Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:29][Si:30]([CH3:37])([CH3:36])[CH2:31][CH2:32][O:33][CH2:34]Cl.C(NC(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][O:33][CH2:32][CH2:31][Si:30]([CH3:37])([CH3:36])[CH3:29])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1cccc2c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 1,1-dimethylethyl 3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 6) (2.21 g, 4.98 mmol) in DCM (20 mL) was added at 0° C. 2-(trimethylsilyl)ethoxymethyl chloride (1.23 mL, 6.97 mmol). Then was added at 0° C. in a dropwise fashion diisopropylamine (1.419 mL, 9.96 mmol) and the reaction mixture was stirred at room temperature. The reaction was quenched with water (50 mL), the organic layer was separated, and the aqueous layer was further extracted with 30 mL of DCM. The organic solutions were combined, dried with an hydrophobic frit and concentrated under reduced pressure to give a yellow oil that was used without further purification (3.12 g) LCMS (System A) RT=1.64 min, ES+ve m/z 574/576 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:21])=[C:5]2[C:14](=[O:15])[C:13]3[C:8](=[C:9]([O:18]C)[CH:10]=[CH:11][C:12]=3[O:16]C)[C:7](=[O:20])[C:6]=12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:21][C:4]1[O:3][C:2]([CH3:1])=[C:6]2[C:7](=[O:20])[C:8]3[C:13](=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=3[OH:18])[C:14](=[O:15])[C:5]=12
Reactant: COc1ccc(OC)c2c1C(=O)c1c(C)oc(C)c1C2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1oc(C)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
In accordance with the Flowchart I, 2,5-dimethyl furan (formula 12) is reacted in step A with CH3CO2 (--C≡C--)CO2CH3 (formula 13) to produce 1,4-dimethyl-7-oxabicyclo[2,2,1]octa-2,5-diene-2,3-dicarboxylic acid, dimethyl ester (formula 14). The latter is catalytically hydrogenated in ethyl acetate (step B) to produce 2,5-dimethyl-3,4-furandicarboxylic acid, dimethyl ester (formula 15), which is treated with aqueous base at reflux for several hours and then acidified to produce 2,5-dimethyl-3,4-furandicarboxylic acid (formula 16). The latter is then treated (Step D) with thionyl chloride at reflux to produce 2,5-dimethyl-3,4-furandicarbonyl chloride (formula 17), which is then reacted in Step E with 1,4-dimethoxybenzene and anhydrous stannic chloride in dichloromethane at 0°-5° C. for several hours, and then acidified under an inert atmosphere. The product is extracted at 40°-45° C. in chloroform and chromatographed, to produce 1,3-dimethyl-5,8-dimethoxynaphtho[2,3-c]furan-4,9-dione (formula 18). Such dione (18) is then treated in step F with anhydrous aluminum chloride in dichloromethane at 40°-45° C. for several hours, acidified and extracted at 50°-55° C. into chloroform and crystallized from glacial acetic acid, to produce 1,3-dimethyl-5,8-dihydroxynaphtho[2,3-c]furan-4,9-dione (formula 19). The latter is then treated in step G with lead tetraacetate in acetic acid and extracted with dichloromethane, to produce 1,3-dimethylnaphtho-[2,3-c]furan-4,5,8,9-tetrone (formula 20).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH2:40][CH2:41][O:42][CH2:43][CH:44]=2)O1>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>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:39]4[CH2:44][CH2:43][O:42][CH2:41][CH:40]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCOCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, cesium carbonate, 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran and tetrakis(triphenylphosphine)palladium (0). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.85 (t, J=6.00 Hz, 1H), 7.95-8.05 (m, 3H), 7.77 (d, J=9.00 Hz, 1H), 6.98 (s, 1H), 4.33-4.35 (m, 2H), 3.86 (t, J=5.48 Hz, 2H), 3.26-3.28 (m, 2H), 2.66-2.70 (m, 2H), 2.00-2.07 (m, 2H), 1.74-1.87 (m, 5H), 1.23-1.31 (m, 2H). m/z: 421 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 4 from above was coupled with tyramine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 456. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.5 (d, 1H) 8.1 (m, 2H) 8.0 (s, 2H) 7.6 (m, 2H) 7.4 s, 1H) 7.0 (d, 2H) 6.7 (d, 2H) 4.5 (s, 2H) 3.6 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.8 (m, 2H) 2.7 (m, 2H) 1.8 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][N:10]2[C@@H:4]([CH2:5][N:6]([C:16](=[O:38])[C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:18]=3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9]2)[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.[ClH:61]>CS(C)=O>[ClH:61].[C:31]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([N:6]3[C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[CH2:9][N:10]4[CH2:11][C:2](=[O:1])[CH2:3][C@@H:4]4[CH2:5]3)=[O:38])=[CH:18][CH:19]=2)=[O:37])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Nc1ccc(C(=O)N2C[C@H]3C[C@@H](O)CN3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C1C[C@@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3CN2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.2 %

