Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17]([O:19]CC)=[O:18])[CH:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4][N:3]=1.O.[OH-].[Li+]>CO.O.CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17]([OH:19])=[O:18])[CH:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: CCOC(=O)C1Oc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n(c23)C1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC(C(=O)O)C3c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate (0.150 g, 0.358 mmol) from Example 23 was dissolved in MeOH (3.0 mL) and lithium hydroxide, monohydrate (0.030 g, 0.72 mmol) dissolved in water (1.0 mL) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with saturated water ammonium chloride, brine, dried over magnesium sulfate and concentrated to give a mixture of the diastereoisomers of the title compound as a solid residue (0.145 g, 100%). LCMS calc. for C21H18N3O5 (M+H)+: m/z=392.1. found: 392.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1.C(O[Cl:16])(C)(C)C>CO>[Cl:16][N:4]1[C:3]([CH2:2][OH:1])([CH3:10])[CH2:7][N:6]([CH3:8])[C:5]1=[O:9]
Reactant: CC(C)(C)OCl
Reactant: CN1CC(C)(CO)NC1=O
Solvent: CO
Product: CN1CC(C)(CO)N(Cl)C1=O
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of 4-(hydroxymethyl)-1,4-dimethylimidazolidin-2-one (250 mg, 1.72 mmol) in methanol (2.5 ml) was cooled to 0° C. tert-Butylhypochlorite (236 ul, 2.1 mmol) was added. The resulting solution was stirred for 30 minutes, then concentrated under reduced pressure to a crude residue. The crude material was purified by column chromatography (1 to 12% methanol in dichloromethane) to give the desired product as a white solid (168 mg, 0.941 mmol, 54%). 1H NMR (400 MHz, D2O) δ 1.16 (s, 3H), 2.74 (s, 3H), 3.25-3.27 (d, J=9.2 Hz, 1H), 3.38-3.41 (d, J=12.6 Hz, 1H), 3.47-3.49 (d, J=9.2 Hz, 2H), 3.64-3.67 (d, J=12.6 Hz, 1H). 13C NMR (100 MHz, D2O) δ 18.1, 30.8, 53.2, 62.8, 64.5, 161.6. LRMS (ESI/APCI) m/z 179 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[N+:14]([O-])=O.O1CCCC1.[BH4-].[Na+].[Cl-].[Cl-].[Cl-].[Al+3]>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[NH2:14]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(N)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
The obtained 2,4-dinitrophenylacetic acid methyl ester (2.28 g) was added into tetrahydrofuran (50 ml), and was dissolved by stirring at room temperature. Sodium borohydride (0.76 g, 0.02 mole) and aluminum trichloride (1.33 g, 0.01 mole) were then added, and reaction was conducted for 2 hours at room temperature. After the reaction, water (10 ml) was added to completely react with the remaining reductant. Solvent was removed by distilling under a reduced pressure to obtain 2,4-diaminophenylacetic acid methyl ester (1.73 g, yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:17])[CH:15]=[CH2:16])([CH3:12])([CH3:11])[CH3:10]>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:9]([O:13][C:14](=[O:17])[CH2:15][CH2:16][S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ccc(S)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-aminothiophenol (2.36 g) in tetrahydrofuran (THF; 20 ml), 2-propenoic acid t-butyl ester (3.51 ml) and 1.0M tetrabutylammonium fluoride in THF solution (340 μl) were added. The mixture solution was stirred for 30 minutes at room temperature to give the title compound. The compound was used for next reaction as such.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.58 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2.2 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.46 g, 85%) of 3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=O)[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([N:27]2[CH2:28][CH2:29][C:24]([CH2:23][C:22]3[CH:31]=[CH:32][C:33]([F:34])=[C:20]([F:19])[CH:21]=3)([OH:30])[CH2:25][CH2:26]2)=[O:11])[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1-c1ccncc1
Reactant: OC1(Cc2ccc(F)c(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccnc1-c1ccncc1)N1CCC(O)(Cc2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (0.30 g), 4-(3,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.38 g), HATU (0.63 g) and triethylamine (0.77 mL) in DMF (4.0 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.32 g).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])OC2C=CC(Cl)=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([NH:39][C:11]([NH:10][C:8]2[O:7][N:6]=[C:5]([C:2]([F:1])([CH3:3])[CH3:4])[CH:9]=2)=[O:20])[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: COc1cc2ncnc(Oc3cc(N)ccc3F)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)F)no4)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
A mixture of 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 257A) (170 mg, 0.571 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (prepared as described in Example 266A steps 1 and 2) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (147 mg, 64%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.44 (brs, 1H), 9.08 (brs, 1H), 8.58 (s, 1H), 7.69 (m, 1H), 7.59 (s, 1H), 7.35-7.42 (m, 3H), 6.14 (s, 1H), 4.00 (s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[C:6]([CH:5]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C(=O)OC)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 15.0 g (74.1 mmol) of methyl 3-ethoxy-4-methoxybenzoate in 45 mL of acetic acid was treated with 15 mL of conc nitric acid dropwise over 12 min. The reaction was kept at 55° C. for 45 min, cooled to 25° C. and poured into ice water. The product was extracted into methylene chloride and the extracts were washed with water and dil sodium hydroxide, dried and evaporated. The yield was 17.8 g of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate as yellow crystals: mass spectrum (electrospray, m/e): M+H 256.0.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1[CH:28]=[CH:27]N=C1)=O.NCCN1CCCC1.FC1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]3[CH2:21][CH2:28][CH2:27][CH2:1]3)=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: Fc1ccc(N2CCNCC2)cc1
Agent: NCCN1CCCC1
Solvent: C1CCOC1
Product: O=C(NCCN1CCCC1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 10.4 g (0.064 mole) of 1,1'-carbonyldiimidazole, 7.3 g (0.064 mole) of N-(2-aminoethyl)pyrrolidine and 11.5 g (0.064 mole) of 1-(4-fluorophenyl)piperazine in a total volume of 500 ml of tetrahydrofuran gave an oil that solidified when triturated with petroleum ether. The collected solid was recrystallized from benzene to give 2.8 g of the title compound as a white solid, m.p. 100°-102° C.
