Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:7]([C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc([N+](=O)[O-])c2)c1C

Procedure:
m-Nitroaniline (10 mmol, 1.4 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 143° C.-145° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:12]([CH3:23])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.O>COCCOC.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>[CH3:23][C:12]1[CH:11]=[C:10]([CH:9]=[CH:8][C:4]2[CH:3]=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:7]=[CH:6][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)COc1ccc(C=Cc2cccc(Br)c2)cc1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: O
Solvent: COCCOC
Product: Cc1cc(C=Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 57 %

Procedure:
Ethyl ({4-[2-(3-bromophenyl)ethenyl]-2-methylphenyl}oxy)acetate (150 mg, 0.40 mmol), Na2CO3 (106 mg, 1.00 mmol), 4-(triflouromethyl)benzeneboronic acid (83.5 mg, 0.44 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) was dissolved in DME and water (2:1, 6 mL) and the mixture heated at reflux for 4 hours. The mixture was allowed to cool to rt, was concentrated under reduced pressure and the residue partitioned between EtOAc (15 mL) and water (15 mL). The aqueous layer was then acidified with aqueous HCl (1N) and extracted with EtOAc and the combined organic layers dried (MgSO4), filtered and reduced to give the title compound (94 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4](N)[CH:3]=1.[C:10](O)(C(F)(F)F)=[O:11].N(OC(C)(C)C)=O>CO>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([O:11][CH3:10])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc(Cl)c(I)cn1
Agent: CC(C)(C)ON=O
Solvent: CO
Product: COc1cc(Cl)c(I)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-5-iodo-pyridin-2-ylamine (64.2 g, 0.25 mol) in methanol (1.1 L) and TFA (93.7 mL, 1.26 mol) was added tert-butyl nitrite (150 mL, 1.26 mol) so as to maintain temperature less than 3° C. The resultant mixture was stirred at RT for 1 h then allowed to warm to RT and stirred for 16 h. The reaction was quenched by the careful addition of water then concentrated in vacuo to ¼ volume. The resultant residue was treated with water (1 L) and the precipitate formed collected by filtration and dried in vacuo at 35° C. to give the title compound (62.3 g, 92%). Contains 16% impurity. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1 H, s), 7.20 (1 H, s), 3.86 (3 H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(#N)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[N:11]([CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN[C@@H](CF)CN1C(=O)OC(C)(C)C
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CF)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A mixture of (2R,5R)-5-fluoromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.371 g, 1.27 mmol), potassium carbonate (0.70 g, 5.1 mmol), benzyl bromoacetate (0.38 g, 1.65 mmol) and acetonitrile (10 mL) was stirred at 20° C. for 18 h. Mixture was poured into water (50 mL) and extracted with DCM (3×30 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in 40-60 petroleum ether) gave the title compound (0.424 g, 87%) as an oil. MS [M+H]+=381.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 30 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-butyl chloroformate. Yield: 30% of theory, C31H35N7O5 (585.7) Rf value: 0.62 (silica gel; dichloromethane/methanol=9:1) ##EQU75##
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][CH2:9][CH:10]([OH:12])[CH3:11].C(O)(=O)C.C([BH3-])#N>CO>[CH:1]1([NH:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: CC(O)CN
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)CNC1CCCCC1

Procedure:
Cyclohexanone (0.98 g, 10 mmol) and 1-amino-propan-2-ol (0.75 g, 10 mmol) were mixed and MeOH (20 mL), acetic acid (12 mg, 0.5 mmol), cyanoborohydride resin (7 g, 14 mmol, 2 mmol/g, prepared as described by A. R. Sande et al, Tetrahedron Letters 1984, 3501) were added. The reaction mixture was heated under reflux for 16 h. The resin was filtered off and the filtrate was evaporated in vacuo. The crude product was used without further purification.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([CH:16]([CH3:19])[CH:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][C:21]([CH:23]=[CH:24][CH3:25])=[CH2:22]>C1(C)C=CC=CC=1>[CH3:20][C:21]1[CH2:22][CH:17]([CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:19])[O:18][CH:24]([CH3:25])[CH:23]=1
Reactant: CC(C=O)c1ccccc1
Reactant: C=C(C)C=CC
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1=CC(C)OC(C(C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A 5-L reaction flask equipped with a reflux condenser was charged with toluene (1 L) and borontrifluride etherate (C4H10BF3O) (16 g, 0.012 mol). The reaction flask was cooled to 0° C. and 2-phenylpropanal (300 g, 2.23 mol) was added over 15 minutes. 2-Methyl-1,3-pentadiene (1.22 Kg, 4.92 mol) was added over 1 hour. During the feed, the reaction exothermed to 10° C. The reaction mixture was aged overnight and then quenched with aqueous sodium hydroxide (50%, 1 L). Vacuum distillation of the resulting mixture afforded 4,6-dimethyl-2-(1-phenyl-ethyl)-3,6-dihydro-2H-pyran (120 g) having a boiling point of 118-120° C. at 3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Agent: O=C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(Cl)cc1

