Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>O.CC(C)=O.CC(OC(C)=O)=O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[N:1]=2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)N=C(c2ccc(F)cc2)OC1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A flask containing 2-amino-2-methyl-propionic acid (500 mg, 4.85 mmol) and sodium bicarbonate (1.29 g, 12.12 mmol) in water (10 mL) and acetone (1 mL) was chilled to 5° C. In a dropwise manner 4-fluoro-benzoyl chloride (0.688 mL, 5.82 mmol) was added. After stirring for 1 hr the mixture was allowed to warm to room temperature. After stirring for an additional 16 hr, the reaction was washed with toluene (2 mL). The aqueous portion was removed and the mixture filtered. The filtrate was partitioned and the organic layer removed. The collected solid was solubulized in water (10 mL) and all the aqueous phases combined. The pH of the combined aqueous was adjusted to 3 by slow addition of 1N HCl, and the acidified mixture was extracted with EtOAc (3×30 mL). The combined organics were washed with brine (20 mL) and dried over Na2SO4. Evaporation of the solvent resulted in a white solid. The solid was heated to 50° C. in Ac2O (2.9 mL) and toluene (0.82 mL) for 2 hr. The reaction was concentrated and azeotroped with HEP. The resulting residue was dissolved in Et2O (65 mL) and extracted with NaHCO3 (15 mL) followed by brine (10 mL). After drying over Na2SO4, the solvent was envaporated to afford the title compound as a white solid: Rt (method A)=1.22 min (M+H)+=208.3.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH:40](=O)[CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:40]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])[CH3:39])[CH:15]([CH3:17])[CH3:16])=[O:19])[C@H:21]([C:26]([NH:28][C@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH2:30]2)=[O:27])[CH2:22]1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)C=O
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)CN1CCN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 7 (250 mg, 0.46 mmol) is dissolved in 1,2-dichloroethane (4 mL), to which is added iso-butyraldehyde (63 μL, 0.69 mmol) and NaBH(OAc)3 (146 mg, 0.69 mmol). This mixture is stirred under N2 at RT overnight. LCMS at this point shows a small amount of unreacted starting material so further quantities of iso-butyraldehyde (63 μL, 0.69 mmol) and NaBH(OAc)3 (146 mg, 0.69 mmol) are added. After a further 4 h. of stirring at RT the reaction mixture is diluted with CH2Cl2 (50 mL) and then washed with water (50 mL), brine (50 mL) and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure to afford an oil which is purified by flash chromatography on silica gel (10-50% Et2O/CH2Cl2). The title compound is isolated as a white foam (255 mg, 92% yield): 1H NMR δ (CDCl3) 6.72-7.27 (m, 5H), 4.37-5.24 br m, 5H), 3.26-3.90 (br m, 2H), 2.67-2.96 (br m, 6H), 1.62-2.19 (m, 1H), 1.48 (s, 9H), 1.23-1.34 (m, 3H), 0.69-0.99 (m, 12H); LCMS (APCl+) 601.3 (MH+, 100%).