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([C:16]([S:18][CH3:19])=N)[N:8]=[C:7]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:3]#[C:4][CH3:5].C([OH:35])C>>[CH2:2]([N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([C:16]([S:18][CH3:19])=[O:35])[N:8]=[C:7]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:3]#[C:4][CH3:5]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=N)SC)c1C(=O)OCC
Reactant: CCO
Agent: Cl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)SC)c1C(=O)OCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
5 ml of a 2N aqueous solution of hydrochloric acid was added to a 30-ml ethanol solution of 0.55 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methyl sulfanylcarbonimidoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was heated at 60° C. for 5 hours. After the reaction solution had been concentrated under reduced pressure, 25 ml of ethyl acetate and 1N sodium hydroxide solution were added thereto. The aqueous layer was extracted with 25 ml of ethyl acetate, and the organic layers were combined together. The mixture was washed with 10 ml of a saturated sodium chloride solution containing 1 ml of 1N sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 0.10 ml of triethylamine and 0.256 g of di-t-butyl dicarbonate were added thereto. The mixture was stirred at room temperature for 15 hours, and then 25 ml of ethyl acetate was added thereto. The mixture was washed successively with 10 ml of 0.1N hydrochloric acid, 10 ml of a saturated sodium bicarbonate solution, and 10 ml of a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.15 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([N:25]([CH2:40][CH3:41])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=1[CH3:39])=[O:30])[CH3:24].N1CCCCC1>C(O)C>[CH2:40]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[C:34](/[CH:37]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:33][C:32]=1[CH3:39])=[O:30])[CH3:41]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: COc1cccc(CS(=O)(=O)c2ccc3c(c2)CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(OC)c4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
To a solution of 5-(3-methoxy-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (84 mg, 0.32 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 1:9 to provide 125 mg (69%) of 5-[5-(3-methoxy-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a pale orange solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:15][CH2:14]2)=[CH:7][C:6]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:28]([C:38]([NH:40][CH3:41])=[O:39])[C:27]=2[CH:42]=1.C(O)(C(F)(F)F)=[O:44]>CO.O.O.CO.C(#N)C.O.C(#N)C>[NH2:1][C:2](=[O:44])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)=[CH:7][C:6]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:30][C:29]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[C:28]([C:38]([NH:40][CH3:41])=[O:39])[C:27]=2[CH:42]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3OCCN)cc12
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3OCC(N)=O)cc12

Procedure:
5-(2-(2-Aminoethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, 2 TFA. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 1.23-1.33 (m, 2H), 1.60-1.67 (m, 2H), 2.89 (d, J=4.77 Hz, 3H), 3.41 (t, J=5.14 Hz, 2H), 4.40 (t, J=5.14 Hz, 2H), 6.58 (br. s., 2H), 7.01-7.11 (m, 1H), 7.16-7.29 (m, 3H), 7.46 (d, J=8.03 Hz, 1H), 7.52-7.70 (m, 4H), 7.93 (dd, J=8.53, 2.26 Hz, 1H), 7.98-8.05 (m, 3H), 8.07 (s, 1H), 8.41 (d, J=4.77 Hz, 1H), 8.56 (s, 1H). LCMS m/z 565.4 (M+H), Rt=1.628 min. HPLC (Sunfire C18) Rt=5.048 min., 99.9% purity and (XBridge Phenyl C18) Rt=10.531 min., 100% purity.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([CH3:18])=[C:11]([CH2:15][CH2:16]O)[C:12](=[O:14])[O:13][C:8]=2[CH:7]=[C:6]([O:19][CH2:20][CH3:21])[CH:5]=1)[CH3:2].C(Cl)(Cl)[Cl:23].C(O)C>>[Cl:23][CH2:16][CH2:15][C:11]1[C:12](=[O:14])[O:13][C:8]2[CH:7]=[C:6]([O:19][CH2:20][CH3:21])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=2[C:10]=1[CH3:18]
Reactant: CCOc1cc(OCC)c2c(C)c(CCO)c(=O)oc2c1
Reactant: ClC(Cl)Cl
Solvent: CCO
Product: CCOc1cc(OCC)c2c(C)c(CCCl)c(=O)oc2c1
Yield: 83 %