Procedure:
4.02 g of 4-chlorobenzoyl chloride—prepared by reacting 4-chlorobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[C:15]=1[OH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1>>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[C:15]=1[O:16][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: OCc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1O
Product: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile and (4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.00 (6H, s), 0.85 (9H, s), 2.50 (2H, t, J=6.4 Hz), 3.68 (2H, d, J=6.4 Hz), 5.12 (2H, s), 6.98-7.02 (2H, m), 7.30-7.34 (3H, m), 7.54 (1H, s), 7.98 (1H, s), 8.58 (1H, d, J=5.2 Hz). [M+H] Calc'd for C24H29FN4O2Si, 453; Found, 453.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O.OS(O)(=O)=O.[CH:22](=O)[CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:23]([CH:22]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCCC1NC(C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 58 %

Procedure:
L-tryptophan (5.10 g, 25 mmol), water (300 ml), H2SO4 (0.5M, 50 ml), n-butyraldehyde (10 ml) and ethanol (100 ml) were added in a 250 ml round-bottom flask, and then stirred and reacted at room temperature for 24 h. After filtration, wash with water and drying, white solids (3.75 g, 58%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:13]([CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)C1CCc2ccc(Br)cc21
Yield: 80 %

Procedure:
(Method 2): 6-Bromo-indan-1-one (0.58 mmol) was dissolved in MeOH. Dimethyl-amine (3.7 mmol), acetic acid (0.059 mmol) and sodium cyanoborohydride (1.74 mmol) were added under argon atmosphere. The suspension was refluxed overnight and then cooled. The crude was evaporated to dryness and then suspended in water. The product was extracted with CH2Cl2 and washed with water. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product (6-bromo-indan-1-yl)-dimethyl-amine (80% conversion LC-MS). The crude product was used in the next synthetic step (Suzuki coupling), without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:9]=[C:8]1[CH3:21])(=[O:3])[CH3:2].CN(C)C=O.P(Cl)(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([Cl:29])[C:10]=2[N:9]=[C:8]1[CH3:21])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OCCn1c(C)nc2c[n+]([O-])c3ccccc3c21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)OCCn1c(C)nc2c(Cl)nc3ccccc3c21
Reaction time: 0.5 h

Procedure:
A dried round bottom flask was charged with a stir bar, 2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (8.7 g, 30.49 mmol), anhydrous dimethylformamide (80 mL), and anhydrous toluene (100 mL) under nitrogen. To this brown mixture was added phosphorus oxychloride (3.1 mL) by syringe at ambient temperature. The reaction solution cleared in a couple of minutes and a slight exotherm was observed. The reaction was judged to be complete after 30 minutes. The volatiles were removed under reduced pressure. The resulting brown solid was partitioned between dichloromethane and 4% aqueous sodium bicarbonate to a pH of 8. The aqueous layer was extracted with dichloromethane (5×). The organic fractions were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure and dried overnight at ambient temperature under reduced pressure to provide 9.2 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate as a brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.[C:34]1([CH2:40][O:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:34]1([CH2:40][O:41][NH:42][C:9]2([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][CH2:16][C:15]3[N:14]=[C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:11][C:10]2=3)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Reactant: NOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(CONC2(Cc3ccccc3)CCCc3nc(OCc4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61.3 %

Procedure:
Trifluoroacetic acid (16.6 g) was added in one portion to a solution of 5,6,7,8-tetrahydro-5-hydroxy-2-(phenylmethoxy)-5-(phenylmethyl)quinoline (50 g), phenylmethoxyamine (44.8 g), and toluene (600 ml) at room temperature. The solution was stirred at room temperature for 19 hrs, and the reaction mixture was quenched with conc ammonium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated. Purification by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) gave 40.0 g (61%) of 5,6,7,8-tetrahydro-N,2-bis(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine
Reaction SMILES: [C@@H:1]1([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[N:19]([O-])=[O:20].[Na+]>O.C(O)(=O)C>[C@@H:1]1([NH:12][C:13]([N:15]([N:19]=[O:20])[CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.1 %

