Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:15][C@H:16]([C:18]2[N:23]=[C:22]3[CH:24]=[CH:25][N:26]([CH3:27])[C:21]3=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH3:17])=[N:5][C:6](S(C)(=O)=O)=[N:7][C:8]=1[CH2:9][CH3:10])#[N:2].[NH3:41]>O1CCOCC1.CCOC(C)=O>[NH2:41][C:6]1[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[N:23]=[C:22]3[CH:24]=[CH:25][N:26]([CH3:27])[C:21]3=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:30][CH2:29]2)[CH3:17])[C:3]([C:1]#[N:2])=[C:8]([CH2:9][CH3:10])[N:7]=1
Reactant: N
Reactant: CCc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a 10 mL vial were added tert-butyl (S)-4-(5-(1-((5-cyano-6-ethyl-2-(methylsulfonyl)pyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (32 mg, 0.056 mmol) in dioxane (2 mL) along with 0.5 M ammonia in dioxane (6.09 μL, 0.281 mmol) to give a yellow solution. The vial was sealed and the reaction mixture was stirred overnight at 75° C. The next day LCMS indicated the reaction was incomplete. Additional NH3 solution (2 eq) was added and the reaction mixture was allowed to stir for 6 hours at 75° C. LCMS showed the reaction was mostly complete. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 4 g, 50-100% EtOAc/hexane gradient) to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].[C:12]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(OCCO)C>[C:2]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:22][CH:21]([OH:23])[CH2:20][O:19][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: Cc1cccc(OCC2CO2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1c(O)cccc1OCC(O)COc1cccc(C)c1
Yield: 99.7 %

Procedure:
A solution of 2,6-dihydroxyacetophenone (15.2 g), m-cresylglycidyl ether (16.4 g) and benzyltrimethylammonium hydroxide (10 drops of a 40% solution) in 2-ethoxyethanol (75 ml) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure to give 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-m-cresyloxypropane (31.5 g) as a viscous amber oil.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:29][CH2:30][CH3:31])=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
A mixture of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (50 mg), 1-iodopropane (48 mg) and potassium carbonate (58 mg) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 2 hours. The mixture was poured into ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to preparative thin layer chromatography (hexane-ethyl acetate, 1:1) to afford 2-benzyl-3-oxo-4-(3-propyloxycarbonylphenyl)-3,4-dihydropyrido[2,3-b]pyrazine (18 mg) as powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:7])[CH2:3][OH:4].[N:16]#[C:17]Br>>[Cl:15][C:10]1[CH:9]=[C:8]([CH:6]([CH3:7])[CH2:5][C@H:2]2[CH2:3][O:4][C:17]([NH2:16])=[N:1]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(C[C@H](N)CO)c1ccc(Cl)c(Cl)c1
Reactant: N#CBr
Product: CC(C[C@H]1COC(N)=N1)c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to example 1b (S)-2-amino-4-(3,4-dichloro-phenyl)-pentan-1-ol was reacted with cyanogen bromide to give (5)-4-[2-(3,4-dichloro-phenyl)-propyl]-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). Colourless oil. MS (ISP): 277.1 ([{37Cl}M+H]+), 275.0 ([{37Cl35Cl}M+H]+), 273.1 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:24]([CH3:25])[C:15]2=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]2[N:13]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:24]([CH3:25])[C:15]2=[N:16][CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:14]2[N:13]=1)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2ccccc2SC(C)(C)C)nc2cc(C(F)(F)F)cnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2S(=O)C(C)(C)C)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a mixture of 2-(2-tert-butylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.87 g) and chloroform (12 ml), 3-chloroperbenzoic acid (purity: not less than 65%) (0.95 g) was added under ice-cooling, heated to room temperature, and stirred for 2 hours. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-tert-butylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 16) and 0.52 g of 2-(2-tert-butylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 17).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[O:10][C:4]2[CH:3]=[C:2]([I:1])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:14]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: O=Cc1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1cc2ccc(I)cc2o1)c1ccc(Cl)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 4-iodo-2-hydroxy-benzaldehyde (5.4 g, 22 mmol) and 2-chloro-1-(2,4dichlorophenyl)ethanone (11.2 g, 50.0 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added K2CO3 (12.0 g, 86.9 mmol). The dark brown reaction mixture was stirred at 90 C for 48 h, then poured onto water (150 mL) and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by column chromatography, eluting with 50% hexanes in dichloromethane. The desired product was obtained as an orange solid (2.06 g, 23%). 1H-NMR (CDCl3) δ 7.98 (s, 1H), 7.70 (dd, J=8.3, 1.3 Hz, 1H), 7.54-7.21 (m, 5H).