Procedure:
Process E; starting material: 5,7-diethoxy-3-(2-hydroxyethyl)-4-methyl-2H-1-benzopyran-2-one (Example 50); yield 83%; m.p. 123°-126° C. (from chloroform/ethanol).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.B(Br)(Br)Br>ClCCl>[N+:15]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: COc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)ccc1-c1ccccc1

Procedure:
4-Methoxy-2-nitro-1-phenylbenzene (1.86 g, 8.31 mmol) was dissolved in dichloromethane (40 mL) and thereto was added, under ice-water cooling, a solution of boron tribromide (2 mL) in dichloromethane (10 mL) After stirring at room temperature for 18 hours, the reaction mixture was poured onto ice to stop the reaction and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-nitro-4-phenylphenol as a crude material.
Reaction SMILES: COC1[C@@H](C(C)C)N=[C:6]([O:15][CH3:16])[C@H:7]([CH2:9][C:10]2[O:14][CH:13]=[CH:12][CH:11]=2)[N:8]=1.Cl.[O:21]1CCOCC1>>[NH2:8][C@@H:7]([CH2:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:15][CH3:16])=[O:21]
Reactant: C1COCCO1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccco1
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-furfurylpyrazine (2 g, 7.6 mmol), 1M HCl (7.6 ml, 7.6 mmol) and dioxane (7.6 ml) was stirred at ambient temperature overnight under N2. Dioxane was removed under reduced pressure and the water phase extracted with diethyl ether (20 ml). Aqueous ammonia was added to the water phase until pH 9, extracted with CHCl3 (3×30 ml ), dried (MgSO4) and the solvent removed under reduced pressure. The valine methyl ester was removed by bulb-to-bulb distillation at 40°-50° C. (0.05 mbar). The undistilled title compound was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[CH:12][N:11]=2.[NH:31]1[C:35]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])=[N:34][N:33]=[N:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:34]1[C:35]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:12][N:11]=3)=[O:40])=[N:31][N:32]=[N:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Reactant: O=C(O)c1cccc(-c2nnn[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4cccc(-c5nnn[nH]5)c4)nc3c2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-((2-(2-aminophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate (85 mg, 0.2 mmol) was taken up in 3 mL of DMF along with 3-(1H-tetrazol-5-yl)benzoic acid (38 mg, 0.2 mmol), HATU (114 mg, 0.3 mmol) and DIEA (35 mL, 0.4 mmol). The reaction mixture was stirred at 50° C. (18 h). It was then diluted with EtOAc (15 mL) and washed with water (3 mL×3). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford crude tert-butyl 4-((2-(2-(3-(1H-tetrazol-5-yl)benzamido)phenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate. This material was taken up in 5 mL of 25% TFA in CH2Cl2 and was allowed to stand at room temperature (18 h). The reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse-phase HPLC to afford 12 mg of N-(2-(6-(piperazin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-3-(1H-tetrazol-5-yl)benzamide as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.5 (br s, 2H), 7.5-9.1 (m, 10H), 4.5 (br s, 1H), 3.5-4.0 (m, 10H). MS (ESI) calcd for C25H23N9OS (m/z): 497.17, found: 498.2 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O=[C:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1.CO.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:17]([O:16][C:15](=[O:21])[NH:14][C@H:11]1[CH2:10][CH2:9][C@@H:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:13][CH2:12]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N2CCOCC2)CC1

Procedure:
To a solution of morpholine (4.08 g) and tert-butyl 4-oxocyclohexylcarbamate (10 g) stirred for 24 hours at room temperature in titanium (IV) isopropoxide (27.5 mL), methanol (10 mL) was added followed by careful addition of sodium borohydride (3.55 g). The reaction mixture was quenched with water/NaOH solution, extracted with ether, dried over magnesium sulfate, filtered, and concentrated. The product was separated from the trans isomer and purified by flash chromatography (silica gel, 50%-100% acetone in hexanes) to provide the title compound.