Procedure:
1-(β-D-glucopyranosyl)-3-n-propylurea (1.50 g) was dissolved in a mixture of water (10 ml) and acetic acid (2 ml), and to the resulting solution was added 560 mg (1.5 mol. equivalents) of sodium nitrite at ambient temperature under stirring to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) for the removal of sodium ion and then concentrated to dryness below 35° C and under a reduced pressure. Crystallisation of the residue from n-propanol gave 1.35 g of the titled compound. Yield 80%. mp. 112° C (decomposition with foaming). [α]D21 -6° (c 1.0, H2O).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Na].[CH3:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]2[N:30]=[C:31]([CH2:36][C:37](O)=[O:38])[NH:32][C:33](=[O:35])[CH:34]=2)[CH2:24]1>CN(C)C=O.N1C=CC=CC=1>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:37](=[O:38])[CH2:36][C:31]2[NH:32][C:33](=[O:35])[CH:34]=[C:29]([N:25]3[CH2:26][CH2:27][O:28][CH:23]([CH3:22])[CH2:24]3)[N:30]=2)=[CH:16][CH:15]=1
Reactant: CC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)Nc3ccc(F)cc3)n2)CCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.46 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 6.7 ml of pyridine and 0.7 ml of 4-fluoroaniline are added to a solution of 700 mg of sodium salt of [4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid in 6.7 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is stirred for 30 minutes. The precipitate formed is filtered off and washed with dichloromethane and with ethyl ether, so as to give 300 mg of N-(4-fluorophenyl)-2-[4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].S(O)(O)(=O)=O.[NH2:21]O>O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:21]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Yield: 124.4 %

Procedure:
A suspension of pivaloylacetonitrile (12.52 g), sodium carbonate (8.74 g) and water (200 ml) is stirred and mixed with hydroxylamine sulfate (9.03 g) at 25° C. pH 7.11. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (12.01 g). Yield, 85.7%. Purity, 95.8%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])[CH:19]=[CH:20][C:21](O)=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(F)c(Cl)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)c(Cl)c3)nc2n(CC)c1=O
Yield: 12.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.01 g (15.1 mmol) of 3-chloro-4-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 560 mg (yield 32%) of Compound 176 as a white powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[CH:13]=[CH2:14]>ClCCl>[O:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:12][CH:13]1[CH2:14][OH:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccccc1O
Solvent: ClCCl
Product: OCC1Cc2ccccc2O1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of meta-chloroperbenzoic acid (96.4 g, 335 mmol) in dichloromethane (500 mL) was added to an ice-cold solution of 2-allylphenol (30 g, 224 mmol) in dichloromethane (1 L) and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 18 hours. The reaction mixture was then re-cooled to 0° C., quenched with 2M sodium hydroxide solution (700 mL) and stirred for 30 minutes. The organic layer was then separated, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by HPLC using a Chiralpak AD 250*4.6 mm column and hexane:isopropanol (90:10) as the eluant, to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](Cl)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[O:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([NH:22][C@@H:23]3[C:32]4[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[O:26][CH2:25][CH2:24]3)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCOc2cc(C(F)(F)F)ccc21
Reactant: O=C(Cl)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(N[C@H]1CCOc2cc(C(F)(F)F)ccc21)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-5-(1-chlorocarbonylpyrrolidin-2-yl)-1H-1,2,4-triazole (60 mg), (S)-4-amino-7-trifluoromethylchroman and DIEA in dry MeCN was stirred overnight at RT. The solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with water and evaporated after drying over Na2SO4. The residue was purified by chromatography (silica gel, hexane:EtOAc (1:1)→EtOAc) to give 40 mg of the desired product.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.C(OC([N:22]1[C:27](=[O:28])[CH:26]2[CH:24]([CH:25]2[C:29]([O-:31])=[O:30])[CH:23]1[C:32]([O-:34])=[O:33])=O)(C)(C)C.O>C(Cl)Cl>[C:29]([CH:25]1[CH:26]([C:27]([CH:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][NH:6]2)=[O:28])[CH:24]1[CH:23]([C:32]([OH:34])=[O:33])[NH2:22])([OH:31])=[O:30]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.6 %

Procedure:
To a solution of AlCl3 (48.7 mg, 0.36 mmol) in dry CH2Cl2 (1 mL) at 0° C., tetrahydroisoquinoline (88 μl, 0.70 mmol) in CH2Cl2 (1 mL) was added dropwise. The mixture was stirred at room temperature for 10 min, and then ethyl (1SR, 2SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (96 mg, 0.28 mmol) in dry CH2Cl2 (1 mL) was added. After stirring at room temperature for 3 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 2/1) to give 95 mg of the desired compound (71% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([CH:31]([CH3:33])[CH3:32])[N:8]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C(=O)C)[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([CH:31]([CH3:33])[CH3:32])[N:8]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)CCN([C@@H](C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c1ccc2cc(O)ccc2c1
Yield: 84.3 %

Procedure:
To a solution of N-isoamyl-N-(6-acetoxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester (0.75 g, 1.53 mmol) in ethanol-water (35 mL-15 mL) is added potassium carbonate (0.422 g, 3.05 mmol), and the reaction is heated to reflux for 16 h. The solvents are removed in vacuo, and the residue is redissolved in water and extracted three times with dichloromethane. The combined organic extracts are washed with sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography (10% hexanes-ethyl acetate) to afford the title compound as a yellow oil (0.58 g, 85% yield).