Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](COCC[Si](C)(C)C)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc(-c3nn(COCC[Si](C)(C)C)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCC1CCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 70 °C
Yield: 50.2 %

Procedure:
To a solution of tert-butyl (1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-yl)methylcarbamate (190 mg, 0.31 mmol) in dioxane (5 mL), was added 10% HCl (1 mL). The reaction mixture was heated at 70° C. for 2 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via reverse phase prep-HPLC eluting with 40% to 80% MeOH in aqueous 0.1% NH4OH solution to afford 278 as a yellow solid (60 mg, 50%). 1H NMR (400 MHz, DMSO) 9.23 (s, 2H), 8.95 (s, 1H), 8.61-8.60 (d, J=2.8, 1H), 8.40-8.38 (m, 1H), 7.68-7.65 (m, 1H), 7.58-7.55 (m, 1H), 7.48-7.46 (m, 1H), 4.96 (s, 1H), 4.53-4.50 (d, J=10.4, 1H), 3.38-3.36 (m, 3H), 2.69-2.68 (d, J=4, 2H), 188-1.86 (d, J=8.3H), 1.32-1.30 (m, 3H). ESI MS m/z=385.2 (M+1)
Reaction SMILES: [K].Cl[C:3]([O:5][CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])=[O:4].Cl.C[N:13]1[CH2:18][CH2:17][C@H:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C@H:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:14]1>C1C=CC=CC=1>[C:30]1([C@H:15]2[C@@H:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[CH2:17][CH2:18][N:13]([C:3]([O:5][CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])=[O:4])[CH2:14]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Agent: Cl
Agent: [K]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.46 g of anhydrous potassium carbohate and 0.5 ml of 2,2,2-trichloroethyl chloroformate are added under nitrogen to a solution of 1.11 g of the free base of cis-1-methyl-3-phenyl-4-(4-trifluoromethylphenoxy)piperidine of Example 22 in 10 ml of dry benzene. After 1 hour at room temperature the mixture is refluxed 18 hours. Another 0.045 ml of 2,2,2-trichloroethyl chloroformate is added, the mixture is again refluxed 18 hours, then cooled and partitioned between ether and water. The organic phase is washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to an oil. This material is dissolved in benzene and filtered through a column of silica gel, then is further purified by preparative chromatography on five 2 mm silica preparative plates, using 3:1 petroleum ether as solvent. A nearly colorless glass of cis-3-phenyl-1-(2,2,2-trichloroethoxycarbonyl)-4-(4-trifluoromethylphenoxy)piperidine is obtained.
Reaction SMILES: [Cl-].[NH4+].O1CCOCC1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH:19][CH:20]=[O:21])=[C:14]([OH:22])[CH:13]=1)([O-])=O>[Fe].O>[NH2:9][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH:19][CH:20]=[O:21])=[C:14]([OH:22])[CH:13]=1
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(NNC=O)c(O)c1
Yield: 77.3 %

Procedure:
A mixture of 120 g of iron powder, 5 g of ammonium chloride, 2 liters of dioxane, and 800 ml of water was heated on a steam bath with stirring and after adding thereto 61 g of 2-(4-nitro-2-hydroxyphenyl)-1-formylhydrazine with stirring, the resultant mixture was refluxed for 40 minutes. Then, insoluble matters were distilled off the filtrate was concentrated under reduced pressure, and water was added to the residue. Crystals thus formed were collected by filtration and washed with acetonitrile to provide 40 g of the desired compound with a yield of 79%.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[NH:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:33]([C:30]3[NH:29][C:28]([CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:32][CH:31]=3)=[O:34])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)NCc1ncc(C(=O)O)[nH]1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnc(CNC(=O)OC(C)(C)C)[nH]1