Procedure:
To a solution of (2R,11aR)-2-hydroxy-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.4 g) prepared in Example 45 and obtained in the form of free base in dimethyl sulfoxide (8 ml), there was added, at room temperature, 1.6 g of N,N′-dicyclohexyl carbodiimide and 0.135 g of trifluoroacetic acid. After stirring the reaction solution at room temperature for 15 hours, a 6N hydrochloric acid solution was added thereto and the reaction solution was stirred for additional 30 minutes. The precipitates separated out were filtered off and washed with water. The filtrate and the wash liquid were combined, the mixture was alkalified with a saturated aqueous solution of sodium carbonate and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/acetone (4/1) to thus give 0.23 g of (11aR)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-2-one in the form of amorphous powder. The resulting amorphous powder (0.23 g) was dissolved in ethyl acetate and 0.12 ml of a 4N hydrochloric acid-ethyl acetate solution was added to the resulting solution at room temperature. After stirring the mixture at room temperature for one hour, the resulting precipitates separated out were recovered by filtration, followed by washing them with ethyl acetate and then dried to thus give 0.15 g (yield 34.2%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COc2ccccc2-c2ccc[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccccc1-c1ccc[nH]1

Procedure:
150 mg of 10% strength palladium-on-charcoal catalyst are added to 1.5 g (6 millimoles) of 2-(o-benzyloxyphenyl)-pyrrole in 30 ml of methanol and hydrogenation is carried out under slightly superatmospheric pressure. The residue which remains after separating off the catalyst and evaporating the solution is recrystallized from a mixture of toluene and petroleum ether (boiling range 40°-60° C.). The yield of 0.8 g corresponds to 84% of theory; melting point 100°-101° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[N:14][CH:15]=1)[CH3:9])=[O:6].[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:16][C:13]1[N:12]=[CH:11][C:10]([C@H:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:27]#[N:28])[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[CH:17]=2)=[O:6])[CH3:9])=[CH:15][N:14]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(-c3ccccc3C#N)c2)nc1

Procedure:
In a 5 mL microwave vial, (R)-3-bromo-5-(5-methylpyridin-2-yl)-N-(1-(2-methylpyrimidin-5-yl)ethyl)benzamide (50.00 mg, 0.1216 mmol), 2-cyanophenylboronic acid (35.72 mg, 0.2431 mmol), cesium carbonate (198.0 mg, 0.6078 mmol), tetra-n-butylammonium iodide (44.90 mg, 0.1216 mmol), and POPd (6.100 mg, 0.01216 mmol) were dissolved in Water (0.09 mL, 5 mmol) and N,N-dimethylformamide (0.4 mL, 6 mmol). The reaction mixture was microwaved for 20 mins at 150 degrees. The reaction was purified directly by reversed phase HPLC (acetonitrile:water gradient) at pH 10. The combined pure fractions were reduced in vacuo to afford the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[CH2:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-amino-3H-benzoxazol-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 142b. Melting Point: 204-206° C. (diethylether)
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.O>CC(=O)CC>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CNC(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CNC(=O)COc1ccc(OCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91 %

Procedure:
A solution of 500 mg of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide in 25 ml of 2-butanone was treated with 762 mg of potassium carbonate and 595 mg of 4-bromomethyl-benzonitrile. The reaction mixture was stirred at room temperature for 60 h. For the working-up, the reaction mixture was treated with water, then extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in ether and the crystals obtained were collected on a filter funnel. After drying there were obtained 744 mg (95% of theory) of 2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=297 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:1]([NH:7][C:26]([C:16]1[N:17]([CH3:25])[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=1)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)c1nc(-c2ccccc2)c(-c2ccccc2)n1C

Procedure:
Using essentially the same procedure as Example 4, Step B, but using n-hexylamine (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][Si](C(C)(C)C)(C)C)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCOC(=O)Cn1ccc2c(O)cccc21

Procedure:
In analogy to the procedure described in example 6 b], [4-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester was treated with tetrabutylammonium fluoride hydrate to obtain (4-hydroxy-indol-1-yl)-acetic acid ethyl ester as yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:32])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[OH:32][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:7][CH2:6][N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]4[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=4[C:15]=3[C:14]=2[CH:13]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCn1ccnc1
Yield: 50 %

Procedure:
Mesylate (205) (70 mg, 0.16 mmol) prepared as described in example 174 was reacted with imidazole according to the procedure described in example 179 to give amine (213) (34 mg, 50%) as a yellow powder, mp>345° C. 1H NMR δ [(CD3)2SO] 11.05 (br s, 1H), 9.34 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.59 (m, 2H), 7.45 (m, 5H), 7.27 (s, 1H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (s, 1H), 6.75 (s, 1H), 4.80 (t, J=5.7 Hz, 2H), 4.41 (t, J=5.7 Hz, 2H). Found: C, 70.36; H, 4.38; N, 12.68. C25H18N4O3.1/4H2O requires: C, 70.33; H, 4.37; N, 13.12.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([O:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH:22]([C:24](OCC)=[O:25])[NH2:23]>CN1C(=O)CCC1.CCOC(C)=O>[O:25]=[C:24]1[NH:22][N:23]=[C:1]([C:3]2[N:8]=[C:7]([O:9][C@H:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=2)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(C#N)n2)C1
Reactant: CCOC(=O)NN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(-c3n[nH]c(=O)[nH]3)n2)C1
Temperature: 175 °C

