Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17]#[N:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12.C(O)(=O)C.[Cl-].[NH4+:28]>CO>[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17](=[NH:28])[NH2:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12
Reactant: [NH4+]
Reactant: N#Cc1nc(Cc2ccccc2F)c2ncccn12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nc(Cc2ccccc2F)c2ncccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, 6.98 g (32.30 mmol) of sodium methylate (25% solution in methanol) was put in 50 ml methanol and 8.000 g (30.76 mmol) of 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carbonitrile dissolved in 40 ml of absolute methanol was added. The reaction mixture was stirred for 1 h at RT. 7.205 g (119.98 mmol) of acetic acid and 1.975 g (36.92 mmol) of ammonium chloride were added and the mixture was stirred for 2 h at 50° C. The reaction mixture was concentrated by evaporation and the residue was distributed between 150 ml water and 100 ml ethyl acetate. The aqueous phase was made basic (pH=10) with 2N sodium hydroxide solution and the phases were stirred for 1 h at RT. Water was added and it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, concentrated by evaporation and the residue was dried under high vacuum. 7.53 g (purity 73%, 66% of theor.) of the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:7][C:6](=[O:8])[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: CO
Reactant: COC(CCC(=O)O)c1ccccc1C
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(OC)c1ccccc1C
Reaction time: 12 h

Procedure:
To a solution of the 4-methoxy-4-o-tolyl-butyric acid obtained above in 6 mL methanol was added 60 μL concentrated H2SO4 at room temperature. After stirring for 12 h the reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over Na2SO4. The product was isolated by flash column chromatography eluting with 0% to 10% ethyl acetate/hexane to give 229 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Cl.[NH:27]([C:29]([NH2:31])=[O:30])[NH2:28]>CO>[F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9](/[C:12](=[N:28]/[NH:27][C:29]([NH2:31])=[O:30])/[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 77 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (100 mg, 0.295 mmol) and hydrazinecarboxamide hydrochloride (44.3 mg, 0.589 mmol) in MeOH was stirred at room temperature for overnight. Solvent was evaporated and the residue was dissolved in a small amount of MeOH. Solid was filtered and dried to give the title compound as a white solid (90 mg, 75%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 9.06 (d, 1H), 8.62 (d, 1H), 8.49 (m, 2H), 8.34 (d, 1H), 8.20 (d, 1H), 8.03 (d, 1H), 7.70 (m, 1H), 6.82 (broad, 2H), 2.07 (s, 3H). LCMS (method B): [MH]+=397.1, tR=2.08 min.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Na].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26](Cl)[N:21]2[N:20]=1)(=[O:18])=[O:17].Cl>CO.C(Cl)Cl.CO>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26]([O:2][CH3:1])[N:21]2[N:20]=1)(=[O:18])=[O:17]
Reactant: C[O-]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Reaction time: 0.17 h