Procedure:
(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (108 mg, 0.42 mmol) was coupled with 2-(tert-Butoxycarbonylaminomethyl)-1H-imidazole-5-carboxylic acid (100 mg, 0.42 mmol) using the method of Example 34(d). After extraction a quantitative yield of the title compound was obtained.
Reaction SMILES: CN([SiH3])[Si:3]([CH3:6])(C)[CH3:4].[F:8][C:9]([F:20])([F:19])[C:10]([O:12]C(=O)C(F)(F)F)=[O:11]>>[F:8][C:9]([F:20])([F:19])[C:10]([O:12][SiH:3]([CH3:6])[CH3:4])=[O:11]
Reactant: CN([SiH3])[Si](C)(C)C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[SiH](C)OC(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing tetramethyldisilazane as the silicon compound D with trifluoroacetic anhydride as the acid D, the trifluoroacetic anhydride immediately reacts therewith to form dimethylsilyl trifluoroacetate as the silicon compound B.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Cl[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1>CN(C)C=O>[C:17]([C:15]1[CH:16]=[C:11]([CH2:10][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])[CH:12]=[CH:13][C:14]=1[OH:20])(=[O:19])[CH3:18]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: O=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CN2CCNC2=O)ccc1O
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20.0 mmol) in 15 mL dry dimethylformamide under argon, cooled in an ice-bath was added dropwise a solution of 2-imidazolidone (1.72 g, 20.0 mmol) in 5 mL dimethylformamide. The ice bath was removed, the mixture was stirred 30 minutes and a solution of 5'-chloromethyl-2'-hydroxyacetophenone (1.85 g, 10.0 mmol) in 5 mL dimethylformamide was added dropwise. The mixture was stirred four hours and the product was isolated in the same manner as in the previous example to give a solid. The solid was stirred under 20 mL n-butylchloride, filtered off, and dried in vacuo to give 1.01 g (43%) product as a white solid, mp 131°-133° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10](=[O:11])[NH:9][C:8]2[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[CH:14][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][C:30]1[N:31]([CH3:35])[N:32]=[CH:33][N:34]=1>CN(C)C=O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]2[CH:14]=[N:13][N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]2=[N:9][C:10]=1[O:11][CH2:29][C:30]1[N:31]([CH3:35])[N:32]=[CH:33][N:34]=1)([CH3:1])[CH3:3]
Reactant: Cn1ncnc1CCl
Reactant: CC(C)(C)c1cc2cnn(-c3ccccc3)c2[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)cc1C(C)(C)C
Temperature: 60 °C
Yield: 71.1 %

Procedure:
To a solution of 1,7-dihydro-5-(1,1-dimethylethyl)-1-phenylpyrazolo[3,4-b]pyridin-6-one (26 mg, 0.097 mmol) in dry N,N-dimethylformamide (4 ml) under nitrogen was added cesium carbonate (95 mg, 0.29 mmol) followed by 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (25 mg, 0.15 mmol). The reaction mixture was heated at 60° C. for 17 h. The mixture was then allowed to cool and partitioned between water and diethyl ether. The aqueous phase was extracted a second time with diethyl ether and the combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a white solid (25 mg, 71%), m.p. 143-145° C. δH (400 MHz; CDCl3) 1.40 (9H, s), 3.93 (2H, s), 5.69 (1H, s), 7.29-7.32 (1H, m), 7.49-7.53 (2H, m), 7.93 (1H, s), 7.98 (1H, s), 8.05 (1H, s), 8.19-8.21 (2H, m); m/z (ES+) 363 (M+H+)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)[nH]c1N
Reaction time: 48 h

