of the aqueous layer was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (eluted with ethyl acetate/methylene chloride) to yield rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid (27 mg, 28%). ES-MS calcd for C28H27F3N4O5 (m/e) 556.54, obsd 557.1 (M+H).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:26])=[CH:20]4)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)C.B(Br)(Br)Br>C(Cl)Cl>[CH3:26][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([NH:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:5]3[CH:4]=[C:3]([OH:1])[CH:8]=[CH:7][CH:6]=3)[N:15]=1)=[CH:25][CH:24]=2
Reactant: COc1cccc(Nc2nccc(Nc3ccc4[nH]c(C)cc4c3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(Nc3ccnc(Nc4cccc(O)c4)n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of N2-(3-methoxylphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine (0.1mmol) in 5 ml CH2Cl2 was placed in an ice bath. To this was added BBr3(0.5 mmol). The reaction mixture was stirred overnight at room temperature, then poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to provide the desired product in a yield of 83%.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[CH3:5][O:6][C:7](=[O:25])[C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:11]([NH2:24])=[N:10][CH:9]=1>CN(C=O)C.O>[CH3:5][O:6][C:7]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:11]2[N:10]([CH:2]=[CH:3][N:24]=2)[CH:9]=1)=[O:25]
Reactant: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=CCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Chloroacetaldehyde (50% aqueous solution, 0.70 mL, 5.7 mmol) was added to a suspension of 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acid methyl ester (28) in DMF (7 mL) contained in a sealed tube. The reaction mixture was heated at 80° C. for four hours and then allowed to cool to room temperature and stir overnight. The dark brown solution was diluted with water (70 mL) the resulting light brown precipitate was collected by filtration and washed with water. The solids were dissolved into THF. Two volumes of ethyl acetate were added and the organic solution washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to provide a brown solid. The aqueous filtrate was extracted with ethyl acetate and the organic extracts were dried over NaSO4, filtered, and concentrated in vacuo. This material was combined with the previously isolated brown solid and the combined material subjected to column chromatography (dichloromethane, followed by 20:1 dichloromethane/methanol). The desired product (29) was isolated as a light yellow solid (0.752 g, 64%). MS (APCI+) m/z 414, 416, 418 (M+; Cl, Br pattern) detected.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:28][N:29]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:30]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)C1
Reaction time: 0.67 h
Yield: 67.7 %

Procedure:
Benzyl chloroformate (0.40 mL, 2.79 mmol) and triethylamine (0.65 mL, 4.64 mmol) were added to a solution of 3-[(tert-butoxycarbonyl)amino]azetidine (400 mg, 2.32 mmol) in dichloromethane (23 mL) at room temperature, followed by stirring for 40 minutes. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1) to obtain 481 mg of the title compound as a white solid (68%).