Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C:31]([CH3:33])([CH3:32])[O:30][C@:4]2([O:8][C@H:7]3[CH2:9][C@H:10]4[C@@H:15]5[CH2:16][CH2:17][C@H:18]6[CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20][C@:19]6([CH3:25])[C@H:14]5[C@@H:13]([OH:26])[CH2:12][C@:11]4([CH3:27])[C@H:6]3[C@:5]2([OH:29])[CH3:28])[CH2:3]1>N1C=CC=CC=1.O=[Cr](=O)(O[Cr](=O)([O-])=O)[O-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>[CH3:1][C@@H:2]1[C:31]([CH3:32])([CH3:33])[O:30][C@:4]2([O:8][C@H:7]3[CH2:9][C@H:10]4[C@@H:15]5[CH2:16][CH2:17][C@H:18]6[CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20][C@:19]6([CH3:25])[C@H:14]5[C:13](=[O:26])[CH2:12][C@:11]4([CH3:27])[C@H:6]3[C@:5]2([OH:29])[CH3:28])[CH2:3]1.[CH3:1][C@@H:2]1[C:31]([CH3:32])([CH3:33])[O:30][C@:4]2([O:8][C@H:7]3[CH2:9][C@H:10]4[C@@H:15]5[CH2:16][CH2:17][C@H:18]6[CH2:23][C:22](=[O:24])[CH2:21][CH2:20][C@:19]6([CH3:25])[C@H:14]5[C:13](=[O:26])[CH2:12][C@:11]4([CH3:27])[C@H:6]3[C@:5]2([OH:29])[CH3:28])[CH2:3]1
Reactant: C[C@H]1C[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@H](O)CC[C@]6(C)[C@H]5[C@@H](O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[C@H]1C[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6CC(=O)CC[C@]6(C)[C@H]5C(=O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Product: C[C@H]1C[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@H](O)CC[C@]6(C)[C@H]5C(=O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %
Yield: 28 %

Procedure:
Oxidation of hippuristanol (1) to yield hippuristanol 11-one (4) and hippuristanol 3, 11-dione (5). To an ice-cooled solution of hippuristanol (1, 31.7 mg) in pyridine (0.5 mL), Cornforth reagent (0.7 mL) was added dropwise. The mixture was kept stirring for 30 min. in an ice bath, then 3 hr at RT. The mixture was taken up in ether and the suspension was filtered. The filtrate was washed with dilute hydrochloric acid, dried over Na2SO4, and concentrated. The resulting product was separated on silica TLC (CHCl3/EtOAc, 3:1, v/v) to give 8.8 mg of hippuristanol 11-one (4, 28%) and 17.7 mg of hippuristanol 3,11-dione (5, 56%). Hippuristanol 3,11-dione (5). white crystals. mp 181-183.5° C.; 1H NMR (CDCl3) δ 4.42 (m, 2H), 3.02 (s, 1H), 2.82 (ddd, J=13.0, 6.5, 2.0 Hz, 1H), 2.63 (d, J=12.0 Hz, 1H), 2.45 (dt, J=6.5, 14.5 Hz, 1H), 2.37 (dd, J=13.0, 8.0 Hz, 1H), 1.31 (s, 3H), 1.22 (s, 6H), 1.20 (s, 3H), 1.11 (s, 3H), 0.99 (d, J=7.0 Hz, 3H); 13C NMR (CDCl3) δ 211.6, 210.0, 115.0, 84.9, 80.4, 79.1, 63.9, 63.4, 58.8, 54.5, 46.9, 46.3, 44.3, 41.8, 40.5, 38.0, 37.0, 35.5, 35.2, 33.7, 32.4, 28.7, 28.5, 28.2, 23.0, 17.3, 14.8, 11.0; IR (KBr) 3510, 1695 cm−1; EIMS m/z 458 (M+, 5), 316 (92), 84 (100%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: OC1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 78.2 %