Procedure:
In a dry three-necked flask, under argon, 75 ml of abs. ethanol and 6.5 g (390 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [for preparation see: Liebigs Ann. Chem., 1895 (1977)] are cooled to 0-5° C. and 2.65 g (390 mmol) of sodium ethanolate are added thereto. Then 5 g (195 mmol) of 2-bromo-1-(4-nitro-phenyl)-ethan-1-one are added and the reaction mixture is allowed to come to RT and then stirred for 48 hours. The reaction mixture is then partitioned between water and ethyl acetate. The ethyl acetate phase is washed three times with water and once with saturated NaCl solution, dried and filtered and the filtrate is concentrated by evaporation. The red-brown residue is suspended in hexane and the title compound precipitates in the form of the crude product (purity 93%), which is used for the next step without further purification; MS: (M)+ =275.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[K].[C:23]([SH:27])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([S:27][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: CC(C)(C)S
Agent: [K]
Product: CC(C)(C)Sc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with the potassium derivative of tertbutanethiol to obtain 4-(tert-butylthio)-7-nitro-2,5-bis-(trifluoromethyl)benzimidazole, m.w., 387.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:40]N(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([C@H:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)([C@H](C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate (0.040 g, 0.067 mmol) from Step A above and HMPA (0.012 mL, 0.067 mmol) in anhydrous THF (1 mL) was added LDA, 2.0M in THF (0.037 mL, 0.074 mmol) at −78° C. Let it stir for 0.5 h at −78° C. Then iodomethane (0.057 mL, 0.913 mmol) was added. After stirring for 1 h, the reaction was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and the filtrate was concentrated under the reduced pressure to provide a yellow oil. This was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[C:13]([CH3:16])([OH:15])[CH3:14].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:12]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[C:9]([F:11])[CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[C:13]([OH:15])([CH3:16])[CH3:14])=[CH:24][CH:23]=1
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cc(F)cc21)C(C)(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cc(F)cc21)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound 3-(4-amino-6-fluoro-1H-indol-1-yl)-3-(4-chlorophenyl)-2-methylpentan-2-ol (176 mg, 0.489 mmol) and NMM (145 mg, 1.467 mmol) in DCM (10.0 mL) was added methanesulfonyl chloride (112 mg, 0.978 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (50 mL). The organic layers was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by Prep-TLC (eluent: ethyl acetate/petroleum=4:1) to obtain the title compound. LC/MS m/z=438.9 [M+H]+. 1H NMR (400 MHz, MeOD) δ 8.02 (s, 1H), 7.57-7.25 (m, 4H), 6.86 (dd, J=10.9, 2.1 Hz, 1H), 6.74 (d, J=3.6 Hz, 1H), 5.85 (d, J=11.1 Hz, 1H), 3.00 (s, 3H), 2.84-2.73 (m, 1H), 2.61-2.47 (m, 1H), 1.31 (s, 3H), 1.27 (s, 3H), 0.64 (t, J=7.3 Hz, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1
Reactant: OC1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidin-4-ol (see EXAMPLE 1.1; 94 mg, 0.25 mmol) was dissolved in anhydrous CH2Cl2 (10 mL), treated with Dess-Martin periodinane (DMP) (195 mg, 0.50 mmol, 2.0 equiv) and stirred at room temperature until complete conversion. The organic layer was washed with an aqueous solution of NaHCO3/Na2S2O3 (3×10 mL)), dried over Na2SO4, filtered and evaporated. The resulting residue was purified by flash chromatography (20% to 40% EtOAc in petroleum ether) to 1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidin-4-one (75 mg, 0.20 mmol, 80% yield) as a white solid. ESI-MS (M+1): 376 calc. for C21H21N5O2 375.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11]C)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br-].O.[CH2:17]1COCC1>>[CH3:17][CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(CC)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diethyl methylmalonate (5.19 g) in 100 mL of THF was added NaH (1.2 g, 60%) at 0° C. in portions. The mixture was stirred at 0° C. for 10 min, and to this solution was then added the bromide intermediate (3.84 g) in one portion. The mixture was warmed to 23° C. and stirred for 1 h before the addition of water. The resulting mixture was extracted with ethyl acetate, concentrated and purified by Biotage (5-10% ethyl acetate in hexane) to give the diester containing some diethyl methyl malonate contaminant as a crude oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:38])[C@H:27]([CH2:36][SH:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH3:24][O:25][C:26](=[O:38])[C@H:27]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:36][S:37][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[CH2:12][CH2:11]2)=[O:23])=[N:4][CH:3]=1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Br)s2)C2CCCCC2)CC1
Product: COC(=O)[C@@H](CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1)NC(=O)OC(C)(C)C