Reaction SMILES: C(=[N:8][N:9]1[C:14]([S:15][CH2:16][CH3:17])=[N:13][C:12](=[O:18])[N:11]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]1=[O:24])C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:8][N:9]1[C:14]([S:15][CH2:16][CH3:17])=[N:13][C:12](=[O:18])[N:11]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]1=[O:24]
Reactant: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
5.2 g (0.015 mol) of 1-benzylideneamino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H,3H)-dione (V-1), 3 g (0.015 mol) of S-ethyl-isothiosemicarbazide hydrobromide (VI-1, X=Br) and a spatula-tip of p-toluenesulphonic acid in 80 ml of toluene are stirred at 50°-55° C. for 12 hours. After the mixture has cooled, 0.6 g (0.015 mol) of sodium hydroxide in 5.4 g of water is added dropwise and the mixture is stirred at room temperature for 1 hour. The solid which has precipitated is filtered off and dried. 3.75 g (=95% of theory) of 1-amino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H,3H)-dione (I-1) of melting point 204°-205° C. are obtained.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])[CH:21]=[CH2:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Hydroxyphthalimide (48.9 g) was dissolved in DMF (200 ml) and triethylamine (43.9 ml) was added followed by addition of allyl bromide. The reaction mixture was stirred at room temperature for 18 hours and the resulting precipitated material was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate, 4 M HCl aq. and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The remaining material was crystallised from hexane/EtOAc, affording 2-allyloxy-isoindole-1,3-dione (43.6 g). This allyl intermediate (2.03 g) was dissolved in toluene (5 ml) and nitroethane (825 mg), phenylisocyanate (2.4 ml) and triethylamine (0.02 eq.) was added. The reaction mixture was stirred at room temperature for 48 hours, and the precipitated material was removed by filtration. The filtrate was evaporated onto silica gel and chromatographed (0 to 50% EtOAc/heptane) and gave 2-(3-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-isoindole-1,3-dione (2.4 g). 13C-NMR (DMSO-d6) δ 162.9, 155.4, 134.7, 128.5, 123.2, 78.0, 76.9, 40.3, 12.4. This phthalimide intermediate (260 mg) was dissolved in methanol (1 ml) and dichloromethane (1 ml) and hydrazine monohydrate (1.0 eq.) was added. The mixture was stirred at room temperature for 20 hours. The formed solid material was removed by filtration. The filtrate was evaporated under reduced pressure and gave the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[C:31]([O:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cccc(OC)c1C(=O)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (2 g, 7.695 mmol) was dissolved in dichloromethane at -78° C. and treated with 4-methylmorpholine (1.8 mL, 16.4 mmol, 2.1 eq.) and 2,6-dimethoxy-benzoyl chloride (1.55 g, 7.73 mmol) in dichloromethane (20 mL). The solution was allowed to warm to 0° C. and stirred for 1.5 hours. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (200 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 2.434 g (75%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[CH:9][N:8]([CH:16]3[C:20]([CH3:22])([OH:21])[CH:19]([OH:23])[CH:18]([CH2:24][OH:25])[O:17]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)[O:28][NH2:29]>C(O)C>[OH:28][NH:29][C:2]1[C:3]2[C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[CH:9][N:8]([CH:16]3[C:20]([CH3:22])([OH:21])[CH:19]([OH:23])[CH:18]([CH2:24][OH:25])[O:17]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)ON
Reactant: CC1(O)C(O)C(CO)OC1n1cc(-c2cnco2)c2c(Cl)ncnc21
Solvent: CCO
Product: CC1(O)C(O)C(CO)OC1n1cc(-c2cnco2)c2c(NO)ncnc21

Procedure:
