Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:16])[C:4]1[O:5][C:6]2[C:7](=[C:9]([C:13]([O-:15])=O)[CH:10]=[CH:11][CH:12]=2)[N:8]=1)[CH3:2].[Li+].Cl.Cl.[NH2:20][C@H:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>>[N:23]12[CH2:22][C@@H:21]([NH:20][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:6]4[O:5][C:4]([N:3]([CH2:1][CH3:2])[CH3:16])=[N:8][C:7]=34)=[O:15])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH2:24]2
Reactant: CCN(C)c1nc2c(C(=O)[O-])cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Agent: [Li+]
Product: CCN(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C1, a mixture of lithium 2-(ethyl(methyl)amino)benzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled and to afford (S)—N-(quinuclidine-8-yl)-2-(ethyl(methyl)amino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:27](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:45][S:46]([C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1)(=[O:48])=[O:47].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:23]([O:22][C:20](=[O:21])[NH:19][C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:27]([C:52]3[CH:53]=[CH:54][C:49]([S:46]([CH3:45])(=[O:48])=[O:47])=[CH:50][CH:51]=3)=[CH:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[C:14]2=[N:15][CH:16]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(NC(=O)OC(C)(C)C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 67.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-tert-butoxycarbonylamino-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (0.5 g, 0.78 mmol), 4-methylsulfonyl phenylboronic acid (468 mg, 2.34 mmol), dichlorobis(triphenylphosphine)palladium (II) (55 mg, 0.08 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.17 mL, 2.34 mmol). The resulting mixture was subjected to microwave irradiation for 3 h at 100° C. The mixture was diluted with ethyl acetate (80 mL), washed with a saturated aqueous sodium bicarbonate solution (2×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 33% ethyl acetate/hexanes) afforded {1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (326 mg, 67%) as a light yellow solid: LC/MS m/e calcd for C32H35N3O6S2 [M+H]+ 622.78, observed 622.1.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH2:14]([O:13][C:11]([O:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6])=[O:12])[CH3:15]
Reactant: N#CC(=NO)C(N)=O
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)ON=C(C#N)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a mixture of water (100 ml) and acetone (15 ml), sodium salt of 2-hydroxyimino-2-cyanoacetic acid amide (19.6 g) is added, and the obtained solution in which a part of the sodium salt is present in a suspended state is cooled at 0°C. Ethyl chloroformate (15 g) is dropwise added thereto, and the resulting mixture is, after adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate, stirred at room temperature for 1 hour and then filtered to collect the precipitated crystals. To the filtrate, a small amount of acetonitrile is added, and the mixture is extracted with ether. The ether layer is washed with water, dried and concentrated to give crystals, which are put together with the above obtained crystals to obtain 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (22.5 g). A part of the product is recrystallized from ethyl acetate to give crystals melting at 194° to 196°C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:49][C:50]1[S:54][C:53](=[S:55])[NH:52][N:51]=1>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:49][C:50]3[S:54][C:53](=[S:55])[NH:52][N:51]=3)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1n[nH]c(=S)s1
Reactant: CC(C)[C@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CC(C)[C@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)C(=O)Nc1n[nH]c(=S)s1

Procedure:
((4-Phenyl)phenylacetyl)-valine (0.98 grams), 1-hydroxybenzotriazole (0.6 grams), dicyclohexylcarbodiimide (0.64 grams) and 5-amino-1,3,4-thiadiazole-2-thione (1.2 grams) were reacted according to the procedure described in Example 1. The resulting product was recrystallized from ethanol/pentane to give a white solid. M.P. 232°-236° C. NMR spectrum (d6 -DMSO) 14.1 (s, 1H), 12.6 (s, 1H), 8.42 (d, 1H, NH), 7.8-7.2 (m, 9H, aromatics), 4.35 (m, 1H), 3.75-3.4 (m, 2H), 2.05 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:15][C:16](OCC)=O)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)([O-])=O.CC[OH:23]>[Ni]>[O:12]1[C:8]2([CH2:13][CH2:14][C:5]3([CH2:15][CH2:16][NH:1][C:4]3=[O:23])[CH2:6][CH2:7]2)[O:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Reactant: CCO