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]([O:7]CC)=O.Cl.[OH:11][CH:12]([CH3:16])[C:13]([NH2:15])=[NH:14].C(O)(=O)C>O>[OH:11][CH:12]([C:13]1[NH:15][C:5](=[O:7])[CH:4]=[CH:3][N:14]=1)[CH3:16]
Reactant: CCOC(=O)C=CO
Reactant: CC(O)C(=N)N
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CC(O)c1nccc(=O)[nH]1
Reaction time: 48 h

Procedure:
To a solution of ethyl 3-hydroxy-acrylate sodium salt (prepared according to the method of Preparation Twelve, Step C, 1301 g, 9.42 mol) in water (1.3 L) was added a solution of 2-hydroxy-propionamidine hydrochloride (prepared according to the method of Preparation Twelve, Step B, 610 g, 4.9 mol) in water (1.3 L) at ambient temperature and stirred for 48 h. The solution was adjusted to pH 7.0 with acetic acid then continuously extracted with chloroform for 48 h. The extract was dried over sodium sulfate and filtered. The filtrate was concentrated to a solid, slurried in ethyl ether, filtered, and dried to give the title compound as a solid, 232 g (38%). mp: 121-124° C.; 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (d, 3H), 4.46 (q, 1H), 5.62 (br s, 1H), 6.13 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.CCOCC.CCOC(C)=O.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH3:34])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
Stir a solution of 25 g (48.8 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate and 8.8 g (64.8 mmol) of 2-methylphenylboronic acid in 200 mL of anhydrous DMF for 15 min while bubbling with argon, then add 12.7 g (60 mmol) of anhydrous potassium phosphate (K3PO4) and 5.76 g (5 mmol) of Pd(PPh3)4 and stir the reaction mixture for 18 h at 90° C. under argon. Then distribute the reaction mixture at RT in 600 mL of ether/EtOAc 1:1 mixture and 600 ml of water. After extraction, extract the aqueous phase again with 100 mL of EtOAc, combine the organic phases and wash with 4×300 mL of water, dry over Na2SO4, then concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 18 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]([O:12][CH2:13][CH2:14]Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH3:11]
Reactant: OCc1ccccc1O
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccccc1CO
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 2-hydroxybenzyl alcohol (2.00 g), 2-bromoethyl ethyl ether (2.7 ml), potassium carbonate (4.45 g) and DMF (20 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate:hexane 1:2) to obtain 2-(2-ethoxyethoxy)benzyl alcohol (2.30 g) as a light yellow oily substance.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:17]=[C:14]([CH:15]=[O:16])[C:13]([OH:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:18][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[CH:17][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A mixture of benzyl bromide (2.04 g, 11.926 mmol), 5-bromosalicylaldehyde (1.844 g, 9.174 mmol), potassium carbonate (5.07 g, 36.696 mmol) and dimethylformamide (15 ml) was stirred at 50° C. for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with methanol to give the title compound (1.2 g, 44.9%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8]C)=O.Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Cl)(C)C>C1COCC1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:8]
Reactant: CNOC
Reactant: COC(=O)CCC(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(CCC(=O)N(C)OC)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of methyl 4,4-dimethoxy-butyrate(4.99 g, 30.8 mmol) and N,O-dimethylhydroxylamine HCl(4.65 g, 47.68 mmol) in 60 mL of THF at −20° C., is added isopropylmagnesiumchloride(46 mL, 92.28 mmol, 2.0M in THF) maintaining the temperature below −20° C. After stirring at −10° C. for 30 min, the reaction mixture is quenched with 50 mL of water and extracted with 3×80 mL of EtOAc. The combined organic layers is dried over Na2SO4 and filtered through a short silica gel pluge. The solution is concentrated to give 4,4,N-Trimethoxy-N-methyl-butyramide(5.9 g, 99%) as pale liquid. M/Z=191.0
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[Cl-].[Li+].[BH4-].[Na+].[C:26](O)(=[O:28])C>O1CCCC1CO.O.C(OCC)(=O)C>[C:17]([O:16][C:14]([N:5]1[CH2:6][C@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:8][C@:4]1([CH2:26][OH:28])[C:3]([OH:2])=[O:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCC1CCCO1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@]1(CO)C(=O)O