Procedure:
To a round bottom flask was added azepan-4-ol (300 mg, 2.60 mmol), 1-fluoro-4-nitrobenzene (368 mg, 2.60 mmol), Cs2CO3 (1018 mg, 3.13 mmol) and DMF (5 mL). The reaction was stirred at 100° C. for 10 hrs. The reaction was diluted with EtOAc (50 ml), washed with water (4×20 ml) and saturated aqueous NaCl (25 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/He) to give the product, 1-(4-nitrophenyl)azepan-4-ol (480 mg, 2.032 mmol, 78% yield) as a light yellow solid. Anal. Calcd. for C12H16N2O3 m/z 236.2, found: 237.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.18-8.03 (m, 2H), 6.71-6.57 (m, 2H), 4.00 (br. s., 1H), 3.74-3.60 (m, 1H), 3.60-3.41 (m, 3H), 2.22-2.01 (m, 2H), 1.95-1.72 (m, 4H); 13C NMR (101 MHz, CDCl3) δ ppm 153.41, 136.89, 126.38, 110.02, 69.88, 49.24, 44.00, 35.87, 34.96, 21.59.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].[CH3:14][N:15](C)[OH:16].[CH3:18][Al](C)C.CCCCCC>C(Cl)Cl>[CH3:18][O:16][N:15]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4]
Reactant: CN(C)O
Reactant: C[Al](C)C
Reactant: COC(=O)c1ccn2ccnc2c1
Solvent: ClCCl
Solvent: CCCCCC
Product: CON(C)C(=O)c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (0.67 g, 3.83 mmol) and dimethylhydroxylamine (0.93 g, 9.57 mmol) in CH2Cl2 (40 ml) at 0° C. was added 2M trimethylaluminium solution in hexane (3.8 ml, 9.57 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h, before being cooled back to 0° C. and quenched with ice. The reaction was filtered and liquid fraction partitioned between CH2Cl2/H2O. The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford the crude product. The residue was purified by silica column chromatography (0-50% MeOH in Et2O) to afford the product (187 mg). MS: [M+H]+=206.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:41](=[O:43])[CH3:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([C:41](=[O:43])[CH3:42])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
To Dowtherm at 250° C. was added Ethyl 2-[(4-bromophenylamino)methylene]-3-oxobutanoate (3.4 g, 10.9 mmol) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (2.2 g, 76%) as a brown solid: ESI MS m/z 266 [C11H8BrNO2+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:13]=1)=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].O=P(Cl)(Cl)[Cl:16].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:16][C:8]1[N:7]=[C:6]2[N:13]=[C:3]([CH2:1][CH3:2])[NH:4][C:5]2=[C:10]([CH3:11])[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2nc(Cl)cc(C)c2[nH]1
Temperature: 80 °C

Procedure:
A mixture of the N-oxide (29.75 g, 0.168 mol), CHCl3 (25 mL) and POCl3 (160 mL) was heated to 80° C. for 1 hours. After pouring over ice, the mixture was neutralized by careful addition of NH4OH and extracted with EtOAc. Concentration gave 23.8 g of 5-chloro-2-ethyl-7-methylimidazo[4,5-b]pyridine as a solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:12]2)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[C:13]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(C=Cc2ccccc2)cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(CCc2ccccc2)cc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.8 %

Procedure:
To a solution of 5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole (204 mg, 0.601 mmol) in EtOH (5 ml) and THF (5 ml) was added 10% palladium on carbon (50 mg). The resulting mixture was stirred under hydrogen (2 atm) for 15 h at room temperature. The mixture was filtered through Celite and washed with EtOH. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (4.5 g) chromatography eluted with chloroform to give 1-methyl-2-(2-phenylethyl)-1H-indol-5-ol (110 mg, 72.8%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[C:19]([OH:22])(=[O:21])[CH3:20].C([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)C>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:27]([CH2:20][C:19]([OH:22])=[O:21])[CH2:28][CH2:29][CH2:30][C:25]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(=O)O
Reactant: CCC1CCCCC1=O
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(Cl)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-chlorophenyl)hydrazine hydrochloride and ethyl-2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:1][C:15](=[O:19])[CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH2:1])[CH2:14][CH2:13][CH2:12]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCCc2cc(OC)ccc21
Product: COc1ccc2c(c1)CCCC(=O)C2
Reaction time: 1 h

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1977, 21, 1827. To a suspension of methyltriphenylphosphonium bromide (11.5 g) in tetrahydrofuran (50 ml) was added dropwise potassium tert-butoxide (1.0 M solution in tetrahydrofuran) (40 ml) on an ice bath under a nitrogen atmosphere, the solution was stirred for 1 hour, then a solution of 6-methoxy-1-tetralone (4.74 g) in tetrahydrofuran (26 ml) was added dropwise thereto followed by stirring for 2.5 hours at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (4.4 g). To a solution of thallium(III) nitrate trihydrate (4.5 g) in methanol (40 ml) was added dropwise a solution of 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (1.7 g) in methanol (13 ml) on an ice bath, and the solution was stirred for 10 minutes at room temperature. Chloroform was added thereto, the solution was stirred, then filtered through celite pad, extracted with diethyl ether, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.7 g).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[C:6]([CH:49]([CH3:51])[CH3:50])=[N:7][N:8]([CH3:48])[C:9]=1[N:10]1[CH2:47][CH2:46][C:13]2[N:14]=[C:15]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:45])=[CH:29][N:30]4S(C3C=CC(C)=CC=3)(=O)=O)[N:16]=[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[C:12]=2[CH2:11]1.[OH-].[K+].[OH-].[NH4+]>ClCCl.O>[Cl:4][C:5]1[C:6]([CH:49]([CH3:51])[CH3:50])=[N:7][N:8]([CH3:48])[C:9]=1[N:10]1[CH2:47][CH2:46][C:13]2[N:14]=[C:15]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:45])=[CH:29][NH:30]4)[N:16]=[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[C:12]=2[CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCCC(C)(C)C6)n4)CN(c4c(Cl)c(C(C)C)nn4C)CC5)cccc32)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1c[nH]c2cccc(-c3nc4c(c(N5CCCC(C)(C)C5)n3)CN(c3c(Cl)c(C(C)C)nn3C)CC4)c12
Temperature: 100 °C