Procedure:
Prepared in 60% (333 mg) yield as described in general procedure (D) using trans-3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-methyl-cyclohexyl)-urea (400 mg, 1.0 mmol) and N-(tert-butoxycarbonyl)-L-cysteine methyl ester (470 mg, 2.0 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]Cl)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[CH2:29][NH:28][CH2:27]1.Cl>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:28]3[CH2:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[CH2:27]3)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: CC1(C)CNCC1(C)C
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1[nH]c2ccc(OCCN3CC(C)(C)C(C)(C)C3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (Example 1, Step A, 0.300 g, 0.873 mmol), 3,3,4,4-tetramethyl-pyrrolidine; hydrochloride (0.571 g, 3.49 mmol), K2CO2 (0.724 g, 5.234 mmol), and KI (0.014 g, 0.087 mmol) in 17.5 mL of acetonitrile was heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated to give 0.379 g (42.0%) of a white solid: mp 181-182° C.;IR(KBr)3283, 2961, 1671, 1652, 1457, 1171, 1074 cm−1; 1HNMR (400 MHz, DMSO-d6) δ 0.85 (s, 12H, NCH2C(CH3)2), 2.46 (s, 3H, CCH3), 2.60 (s, 4H, NCH2C(CH3)2), 2.81-2.84 (m, 2H, OCH2CH2),3.83 (t, J=6.12 Hz, 2H, OCH2CH2), 5.27 (s, 2H, OCH2Ar), 6.67 (dd, J=8.31, 3.20 Hz, 1H, ArH), 7.20 (d, J=8.40 Hz, 1H, ArH), 7.23-7.40 (m, 4H, ArH), 7.46 (d, J=7.89 Hz, 2H, ArH), 11.70 (s, 1H, NH); MS(APCI+): m/z 435.3 (MH+). Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C, 74.31; H, 7.98; N, 6.19.
Reaction SMILES: Cl.F[C:3]1[C:8]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[CH:18]1.O1CCOCC1>>[NH2:16][C:11]1[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:8]2[C:3]([NH:26][C:21]3[C:20]4[CH:19]=[CH:18][NH:17][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[N:10]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc3[nH]ccc23)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
2 N HCl (aq) (0.42 mL, 833 μmol) was added to a stirred mixture of 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (171 mg, 833 μmol) and 1H-indol-4-amine (132 mg, 1000 μmol) in 1,4-dioxane (4.00 mL, 46762 μmol) and the brown mixture was heated at 100° C. overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and mixed with SiO2. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 5% MeOH in DCM) followed by washing the eluent concentrates with EtOAc to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)-1H-indol-4-amine (58 mg, 22%) as a yellow solid. LCMS (API-ES) m/z 318 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ ppm 12.00 (s, 1H) 11.15 (br. s., 1H) 8.77 (dd, J=7.78, 1.76 Hz, 1H) 8.38 (dd, J=4.52, 1.51 Hz, 1H) 8.09 (d, J=6.02 Hz, 1H) 7.53-7.81 (m, 2H) 7.35 (t, J=2.76 Hz, 1H) 6.99-7.19 (m, 2H) 6.90 (dd, J=7.78, 4.77 Hz, 1H) 6.66 (br. s., 1H) 2.55 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([O:13]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:12].[OH-].[K+].C(O)C.Cl>O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([OH:13])=[O:12]
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)C1=Cc2ccccc2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C(=O)O)C1=Cc2ccccc2C1

Procedure:
A mixture of m-phenoxylbenzyl 2-(2-indenyl)-3-methylbutanoate (8 mmol), potassium hydroxide (24 mmol), ethanol (25 ml) and water (4 ml) is heated to reflux for about 3 hours. After cooling, the reaction is acidified with dilute hydrochloric acid. The mixture is extracted with ether, and the ether phase is washed to neutrality with saturated NaCl solution. Removal of solvent by evaporation yields 2-(2-indenyl)-3-methylbutanoic acid.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I[CH2:18][CH3:19].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:1]([N:13]([CH2:14][CH2:15][OH:16])[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCI
Reactant: CCCCCCCCCCCCNCCO
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCN(CC)CCO
Yield: 73.4 %

Procedure:
2-[Dodecylamino]ethanol (2.0 g, 8.73 mmol), 1-iodoethane (1.63 g, 10.48 mmol) and N,N-diisopropylethylamine (2.51 g,17.5 mmol) in isopropanol (25 ml )were heated under reflux for 4 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent followed by chromatography on silica gel (ethyl acetate/methanol 90:10 to 80:20) afforded the title compound (1.65 g, 73%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][CH:16](O)[CH2:17][CH:18](O)[CH3:19]>>[CH3:15][CH:16]1[CH2:17][CH:18]([CH3:19])[O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12]1
Reactant: CC(O)CC(C)O
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Product: CC1CC(C)OP(=O)(Cc2ccc([N+](=O)[O-])cc2)O1

Procedure:
With 4-nitrobenzylphosphonic acid and 2,4-pentanediol, the same procedure as in Reference Example 11 was followed, to yield 4,6-dimethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless needles having a melting point of 152° to 153° C.