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-methanesulfonyloxyproline methyl ester (10.0 g, 30.9 mmol) in tetrahydrofuran--methanol (1:1, 100 ml) were successively added lithium chloride (3.93 g, 92.8 mmol) and sodium borohydride (3.51 g, 92.8 mmol). The reaction solution was stirred at room temperature for 11 h. Acetic acid (2 ml) was added to the reaction solution, and ethyl acetate and water were added thereto. The mixture was concentrated in vacuo. The residue was dissolved in water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to obtain a residue of (2S,4R)-N-tert-butoxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxyproline (9.41 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:17]2[C:18]([N+:22]([O-])=O)=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:25].O1CCOCC1>CO.[Pd]>[NH2:22][C:18]1[C:17]2[N:12]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:13](=[O:25])[CH2:14][O:15][C:16]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1COc2cccc([N+](=O)[O-])c2N1Cc1ccc2ccccc2c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2

Procedure:
A solution of 4-naphthalen-2-ylmethyl-5-nitro-4H-benzo[1,4]oxazin-3-one, I-59 (0.65 g) in methanol (30 mL) and dioxane (7.0 mL) was hydrogenated in presence of 10% Pd—C at 45 psi for 22 h. Reaction mixture was filtered and the filtrate was concentrated to give 5-Amino-4-naphthalen-2-ylmethyl-4H-benzo[1,4]oxazin-3-one, I-60 (620 mg).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F:9][CH:10]([F:34])[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31](=[O:33])[CH3:32])[CH:29]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:12]=1.[F-].[Cs+].Cl>C1COCC1.CS(C)=O.O>[F:34][CH:10]([F:9])[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31]([CH3:32])([OH:33])[C:2]([F:4])([F:3])[F:1])[CH:29]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:12]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(C)(O)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Trifluoromethyl)trimethylsilane (0.103 ml, 0.70 mmol) was added to a 20° C. solution of 1-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-one (100 mg, 0.28 mmol) and cesium fluoride (4.3 mg, 0.028 mmol) in THF (1 mL). The reaction was allowed to stir for 60 minutes at room temperature and additional cesium fluoride (4.25 mg, 0.03 mmol) and (trifluoromethyl)trimethylsilane (0.103 ml, 0.70 mmol) were then added. The reaction was stirred for 18 hours and filtered through a plug of glass wool. The filtrate was treated with hydrochloric acid (6N, 1 mL, 6 mmol) and stirred for 30 minutes. The reaction was concentrated under reduced pressure to afford the crude product residue. The crude product residue was dissolved in DMSO/water and purified by mass triggered reverse phase HPLC (ACN/water+0.1% TFA) to afford racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol. MS ESI calcd. for C19H19F5N5O [M+H]+ 428. found 428. The racemic mixture was purified by chiral SFC (Chiralpak, IA, 21×250 (mm), 70 mL/min, 25% Methanol/CO2) to afford (S or R)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OC)(OC)(=O)=O.Cl.NO.C([N:30](CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)=O>C(#N)C.C1(C)C=CC=CC=1.O.ClCCl>[C:1]1([NH:7][C:8]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[N:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(Nc1ccccc1)Nc1ccccn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Solvent: ClCCl
Product: c1ccc(Nc2nc3ccccn3n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 1-phenyl-3-pyridin-2-yl-thiourea (1.0 g, 4.4 mmol) and dimethyl sulfate (0.45 mL, 4.8 mmol) in acetonitrile (6 mL) was heated at reflux for 4 hours. The mixture was cooled to room temperature and the volatiles were evaporated. 1b) To the residue was added hydroxylamine hydrochloride (0.67 g, 9.6 mmol), N,N-diisopropylethylamine (3.3 mL, 19 mmol) and dichloromethane (8 mL). The mixture was stirred at room temperature for 18 hours. Water (10 mL) was added. A nitrogen sparge tube connected to a bleach scrubber was fitted to the reaction flask. The mixture was sparged with nitrogen. The resulting oily liquid was partitioned between ethyl acetate (100 mL) and water. The organic layer was washed with water (3×20 mL), dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. 1c) To the residue in acetonitrile (10 mL) at −5° C. was added potassium carbonate (1.5 g, 11 mmol) followed by dropwise addition of 20% phosgene in toluene (1:4, phosgene:toluene, 2.6 mL, 4.9 mmol). The mixture was stirred for 1 hour at −5° C. then warmed to room temperature. Additional 20% phosgene in toluene (1.0 mL) and potassium carbonate (1.0 g) was added to the mixture and stirred for 48 hours. The volatiles were evaporated and the residue was partitioned between ethyl acetate (100 mL) and water. The organic layer was washed with water (3×20 mL), dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure and the product was purified via flash chromatography utilizing an ISCO automated purification apparatus (silica gel column, elution gradient of 5%→100% ethyl acetate in heptane). Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine was isolated as a yellow solid (0.17 g, 18%). MP=180-184° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46-8.42 (m, 1H), 7.63-7.59 (m, 2H), 7.51-7.41 (m, 2H), 7.38-7.33 (m, 2H), 7.31 (br s, 1H), 7.02-6.97 (m, 1H), 6.90-6.85 (m, 1H). MS=211 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:12]2[CH:13]=[C:14]([NH:17][C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=4)=[O:19])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[Na+]>CO.C1COCC1>[Cl:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]3[O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:30])=[O:3])[C:12]=3[CH:13]=1)=[O:19])=[CH:28]2
Reactant: CCOC(=O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid ethyl ester (10 mg, 0.023 mmol, 1 eq.) was dissolved in a mixture of 1 mL of MeOH and 1 mL of THF and treated with 1 mL 1N NaOH. The reaction was stirred at room temperature for 3 hrs at which time the solvents were removed by evaporation and the residue acidified with 1N HCl. The precipitate was collected on a filter, dried and purified on preparative TLC in 9:1 CH2Cl2/MeOH to afford 9 mg of the product as a white solid. LC MS: AP+ 400/402,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 2-bromopyridine (1.58 g) in 50 mL of anhydrous tetrahydrofuran at -78° C. was added tert-butyl lithium (6.5 mL of 1.7M) and the reaction mixture was stirred at -78° C. for 1 hour. At the end of this period, a solution of 1-benzyloxycarbonyl-4-oxopiperidine (2.34 g) in 20 mL of anhydrous tetrahydrofuran was added and the reaction mixture was allowed to stir at -78° C. for an additional 1 hour. Upon warming the reaction mixture to room temperature, aqueous ammonium chloride was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with sodium chloride, dried over magnesium sulfate and evaporated to afford the crude product. This a material was purified by column chromatography; elution with 1:1 hexane:ethyl acetate afforded the named product (1.0 g); MS: 313; NMR: 6.63 (m, 3), 1.94 (m, 2), 3.37 (m, 2), 4.13 (m, 2).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH3:8])=[S:5])[CH3:2].[C:9]([C:14](O)=[O:15])#[C:10][C:11]([OH:13])=[O:12]>>[CH2:1]([N:3]1[C:14](=[O:15])[C:9](=[CH:10][C:11]([OH:13])=[O:12])[S:5][C:4]1=[N:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCNC(=S)NCC
Reactant: O=C(O)C#CC(=O)O
Product: CCN=C1SC(=CC(=O)O)C(=O)N1CC
Yield: 82.1 %

Procedure:
Prepared by the method described in Example 1 from N,N'-diethylthiourea (1.0 g, 8 mmoles) and acetylenedicarboxylic acid (1 g, 9 mmoles). Crystallization from hexane gave the product (1.5 g), mp 148°-152° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH: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>CCO.[Pd]>[CH3:20][C:17]1([CH3:21])[C:16]2[C:11]([O:10][C:7]3[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:12][CH:13]=[C:14]([CH3:22])[C:15]=2[O:19][CH2:18]1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c2c1OCC2(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC2(C)C

Procedure:
5-Nitro-2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridine (Intermediate 28, 920 mg, 3.0 mmol) was dissolved in EtOH (13.5 mL) and stirred under hydrogen atmosphere (2 bar) in the presence of Pd/C 10% w/w (46 mg, 5% w/w) at room temperature for 30 minutes. The catalyst was filtered off, washed with THF and the resulting solution evaporated to dryness to afford an orange solid. The crude product was crystallized from MeOH to the title compound (565 mg) as a beige solid.
Reaction SMILES: Cl[C:2]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.CC(O)C.[NH3:37]>C1COCC1>[NH2:37][C:2]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1
Reactant: Cn1cncc1C(Cl)(c1ccoc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cncc1C(N)(c1ccoc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 5 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 6-[chloro-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (obtained in stage b) (0.0045 mol) in THF (30 ml) was cooled to 5° C. 2-Propanol-NH3 saturated (30 ml) was added dropwise quickly. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated till dryness. The residue was taken up in DCM and water and the mixture was decanted. The organic layer was dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.2 g) was purified by column chromatography over silica gel (eluent: toluene/2-propanol/NH4OH 85/13/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN and DIPE. The precipitate was filtered off and dried, yielding 0.55 g (27.5%) of (±)-6-[amino-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, melting point 197° C.