Procedure:
Ethanol (1.8 mL) was added to 6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-(3,3-dimethylpiperidin-1-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (74 mg, 0.108 mmol) in a microwave vial. Next, KOH (61 mg, 1.08 mmol) was added followed by 28% aqueous ammonium hydroxide (0.6 mL, 4.35 mmol). The vessel was sealed and heated via microwave irradiation at 100° C. for 75 minutes. The reaction mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the organic layer was dried by passing through a phase separator. The eluent was concentrated and the resulting residue was purified by reverse phase HPLC (20-55% MeCN/Water (0.1% TFA)). The eluent from the HPLC was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extract was dried by passing through a phase separator and concentrating to provide 6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-(3,3-dimethylpiperidin-1-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:15][CH2:14][CH2:13][Cl:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCl)cc1
Temperature: 2.5 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
In a typical run, p-toluenesulfonyl chloride (TsCl, 70.5 g, 0.37 mol) was added slowly to a solution of 2-chloroethanol (38; 25.0 g, 0.31 mol) in pyridine (100 mL) at 0° C. The reaction mixture was stirred at 0-5° C. for 18 h. Ice water (300 mL) was added and the resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with 1 N HCl (3×100 mL), water (100 mL×3), dried (Na2SO4) and concentrated under reduced pressure to afford 2-chloroethyl 4-methylbenzenesulfonate 39 (64.3 g, 88%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([NH:26][NH:27][C:28](=O)[CH2:29][N:30]1[C:34]([CH2:35][CH3:36])=[C:33]([O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[C:32]([CH2:46][CH3:47])=[N:31]1)(=O)[CH3:24]>O1CCCC1>[CH2:46]([C:32]1[C:33]([O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)=[C:34]([CH2:35][CH3:36])[N:30]([CH2:29][C:28]2[S:10][C:23]([CH3:24])=[N:26][N:27]=2)[N:31]=1)[CH3:47]
Reactant: CCc1nn(CC(=O)NNC(C)=O)c(CC)c1Oc1ccc(C#N)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCc1nn(Cc2nnc(C)s2)c(CC)c1Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
Lawesson's reagent (213 mg, 0.53 mmol) was added to a solution of the acetyl acetohydrazide of step (b) of Example 140 (170 mg, 0.48 mmol) in tetrahydrofuran (10 ml) and the reaction mixture was stirred at room temperature for 18 hours. It was then evaporated to dryness and purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (1:1 then 2:1, by volume) to provide the title compound (80 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([O-:16])=O.C(Cl)(=O)C(Cl)=O.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[F:23][C:24]([F:33])([F:34])[O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:14](=[O:16])[C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=2[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:31][CH:32]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(OC)c(C(=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
1-Ethyl 4-methoxyisophthalate (150 mg) obtained in step D, and 3 μL of N,N-dimethylformamide were dissolved in 10 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 88 μL of oxalyl chloride was added little by little, and the mixture was stirred for 20 minutes at 0° C., followed by stirring the mixture for. 16 hours at room temperature. The reaction mixture was distilled under reduced pressure, and dried to obtain a light yellow solid. This solid was dissolved in 9 mL of dichloromethane, and 3 mL of the solution was added to a solution of 42 mg of 4-trifluoromethoxyaniline and 123 μL of N,N-diisopropylethylamine-dissolved in 2 mL of dichloromethane. The mixture was stirred for 6 hours at room temperature, and then dichloromethane was distilled off under reduced pressure. The resulting residue was purified by column chromatography (5 g of silica gel) using a 1:1 mixture of dichloromethane and n-hexane as an elution solvent, thereby obtaining 79 mg (92%) of ethyl N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamate.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]([O:14][CH3:15])[O:12][CH3:13])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:6]1[C:5]([CH2:4][OH:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cccnc1C(OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COC(OC)c1ncccc1CO
Reaction time: 3 h
Yield: 48.6 %