Procedure:
A sodium methoxide-methanol solution was made by dissolving 0.3 g (13 mg-atom) of sodium metal into 20 ml of absolute methanol. To this solution was added 1.0 g (2.5 mmol) of N-(2,6-dichlorophenyl)-7-chloro-5-methyl-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonamide. A mild exotherm ensued and the reaction was complete within 10 min as determined by TLC (20 percent methanol-methylene chloride). The solution was acidified with 6N aqueous HCl and the resulting white solid collected. Recovered 0.9 g (93 percent) of a white powder; mp 214°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[NH:5][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cccc(O)c1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-hydroxyphenylalanine methyl ester (1 g) in CH2Cl2 (20 mL) at 0° C. was added triethylamine (2 mL) followed by DMAP (527 mg) and benzoyl chloride (1.1 mL). When addition was complete, the mixture was stirred for 17 hr at r.t. and then NH4OAc buffer was added. The aqueous phase was extracted with CH2Cl2 (3×) and the combined organics were washed with buffer, brine, dried (MgSO4) and concentrated. The residue was dissolved in MeOH (15 mL) and THF (1.5 mL) and NaOMe (1M in MeOH; 2.4 mL) was added at 0° C. After 2.5 hr, saturated aq. NH4Cl was added and the aqueous phase extracted with EtOAc (3×). The combined organics were washed with NH4OAc buffer (2×), H2O, brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (1:1)) provided N-benzoyl-3-hydroxyphenylalanine methyl ester as a foam. A portion of this material (1.25 g), K2CO3 (866 mg) and methyl iodide (312 μL) in DMF (12 mL) were stirred at r.t. for 18 hr and then H2O (150 mL) was added. The mixture was extracted with EtOAc (3×) and the combined organics washed with NH4OAc buffer, H2O (2×) and brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (55:45)) provided N-benzoyl-3-methoxyphenylalanine methyl ester as a gum. A portion of this material (950 mg) was dissolved in refluxing xylene (25 mL) and P2O5 (10.9 g) was added periodically over 5 hr. After refluxing for 5.5 hr, the mixture was cooled to r.t. and the xylene was decanted. The residual solid was dissolved in cold H2O (600 mL) and neutralized with solid NaHCO3. The aqueous mixture was extracted with EtOAc (3×) and the combined organics were washed with NH4OAc buffer (2×), brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (3:2)) provided the title compound as a gum.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:12][CH:11]=1)[CH3:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To a solution of acryloyl chloride (1.08 mL, 13.32 mmol) in dry dichloromethane (10 mL) was slowly added dropwise, via addition funnel, a solution of 4-aminobenzoic acid ethyl ester (2.0 g, 12.11 mmol) and triethylamine (1.86 mL, 13.32 mmol) in dry dichloromethane (5 mL) over about 30 minutes. The reaction was stirred at room temperature for 16 hours. The solution was then partitioned between dichloromethane and water in a separatory funnel. The organic layer was washed with 2 N HCl, dried with sodium sulfate, and concentrated in vacuo to dryness. The resulting residue was triturated with hexane, and vacuum filtered to yield 2.02 g (76%) of 4-acryloylaminobenzoic acid ethyl ester as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 4-oxo-azepane-1-carboxylic acid tert-butyl ester (13.6 g, 63.8 mmol) in methanol (10 mL) and tetrahydrofuran (30 mL) at 0° C. is added lithium borohydride (1.40 g, 63.8 mmol). The mixture is stirred at 0° C. for 60 minutes. Hydrochloric acid (1.0 M, 40 mL) is added. The mixture is concentrated under reduced pressure and extracted with ethyl acetate (2×). The combined ethyl acetate layers are dried (Na2SO4) and concentrated to a residue. The residue is purified on silica using a gradient of ethyl acetate in hexanes (40 to 80%) to yield the title compound (13.6 g, 99.1%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[C:17]([F:18])([F:19])[F:20])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)cn1
Yield: 81.7 %

Procedure:
A mixture of 4-methylimidazole (0.63 g, 7.67 mmol), 1-fluoro-2-(trifluoromethyl)-4-nitrobenzene (1.06 g, 5.1 mmol), and K2CO3 (1.06 g, 7.67 mmol) in acetonitrile (20 mL) was refluxed for 6 hs. The mixture was filtered through Celite and filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel (PE/EtOAc 1:1) to give 1.13 g product as light green oil (81.8%). 1H NMR (300 MHz, CDCl3) δ: 8.71 (1H, s), 8.52-8.55 (1H, d, J=8.4 Hz), 7.59-7.62 (2H, m), 6.90 (1H, s), 2.32 (3H, s). LCMS: m/z [M+H]+ 272.0660.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[OH-].[Na+].[CH:25](O)=O>C(Cl)(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]3[C:6]([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:25]=[N:22][C:4]=3[C:3]=1[O:2][CH3:1])=[N:7][CH:8]=[N:9]2
Reactant: O=CO
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)N=CN3c1ccccc1