Procedure:
To crude (S)-tert-butyl 3-((6-cyanopyridin-2-yl)oxy)pyrrolidine-1-carboxylate (1.044 g) in NMP (1.5 mL) was added ethyl hydrazinecarboxylate (0.752 g, 7.22 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled and diluted with EtOAc. The organic phase was washed with saturated aqueous NH4Cl, dried, and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH3:28])=[C:21]([CH:24]=3)[C:22]#[N:23])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8]C(C)C.ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH3:28])=[C:21]([CH:24]=3)[C:22]#[N:23])[O:14][N:13]=2)=[CH:3][C:2]=1[I:1]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1C#N
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1C#N
Yield: 74 %

Procedure:
When the product of Step B was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 74% yield, as creamy solid. 1H NMR (CDCl3) 8.46 (d, 1H, J=1.95 Hz); 8.4 (d, 1H, J=2.13 Hz); 8.31 (dd, 1H, J=8.88, 2.19 Hz); 8.02 (dd, 1H, J=8.49, 1.68 Hz); 7.1 (d, 1H, J=8.94 Hz); 7.09 (d, 1H, J=8.49 Hz); 5.64 (bs, 1H); 4.12 (t, 2H, J=6.48 Hz); 2.02-1.86 (m, 2H); 1.1 (t, 3H, J=7.38 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:14]2[N:15]=[CH:16][C:11]3[CH:10]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=3[N:13]=2)=[CH:28][CH:27]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(Cl)cc3)nc21
Temperature: 238 °C
Reaction time: 0.08 h

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 in 0.50 g (3.90 mmol) of 4-chloroaniline was heated, with stirring, at the boiling point (238° C.) for 5 minutes. Ethyl acetate (3 mL) was added to the cooled dark blue reaction solution. Petroleum ether (3 mL) was added to completed precipitation of a dark solid. This was filtered and washed with 50% hexane-ethyl acetate; wt 0.078 g. The crude solid was purified to remove dark colors by silica gel chromatography, eluting with chloroform and then 50% hexane-ethyl acetate to obtain pure crystalline product; wt 0.056 g; mp 255°-256° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:33]1[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]1>O>[CH3:7][C:6]1[N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:33]1[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]1
Reactant: Cc1c(I)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-iodo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (700.0 mg, 1.789 mmol) in THF (20 mL, 300 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (5.5 mL, 7.2 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL, 8.9 mmol), and allowed to stir at rt for 2 h. Water was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 10% EtOAc/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.30 (s, 12H), 1.48 (s, 9H), 1.84 (d, J=10.4 Hz, 2H), 1.99 (dtd, J=12.6, 12.3, 12.3, 4.5 Hz, 2H), 2.47 (s, 3H), 2.94 (br. s., 2H), 4.21 (d, J=13.6 Hz, 2H), 4.30-4.42 (m, 1H), 7.57 (s, 1H). MS (ES+): m/z=391.26/392.26/393.27 (50/100/50) [MH+]. HPLC: tR=1.70 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([NH2:25])[CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:23]1[CH:24]=[C:19]([CH3:18])[CH:20]=[CH:21][C:22]=1[S:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Nc1cc(C)ccc1Sc1ccccc1

Procedure:
The product from Example 20a (438 mg, 2.03 mmol) was reacted with the product from Example 7f (510 mg, 2.03 mmol) for 10 min following the procedure from Example 7g giving the title compound which was purified by silica gel column chromatography eluting with 4% MeOH/CH2Cl2 as a solid (114 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (t, J=6.99 Hz, 3 H) 2.16 (s, 3 H) 2.62 (s, 3 H) 4.29 (q, J=7.11 Hz, 2 H) 6.86 (s, 1 H) 7.04 (d, J=8.09 Hz, 1 H) 7.15-7.34 (m, 6 H) 7.39 (d, J=7.72 Hz, 1 H) 7.69 (d, J=8.82 Hz, 1 H) 9.17 (s, 1 H) 10.13 (s, 1 H); MS (ESI+) m/z 430 (M+H)+, (ESI−) m/z 428 (M−H)−.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[N:21]3)[C:17]([Cl:29])=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6].Cl>C1COCC1.O>[N:20]1([C:18]2[C:17]([Cl:29])=[CH:16][N:15]=[C:14]([NH:13][C@H:10]3[CH2:9][CH2:8][C@H:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]3)[N:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: COC(=O)C1CCC(Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of NaOH (2 M, 10 mL) was added to a colorless solution of 4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexanecarboxylic acid methyl ester (482 mg, 1.25 mmol) in THF (10 mL) at RT. The reaction mixture was stirred at RT overnight; it was then diluted with water (15 mL) and acidified until pH 3 by addition of HCl (2 M). The white precipitate formed was collected by filtration, washed with water and air dried to give 435 mg (85% yield) of trans-4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexane-carboxylic acid as a white solid. MS: 373.12 (M+1)+, 345.15 ((M+1)+−28).