Procedure:
A mixture of 11.3 g (0.05 mol) of 2-dimethoxymethyl-nicotinic acid ethyl ester dissolved in 150 mL of ether and 2.09 g (0.055 mol) of lithium aluminum hydride is stirred at room temperature for 18 hours. An additional 530 mg of lithium aluminum hydride is added and the reaction mixture stirred for another 3 hours. The reaction mixture is cooled using an ice bath and quenched with 6 mL of 1N NaOH and 8 g of sodium sulfate decahydrate. After a ½ hour the reaction mixture is filtered and the filtrate evaporated. The residue is chromatographed on 180 g of silica gel using ethyl acetate as the eluant. Appropriate fractions are combined and evaporated to yield 4.45 g of (2-dimethoxymethyl-pyridin-3-yl) methanol. 1H NMR (CDCl3) δ8.40 (d, 1H), 7.70 (d, 1H), 7.20 (m, 1H), 5.35 (s, 1H), 4.75 (s, 2H), 3.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5](NN)=[O:6])[C:3]=1[C:12]([NH:14][NH2:15])=[O:13].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1>C(O)(=O)C>[CH:10]1[CH:11]=[C:2]([NH2:1])[C:3]2[C:12]([NH:14][NH:15][C:5](=[O:6])[C:4]=2[CH:9]=1)=[O:13].[C:16]([OH:21])(=[O:22])/[CH:17]=[CH:18]\[C:19]([NH2:1])=[O:20]
Reactant: NNC(=O)c1cccc(N)c1C(=O)NN
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: NC(=O)/C=C\C(=O)O
Product: Nc1cccc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 147.1 %

Procedure:
A mixture of 1.77 grams (0.01 mol) of 3-amino phthalhydrazide and 1.5 grams of maleicanhydride in 10 milliliters of acetic acid was stirred at ambient temperature for 2 hours. The reddish product was filtered and washed with ether. 2.15 grams of luminol-maleamic acid was obtained. IR (KBR) showed bands at 3100; 3020; 2940; 2920; 2600; 1720; 1703; 1650; 1630; 1592; 1560; 1528; 1492; 1460; 1330; 1300; 1285; 1230; 1180 and 1120 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=N2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.ClC1C=CC([C@@H](O)C(F)(F)F)=C(N2CCCC2=[O:52])C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH2:38][CH2:37][CH2:36][C:39]2=[O:52])[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: O=C1CCCN1c1cc(Cl)ccc1[C@@H](O)C(F)(F)F
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2N2CCCC2=O)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-chloro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)pyrrolidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:30])[O:4][N:3]=1.B(F)(F)F.S(C)C>C(Cl)Cl.CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([S:24]([N:27]([CH3:28])[CH3:29])(=[O:26])=[O:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)n(S(=O)(=O)N(C)C)c3ccccc23)cc1
Agent: FB(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1S(=O)(=O)N(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-N,N-dimethyl-1H-indole-1-sulfonamide (23 mg, 0.05 mmol) was dissolved in DCM and the mixture was cooled at 0° C. BF3.SMe2 (0.7 ml) was added drop wise and the reaction mixture was stirred in the fridge for 16 h. A few drops MeOH were added to the cool mixture. The mixture was then extracted with H2O/DCM using an isolute phase separator. Concentration gave a crude product which was purified using HPLC (40-70% AcN, 25 min gradient). 5.6 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-N,N-dimethyl-1H-indole-1-sulfonamide was obtained. ES/MS m/z: 412.06 (M+H), 410.16 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.18 (m, 1H), 7.60 (m, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.12 (m, 2H), 6.88 (m, 2H), 2.70 (s, 6H), 2.10 (s, 3H) and 2.09 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN1CCCC1=O.O>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[CH:7][N:6]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(Nc2ncncc2[N+](=O)[O-])cc1
Reactant: Clc1nc2ccccc2o1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 42.9 %

Procedure:
A mixture of N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (256 mg), 2-chloro-1,3-benzoxazole (110 mg) in N-methylpyrrolidone (3 mL) was stirred at 120° C. for 45 min. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:3 ethyl acetate/methylene chloride) to afford N-1,3-benzoxazol-2-yl-N′-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (107 mg) as a red solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C[N:25](C=O)C>>[Br:8][C:5]1[N:4]=[C:3]2[N:9]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:25]=[N:1][C:2]2=[N:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2nc(Br)cnc2N)C1
Product: CC(C)(C)OC(=O)N1CCCC(Cn2nnc3ncc(Br)nc32)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, 5.70 mmol) was dissolved in DMF (15 ml), and isoamylnitrile (0.92 ml, 6.84 mmol) was slowly dropped at 0° C. After that, the mixture was stirred at 70° C. for 1 hour. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:8), to give tert-butyl 3-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (1.39 g, 62%).