Procedure:
A solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (80 mg, 0.27 mmol) (from Example 1, Step C, supra) in formic acid (5 mL) was heated at 110° C. for 2 hours. Aqueous NaOH solution was then added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 8,9-dimethoxy-3-phenyl-3H-1,3,4,6-tetraaza-phenalene as a white solid. (Yield 45 mg, 54%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:17](Cl)(Cl)=[S:18].O>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[C:17]=[S:18]
Reactant: S=C(Cl)Cl
Reactant: COCCN(CCOC)c1ccccc1N
Solvent: C1COCCO1
Solvent: O
Product: COCCN(CCOC)c1ccccc1N=C=S
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of N,N-bis(2-methyoxyethyl)benzene-1,2-diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) which had been cooled to 0° C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice water (50 ml) was added and the mixture extracted with ether (3×20 ml). The extract was washed with water (50 ml) and brine (50 ml), dried and evaporated to give a residue which was heated at 45° C. under vacuum (100 mm/Hg) to give 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC(C)([O-])C.[Na+].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1>COCCOC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1
Reactant: COCCO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 110 °C

Procedure:
2-Methoxyethanol (3.2 mL) was diluted with 1,2-dimethoxyethane (20 mL). To this was added sodium tert-butoxide (3.9 g) gradually and the reaction mixture was stirred under nitrogen until it was homogenous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.5376 g) was then added to the reaction mixture, followed by 1,2-dimethoxyethane (20 mL). The reaction mixture was then heated to reflux (110° C., external) overnight. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL, twice). The combined organic layers were then washed with brine (100 mL). The organic layer was then dried by passing through a hydrophobic frit and then evaporated under reduced pressure (followed by azeotroping with toluene (100 mL, twice)). This gave an amber oil that under high vacuo gave gummy foam. This material was triturated with diethyl ether (with cooling) until this gave the title compound, a pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][NH:16]3)=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][C:24]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][N:16]3[CH2:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[CH:25][C:24]=3[O:36][CH3:37])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Reactant: O=Cc1c[nH]c2cc(C(=O)NCC3CCCC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(C(=O)NCC3CCCC3)cc21
Reaction time: 48 h
Yield: 71.9 %