Agent: [Ni]
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
To a solution of ethyl 2-(8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-yl)acetate (109 g, 379.38 mmol) in EtOH (600 mL) was added Raney Ni (10 g). The reaction mixture was stirred under H2 atmosphere at rt for 72 h and filtered. The filter cake was washed with a mixture of DCM and MeOH (1/1 (v/v), 500 mL). The filtrate was concentrated in vacuo and the residue was washed with a mixture of PE and EtOAc (10/1 (v/v), 800 mL) and filtered to give the product as a white solid (67 g, 83.8%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][C:13](=O)[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([NH:25][C:26]([NH2:28])=[NH:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[C:21]([O:20][C:18]([N:25]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:17])[N:27]=[C:26]1[NH2:28])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(CBr)CCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCCC(=O)OCc2ccccc2)nc1N
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-bromo-5-oxo-hexanoic acid benzyl ester (3.42 g, 11.99 mmol) and Boc-guanidine (5.73 g, 35.97 mmol) were dissolved in DMF (35 mL) and allowed to stir at room temperature. After 48 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (30-100% EtOAc/Hexanes) to obtain the title compound (2.79 g, 66%) as a colorless oil which solidified upon prolonged standing. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 6.51 (s, 1H), 5.91 (s, 2H), 5.12 (s, 2H), 2.41 (m, 4H), 1.94 (quint., 2H, J=7.2 Hz), 1.57 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.45, 150.31, 149.59, 138.27, 136.36, 128.67, 128.29, 128.27, 107.05, 84.73, 66.23, 33.82, 28.16, 27.62, 23.79; HRMS (ESI) calcd for C19H26N3O4 (MH)+360.1917, found 360.1919.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)c(O)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of 4-bromo-3-hydroxybenzoic acid (30 mmol) in methanol (100 mL) was added concentrated sulfuric acid (2.6 mL). The solution was heated at reflux for 5 hours, cooled to 0° C., and brought to pH 7 by adding saturated. aqueous sodium carbonate. The solution was evaporated to one-third the original volume. Water was added and the product was extracted into ethyl acetate. The organic extracts were washed with water and brine, and dried over anhydrous sodium sulfate. Evaporation gave 6.15 g (89%) of the title compound as a white solid. This was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH3:29])=[CH:13][CH:12]=2)[CH:5]=1.O[Li].O>C1COCC1.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:30])=[O:2])=[CH:12][CH:13]=2)=[C:20]([CH3:29])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: COC(=O)c1cccc(Cc2ccc(CNc3ccc(C(C)=O)c(O)c3C)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NCc2ccc(Cc3cccc(C(=O)O)c3)cc2)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To 3-{4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-benzyl}-benzoic acid methyl ester (356 mg, 0.88 mmol) in THF (14 mL) is added a solution of LiOH.H2O (185 mg, 4.4 mmol) in H2O (7 mL). The reaction mixture is stirred at RT overnight. The reaction mixture is acidified to pH=7 and concentrated. The residue is purified by reverse phase HPLC using 90:10 to 20:80 (H2O/0.1% TFA)/CH3CN. Obtained is the title compound as a brownish solid (158 mg, 46%). LC-MS (m/e): 390 (M+1); 1H NMR (DMSO-d6) δ 13.16 (1H, s), 12.84 (1H, bs), 7.71 (2H, m), 7.43 (2H, m), 7.36 (1H, dd), 7.19 (2H, d), 7.14 (2H, d), 6.75 (1H, t), 6.05 (1H, d), 4.38 (2H, d), 3.92 (2H, s), 2.35 (3H, s), 1.94 (3H, s).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]([NH:20][CH3:21])=[O:19])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:15][C:12]2=[CH:13][N:14]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[O:15][C:12]3=[CH:13][N:14]=[C:9]([OH:8])[CH:10]=[C:11]3[C:17]=2[C:18]([NH:20][CH3:21])=[O:19])=[CH:27][CH:26]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cnc(O)cc12
Reaction time: 0.33 h
Yield: 91.4 %

Procedure:
Pd/C (178 mg, 0.084 mmol) (10%; 50% wet) was added to a stirring solution of 5-(benzyloxy)-2-(4-fluorophenyl)-N-methylfuro[2,3-c]pyridine-3-carboxamide (630 mg, 1.674 mmol) in THF (83 ml) at room temperature. It was placed under an atmosphere of H2 and allowed to stir for 20 minutes after which a precipitate had formed. The reaction was purged with N2 and diluted with MeOH until all solids had dissolved. The mixture was filtered through a pad of celite washing with MeOH and the filtrate was concentrated to give the expected product 2-(4-fluorophenyl)-5-hydroxy-N-methylfuro[2,3-c]pyridine-3-carboxamide (460 mg, 1.53 mmol, 91% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30-8.40 (2H, m), 7.98 (2H, dd, J=8.78, 5.77 Hz), 7.35-7.45 (3H, m), 6.61 (1H, s), 2.81 (3H, d, J=4.52 Hz). LC-MS retention time: 0.847 min; m/z (MH+): 287. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19]C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH2:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)[C@H](c2ccccn2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccccn2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-tert-butyloxycarbonyl-trans-3-benzyloxycarbonylamino-4-(2-pyridyl)pyrrolidine from step 6 above (3.9 g, 9.8 mmol) in EtOH (25 mL) was added 10% Pd on carbon (1.5 g). The mixture was shaken under an atmosphere of hydrogen (40 psi) at ambient temperature for 18 h on a Parr apparatus. The catalyst was removed by filtration and the solvent was removed in vacuo to give the title compound as an oil (2.5 g, HPLC RT=3.96 min, method A).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCc2csc(NC(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of benzyl 4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-ylcarbamate (1.4 g), palladium on carbon (140 mg) and methanol (2 ml) was stirred under hydrogen atmosphere (4 atm) at ambient temperature for 8 hours. The catalyst was filtered off, and the filtrate was concentrated in vacuo to give benzyl 4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-ylcarbamate (1.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared according to the coupling procedure for Example 17 from 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and 3-chlorophenyl boronic acid. A yellowish solid: mp 108-109° C.; 1H-NMR (DMSO-d6) δ 7.69 (t, 1H, J=1.7 Hz), 7.59 (d, 1H, J=7.8 Hz), 7.35-7.50 (m, 3H), 7.32 (dt, 1H, J=8.1, 1.1 Hz), 6.91 (s, 1H), 6.87 (d, 1H, J=8.4 Hz), 5.35 (m, 1H), 1.60 (s, 3H), 1.59 (s, 3H); MS (ESI) m/z 340 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O.[C:30]([OH:34])(=[O:33])[CH:31]=O.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][CH2:31][C:30]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)CNCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (83 mg, 0.213 mmol) was added glyoxylic acid monohydrate (39 mg, 0.426 mmol) and DCM (1 mL) before it was stirred for 5 h at ambient temperature. The reaction mixture was concentrated before adding concentrated hydrochloric acid (2.13 mL, 4.26 mmol) and heating to reflux for 16 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with water, washed 1 time with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after preparatory LC. MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=O.COC1C=CC(/C=[C:36]2/[C:37]([NH:39][C:40]([S:42]/2)=[NH:41])=[O:38])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:41][C:40]1[S:42]/[C:36](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])/[C:37](=[O:38])[N:39]=1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1OCC(F)(F)F
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1OCC(F)(F)F

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-(2,2,2-trifluoro-ethoxy)-quinoline-3-carbonitrile (example 43b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2,2,2-trifluoro-ethoxy)-quinoline-3-carbonitrile. LC-MS m/e 379 (MH+).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.C(OCC)C>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])=[O:5]
Reactant: CC(=O)c1cccc(NC(=O)c2cc(C)on2)c1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)Nc2cccc(C(=O)CBr)c2)no1
Reaction time: 0.5 h

Procedure:
A solution of bromine (12.5 g) in chloroform (60 ml) was added to a slurry of 3'-acetyl-5-methyl-3-isoxazolecarboxanilide. 1/4 hydrate (19 g) in chloroform (190 ml). The mixture was stirred for 1/2 hour and diluted with diethyl ether. The product was filtered and dried. Yield 21.0 g = (84%,) m.p. 172°-174°.