The compound from Step 2 is suspended in dry ethanol and O-trimethylsilyl hydroxylamine (10 eq.) is added. The mixture is refluxed for 2 h, evaporated and the crude mixture purified by RP HPLC on a Phenominex column (250×20 mm) using a gradient of acetonitrile in water from 0 to 30% over 30 minutes at 10 mL/minute to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:14]=[N:13][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[N:17][CH:16]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ncc(Cl)cn2)cc1
Temperature: 110 °C
Yield: 89.6 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (555 mg, 4.02 mmol) in DMF (15 mL) was added 2,5-dichloropyrimidine (570 mg, 3.83 mmol) and K2CO3 (635 mg, 4.59 mmol). The mixture was heated at 110° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (861 mg, 3.43 mmol, 90% yield). LCMS: rt=2.38 min, [M+H+]=251
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[N:6][CH:7]=1.O1CCOCC1.[Na+].[I-:22].CN(C)CCN>CCOC(C)=O.[Cu]I>[I:22][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: [I-]
Reactant: Brc1ccc(Oc2cncnc2)nc1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Ic1ccc(Oc2cncnc2)nc1
Temperature: 110 °C

Procedure:
A mixture of 550 mg (2.18 mmol) 5-(5-bromopyridin-2-yloxy)pyrimidine and 2.5 mL 1,4-dioxane is charged with 42 mg (0.22 mmol) CuI, 650 mg (4.36 mmol) NaI and 50 μl (0.44 mmo) N,N-dimethylethylendiamine. The reaction mixture is stirred at 110° C. over night. The mixture is allowed to cool down to r.t. and diluted with EtOAc. The mixture is washed with 5% aq. ammonia solution and water. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo to yield the desired product without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:75]=[CH:74][C:65]([CH2:66][N:67]2[CH2:72][CH2:71][CH2:70][CH:69]([OH:73])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:75]=[CH:74][C:65]([CH2:66][N:67]4[CH2:72][CH2:71][CH2:70][CH:69]([OH:73])[CH2:68]4)=[CH:64][CH:63]=3)[CH3:59])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CNCc1ccc(CN2CCCC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.036 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}piperidin-3-ol dihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:19].[CH3:20][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH3:22].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(O)C>[ClH:19].[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH:21]([CH3:22])[CH3:20])[CH:14]2[CH2:13][CH2:12][C:11]([C:17]#[N:18])([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][CH2:15]2)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1OC
Reactant: COc1ccc(CCCCNC(C)C)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CCCCN(C(C)C)C2CCC(C#N)(c3ccc(OC)c(OC)c3)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexane (5 mmol), N-(1-methylethyl)-4-(3,4-dimethoxyphenyl) butylamine hydrochloride (5 mmol), triethylamine (6 mmol) and sodium cyanoborohydride (6 mmol) in 25 ml ethanol was stirred at 25° C. for 72 hours and worked up and recrystallized. ##STR8##
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:31])C(=O)C1>C(Cl)Cl>[I:31][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To the solution of 1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (2.3 g, 9.73 mmol) in CH2Cl2 (6 ml) was added TFA (3.0 ml, 38.9 mmol), and NIS (2.41 g, 10.71) at rt. After being stirred at rt for 3 h, the reaction mixture was diluted with CH2Cl2, quenched with NaHCO3 (aq), washed with aq Na2S2O3, water and brine. Dried over Na2SO4, filtered and concentrated to afford 5-iodo-1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (3.4 g) which was used in the next step without further purification. LCMS: [M+1]+=363.0
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[C:8]([C:11]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:21]=[CH:20]4)([OH:16])[C:12]([F:15])([F:14])[F:13])[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=[O:36]>O.O1CCOCC1.C([O-])(O)=O.[Na+]>[F:13][C:12]([F:15])([F:14])[C:11]([C:8]1[C:4]2[N:5]=[CH:6][NH:7][C:2](=[O:36])[C:3]=2[NH:10][CH:9]=1)([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[N:21]=[CH:20]2)[OH:16]