Procedure:
A mixture of 6-(N-cyclopentylmethylcarbamoyl)-3-formylindole (0.92 g), t-butyl 4-bromomethyl-3-methoxybenzoate (1.2 g), and potassium carbonate (0.7 g) in N,N-dimethylformamide (17 ml) was stirred for 48 hours under a nitrogen atmosphere. Water was added to give a precipitate which was collected by filtration and dried to yield t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-formylindol-1-ylmethyl]-3-methoxybenzoate (1.2 g, 71%) as an ivory powder; mp 134°-135°.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH3:25][C:26]1[O:27][C:28]([C:34]2[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=2)=[C:29]([C:31](Cl)=[O:32])[N:30]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:31]([C:29]1[N:30]=[C:26]([CH3:25])[O:27][C:28]=1[C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)=[O:32])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Cl)c1
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2nc(C)oc2-c2cccc(C)c2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-methyl-5-m-tolyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.32. LC-MS-conditions 02: tR=1.10 min, [M+H]+=482.06.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21]>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:12]1[CH2:13][CH:14]2[CH:10]([CH2:9][N:8]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)[CH2:15]2)[CH2:11]1)=[O:21]
Reactant: Cc1ccnc(N2CC3CNCC3C2)n1
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)N1CC2CN(c3nccc(C)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 27 and 2-methoxybenzoic acid. MS (ESI): mass calculated for C19H22N4O2, 338.41; m/z found 339.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:35])[N:26]([C@H:28]([CH:33]=O)[CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:27])([CH3:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[C:20]([O:24][C:25](=[O:35])[N:26]([C@H:28]([CH2:33][NH:12][CH2:11][CH2:10][CH2:9][CH:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)C[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](CNCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
4,4-bis-(4-fluorophenyl)-butylamine (200 mg, 0.77 mmol) was dissolved in CH,2Cl2 (5 mL), treated with (S)-(1-formyl-3-methyl-butyl)-methyl-carbamic acid tert-butyl ester (229 mg, 1.0 mmol), stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3 (245 mg, 1.16 mmol), and stirred overnight at room temperature. The reaction was diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 257 mg (70%) of the desired product as an oil. MS: 475.4 (M+1 for C28H40N2O2F2); an oil; TLC (SiO2), Rf 0.26 (4% MeOH/CH2Cl2); HPLC (1:1 CH3CN/H2O with 0.1% TFA, C-18 column) 100%, RT=15.013 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:16]=2)[NH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55][CH3:56]>CN(C=O)C.CS(C)=O>[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][N:55]([CH3:56])[C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[CH:19]=1
Reactant: CNCCN(C)C
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)CCN(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (21 mg, 0.06 mmol) in anhydrous DMF (1 mL) was added HATU (23 mg, 0.06 mmol) and N,N,N′-trimethylethylenediamine (7.9 μL, 0.06 mmol). The reaction solution was stirred 16 hours at ambient temperature then diluted with DMSO (1 mL), filtered through a 0.45 um syringe filter, and purified by reverse phase chromatography in a mobile phase of H2O and acetonitrile (with 0.1% formic acid as the modifier). Clean fractions were combined and lyophilized, affording the title compound as a white powder (14.0 mg, 54% yield). 1H NMR (500 MHz, CD3OD) δ8.51 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.83 (br s, 1H), 7.81 (bs, 1H), 7.69 (s, 1H), 7.60 (m, 2H), 7.49 (m, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.13 (d, 8.5 Hz, 1H), 7.07 (t, J=6.5 Hz, 1H), 3.90 (t J=6.0 Hz, 2H), 3.86 (s, 3H), 3.33 (s, 3H), 3.17 (s, 3H), 2.91 (s, 3H), 2.80 (br s, 2H). MS: m/e 429.1 (M+H+).
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH:18]=3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)[N:10]=1)(C)(C)C.[OH-:34].[Na+]>Cl>[NH2:5][C:6]1[S:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]([NH2:24])=[O:34])[CH:18]=3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)[N:10]=1
Reactant: [OH-]
Reactant: CC(C)(C)NC1=NC2(CS1)CC(c1ccccc1)Oc1ccc(-c3cccc(C#N)c3)cc12
Agent: Cl
Agent: [Na+]
Product: NC(=O)c1cccc(-c2ccc3c(c2)C2(CSC(N)=N2)CC(c2ccccc2)O3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 3-(2′-(tert-butylamino)-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (30 mg, 0.066 mmol) in concentrated HCl (5 mL) was stirred at 100° C. for 2 h. Aqueous NaOH (6 N) was added until pH=8. The mixture was extracted with EtOAc and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzamide (20 mg, 73%).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[C:5](F)=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8].Cl>CN1CCN(C)C1=O>[Cl:3][C:4]1[C:5]([OH:1])=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: Cl
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1ccc(F)c(Cl)c1O
Temperature: 140 °C

Procedure:
Sodium hydroxide (208 g, 5.21 mol) was added in portions to a stirred solution of 3-chloro-2,4-difluorobenzoic acid (200 g, 1.04 mol) in 1,3-dimethyl imidazolidin-2-one (1 L), and the mixture was heated to 140° C. for 2 hours. The reaction mixture was cooled to room temperature and neutralized with ice-cooled 2N HCl (350 mL) precipitating a white solid that was collected by filtration. The filtered solid was dissolved in methyl t-butyl ether (500 mL), washed with saturated brine solution (150 mL) and dried over Na2SO4. Removal of solvent under vacuum afforded the title compound as off white solid. Yield: 180 g (91%). 1H NMR (300 MHz, MeOH-d4) δ: 6.8 (t, 1H), 7.90 (dd, 1H), 11.3 (s, 1H). MS (ES) MH−: 189 for C7H4ClFO3.