Reaction SMILES: [Br:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=O)=[O:4].Cl.CN(CCCN=C=NCC)C.[Cl:30][C:31]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:32]=1[NH2:33].O>ClCCl>[Cl:30][C:31]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:32]=1[NH:33][C:7](=[O:9])[C:6]([NH:5][C:3](=[O:4])[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[Br:1])([CH3:11])[CH3:10]
Reactant: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)O
Reactant: Nc1cc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)Nc1cc(Cl)ccc1Cl
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A solution of 2-(α-bromophenylacetylamino)isobutyric acid (1.9 g) in dichloromethane (30 mL) was cooled to 0° C., to which dimethylaminopropylethylcarbodiimide hydrochloride (1.3 g) was added. The mixture was stirred for 10 minutes at 0° C. to room temperature. 2,5-Dichloroaniline (1.0 g) was added to the mixture, which was stirred overnight at room temperature. The reaction solution was poured into water and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent, 2.3 g of N-(2,5-dichlorophenyl)-2-(α-bromophenylacetylamino)isobutyramide was obtained as viscous liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.[CH3:11][S:12]([CH2:14][S:15][CH3:16])=[O:13].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[CH3:11][S:12]([C:14]([S:15][CH3:16])=[CH:4][C:3]1[C:2]([CH3:1])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:10])=[O:13]
Reactant: Cc1cccc(C)c1C=O
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CSC(=Cc1c(C)cccc1C)S(C)=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of 2,6-dimethyl-benzaldehyde (14.6 g, 109 mmol) in 1,4-dioxane (24.7 mL) was added methyl methylsulfinylmethyl sulfide (13.5 g, 109 mmol) followed by benzyltrimethylammonium hydroxide (9.10 g, 54.4 mmol). The resulting mixture was heated at 80° C. After 16 h, the mixture was cooled to rt and concentrated. The resulting residue was purified by FCC to afford a yellow oil (17.9 g, 68%). MS (ESI): mass calcd. for C12H16OS2, 240.1; m/z found, 241.1 [M+H]+. 1H NMR (CDCl3): 7.71 (s, 1H), 7.19-7.13 (m, 1H), 7.07 (d, J=7.5 Hz, 2H), 2.82 (s, 3H), 2.24 (s, 6H), 2.06 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[O:3]1.[Br:18]Br>C(O)(=O)C>[Br:18][C:5]1[CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10]2
Reactant: CCOC(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)c2c(c1)CCC(C)(C)O2

Procedure:
Reaction Scheme 6B discloses a synthetic route to specific preferred benzopyran (chromene) compounds of the invention where with reference to Formula 1 the Z group is also CONH (amide derivatives). In accordance with this scheme, dihydrocoumarine (Compound 213) is subjected to a Grignard reaction with methyl magnesium chloride followed by heating a tertiary alcohol intermediate with acid, to provide 2,2-dimethylchroman (Compound 214). Compound 214 is converted into 6-acetyl-2,2-dimethylchroman (Compound 215) in a Friedel--Crafts reaction, and the latter is oxidized with NaOCl in the presence of sodium hydroxide and thereafter esterified to give ethyl 2,2-dimethylchroman-6-carboxylate (Compound 216). Compound 216 is treated with bromine in glacial acetic acid to give ethyl 8-bromo-2,2-dimethylchroman-6-carboxylate (Compound 217). Compound 217 is oxidized with chromium trioxide to form a ketone function in the 4-position of the chroman ring and yield ethyl 8-bromo-2,2-dimethyl-4-chromanone-6-carboxylate (Compound 218). Reaction of Compound 218 with the Grignard reagent made from 4-bromotoluene, and subsequent heating with p-TSOH to complete dehydration of the intermediate tertiary alcohol, provides ethyl 8-bromo-2,2-dimethyl-4-tolyl-4(2H)-chroman-6-carboxylate (Compound 219). Saponification of Compound 219 with base gives the corresponding free carboxylic acid, 8-bromo-2,2-dimethyl-4-tolyl-4(2H)-chroman-6-carboxylic acid (Compound 220). Compound 220 is condensed with ethyl 2-fluoro-4-aminobenzoate and ethyl 2,6-difluoro-4-aminobenzoate, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and of 4-dimethylaminopyridine (DMAP) to provide ethyl 2-fluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoate (Compound 221) and ethyl 2,6-difluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoate (Compound 222), respectively. Saponification of Compounds 221 and 222 yields the corresponding free carboxylic acids, 2-fluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoic acid (Compound 204) and 2,6-difluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoic acid (Compound 205), respectively. ##STR14##