Reactant: O=C(O)C(F)(F)F
Reactant: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2c(Cl)ncnc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]cnc2c(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)c[nH]c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
A mixture of 1-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol (43 mg, 0.09 mmol) and 1 mL of trifluoroacetic acid in 1 mL of water and 2 mL of dioxane was warmed at 70° C. After 18 hours, the reaction was diluted with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was dissolved in 1 mL of DMF and purified by reverse phase HPLC (5-95% CH3CN/water+0.1% TFA). The desired fractions were combined and the CH3CN was removed in vacuo. The aqueous layer was made basic with saturated sodium bicarbonate and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo to provide 18 mg (44%) of the title compound as a white solid. MS m/z 444.27 (MH+).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:20])[CH2:17][NH:18][CH3:19])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[CH:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)=O.C(O)(=O)C>CO>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH3:20])[CH2:17][N:18]([CH2:21][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[CH3:19])=[CH:13][CH:14]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: Cn1cc(C=O)cn1
Reactant: CNCC(C)Cc1ccc(C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN(C)Cc1cnn(C)c1
Reaction time: 8 h

Procedure:
Route B-2: After suspending 200 mg (3.2 mmol) of sodium cyanoborohydride in 2 ml of absolute methanol, 380 mg (1.7 mmol) of 3-(4-t-butylphenyl)-N,2-dimethylpropylamine (IV-1) was added thereto. Subsequently, to this was added a solution of 170 mg (1.6 mmol) 4-formyl-1-methylpyrazole/2 ml absolute methanol by portions, the pH was adjusted to 7 with acetic acid, and then stirring was conducted at room temperature for 8 h.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:18][C@H:19]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:20]1[CH3:34])(=O)=O>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][CH:19]2[CH:20]([CH3:34])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:22](=[O:24])[CH2:23]2)[CH:6]=1
Reactant: COc1ccc(CN2C(=O)C[C@H](COS(C)(=O)=O)[C@H]2C)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)CC(Cn3cc(I)cn3)C2C)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4-Iodo-1H-pyrazole (0.93 g, 4.77 mmol) and cesium carbonate (2.59 g, 7.95 mmol) were added to a solution of [(2R,3S)-1-(4-methoxybenzyl)-2-methyl-5-oxopyrrolidin-3-yl]methyl rac-methanesulfonate (1.3 g, 3.98 mmol) in DMF (26 mL). The mixture was stirred at 90° C. under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford rac-(4R,5R)-4-[(4-iodo-1H-pyrazol-1-yl)methyl]-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one. MS ESI calc'd. for C17H21IN3O2 [M+H]+ 426. found 426. 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.17 (d, J=8.5 Hz, 2H), 6.95 (s, 1H), 6.90 (d, J=8.5 Hz, 2H), 4.99-4.94 (m, 1H), 4.02-3.99 (m, 1H), 3.90-3.85 (m, 1H), 3.85 (s, 3H), 3.82-3.79 (m, 1H), 3.15-3.06 (m, 1H), 2.69-2.63 (m, 1H), 2.58-2.48 (m, 1H), 2.18-2.09 (m, 1H), 1.06 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7].S(Cl)([Cl:13])=O>>[Br:1][CH2:2][CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:13])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CCBr)CC(=O)O
Product: CC(C)(CCBr)CC(=O)Cl
Yield: 89 %

Procedure:
5-Bromo-3,3-dimethylpentanoic acid (40 g, 0.192 mol) was converted into the corresponding acid chloride by heating it on a water bath with thionyl chloride (29.6 g, 1.3 equivalents). The title compound was obtained by vacuum distillation as a colourless liquid, 38.8 g (89% yield), b.p. 77° C./0.75 mm Hg. 1H NMR (CDCl3) δ3.40 (2H, t), 2.85 (2H, s), 2.00 (2H, t), and 1.10 (6H, s).