Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(I)c1
Reactant: COc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1cccc(Sc2cccc(C=O)c2)c1
Yield: 83.9 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzaldehyde (232 mg, 1.0 mmol), 3-methoxythiophenol (124 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-(3-methoxyphenyl)sulfanylbenzaldehyde (205 mg, 85% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=15/1). Rf=0.4 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 9.91 (s, 1 H), 7.76-7.77 (m, 1 H), 7.71 (dt, 1 H, J=1.2 Hz, 7.2 Hz), 7.45-7.53 (m, 1 H), 7.42 (t, 1 H, J=7.5 Hz), 7.25 (t, 1 H, J=7.5 Hz), 6.91-6.98 (m, 2 H), 6.84 (ddd, 1 H, J=1.2 Hz, 2.4 Hz, 8.1 Hz), 3.77 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 191.7, 160.3, 138.4, 137.3, 135.8, 135.0, 131.1, 130.5, 129.9, 127.9, 124.6, 117.6, 114.0, 55.7. IR (neat, cm−1) 3060, 3006, 2960, 2937, 2834, 2726, 1698. MS (EI) m/z (relative intensity) 244 (100), 227 (30), 211 (40). Anal. Cald. for C14H12O2S, Cald. C, 68.83; H, 4.95. Found C, 69.04; H, 4.94.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8]O)[CH:4]=[N:3]1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(CCO)cn1
Product: Cn1cc(CCCl)cn1

Procedure:
To excess thionyl chloride (250 mL) at 0° C. was added 2-(1-methyl-1H-pyrazol-4-yl)ethanol (82 g, 0.651 mol). The reaction mixture was heated to reflux for 15 minutes. The excess thionyl chloride was removed in vacuo and the crude product was purified by recrystallization from EtOH to afford the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]2=[N:8][CH:9]=[CH:10][N:5]2[N:4]=1.C1C(=O)N([I:18])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N>[I:18][C:10]1[N:5]2[C:6]([S:7][C:3]([S:2][CH3:1])=[N:4]2)=[N:8][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1nn2ccnc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CSc1nn2c(I)cnc2s1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2-Methylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazole (100.00 mg; 0.43 mmol; 1.00 eq.) was dissolved in CH3CN (4.00 ml) protected from light. Then, n-iodosuccinimide (97.22 mg; 0.43 mmol; 1.00 eq.) was added and the reaction was stirred overnight. The reaction was not completed. N-iodosuccinimide (388.88 mg; 1.73 mmol; 4.00 eq.) was added and the reaction was stirred at room temperature. After 1 day, the reaction was finished. A saturated solution of sodium thiosulfate was added and the aqueous phase was extracted 2 times with DCM. The combined organics were washed with saturated aqueous NaHCO3, NH4Cl, brine, dried over MgSO4 to give 127.6 mg of the desired product as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH2:11]Cl)=[CH:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH3:38])([CH3:29])[CH3:28])[CH3:24].[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:11][C:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)=[CH:33][C:32]=1[CH3:38])([CH3:28])[CH3:29])[CH3:24]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a solution of 400 mg (1.22 mmol) 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 115C]) and 290 mg (1.22 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) in 4 ml DMF was added 90 mg (2.06 mmol) of sodium hydride (55% in oil). The reaction mixture was stirred for 2 h at RT, taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to provide 347 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]NC([C@@H]1CCCNC1)=O>>[CH3:15][N:8]([C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCNC1

Procedure:
Prepared from (S)-3-(tert-butoxycarbonylamino)piperdine in the same scale and manner as the (3R) isomer described in Preparative Example 35. Yields were 96% and 93% for the first two steps. Product yield was treated as quantitative for last step and used as reagent in a further reaction (Example 94). LC/MS 1.30 min, [M+1]+ 215.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([C:18]#[N:19])[CH:16]=2)[CH:11]=[C:10]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:9]=1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[C:18]#[N:19])[C:8]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[N:9][C:10]([NH:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)=[CH:11]2
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C#N
Reactant: OC1CCOC1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCOC3)c2cc1C#N

Procedure:
Similar procedure as described in example 400 was used, starting from 3-hydroxy-tetrahydrofuran and of 1-Chloro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carbonitrile to give 6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-1-(tetrahydro-furan-3-yloxy)-isoquinoline-7-carbonitrile. LC-MS: m/e 366(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([OH:28])[CH3:27])[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:29]([O:28][CH:26]([C:24]1[O:23][N:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[CH:25]=1)[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)isoxazole-3-carboxamide (28 mg, 0.070 mmol) and DMAP (0.864 mg, 7.00 μmmol) were dissolved in pyridine under nitrogen atmosphere. The reaction mixture was cooled to 0° C., acetic anhydride (7.51 mg, 0.074 mmol) was added and the reaction mixture stirred for 2 h. The solvent was evaporated. Yield 82%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), δ 1.64 (d, 3H), 2.11 (s, 3H), 4.25 (dd, 1H), 4.43 (dd, 1H), 4.54-4.63 (m, 1H), 6.05 (q, 1H), 6.63 (d, 1H), 6.65 (d, 1H), 7.48 (d, 1H), 7.70 (d, 1H), 7.84 (dd, 1H), 7.89 (d, 1H), 8.06 (d, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O>[C:5]([NH:4][CH2:3][CH2:1][OH:2])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Solvent: c1ccncc1
Solvent: O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of ethanolamine, trityl chloride and pyridine was refluxed for 15 h. Water was added slowly to the cooled reaction and the precipitate collected by filtration. The crude product recrystallized from a 1:1 mixture of ethanol and water.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH3:24])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Reactant: CC1CCCN1
Product: CC1CCCN1c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and 2-methylpyrrolidine. Brown foam. MS (ESI): 401.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=O.[CH3:14][CH2:15][O:16][C:17]([CH3:19])=[O:18]>C1COCC1.[Rh]>[CH2:15]([O:16][C:17](=[O:18])[CH2:19][CH:8]1[C:9]2[C:5](=[C:4]([Cl:3])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH3:14]
Reactant: O=C1CCc2c(Cl)cccc21
Reactant: CCOC(C)=O
Agent: [Rh]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Use of 2-chlorocinnamic acid (Intermediate TWENTYTHREE-1) (commercially available from Aldrich) in the applicable process steps described in Method TWENTY produced 4-chloro-indan-1-one (Intermediate TWENTYFOUR-1). Triethylphosphonoacetate (3.5 mL, 17.2 mmol) was added to a mixture of NaH (0.69 g, 12.2 mmol) in THF (25 mL). After 30 m, a solution of 4-chloro-indan-1-one (Intermediate TWENTYFOUR-1) (1.46 g, 8.8 mmol) in THF (20 mL) was added to the mixture. The reaction mixture was allowed to stir for 16 h at rt. The solution was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was dried over MgSO4, filtered and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel with 3% EtOAc:hexane. The fractions that contained the unsaturated esters were collected and evaporated to give the product, 1.67 g. The mixture of esters (1.67 g, 7.06 mmol) in EtOAc was hydrogenated in the presence of 5% Rh on Alumina (0.14 g) at 40-50 psi H2 at rt for 2 d. The mixture was filtered through a plug of Celite® and concentrated in vacuo to produce (4-chloro-indan-1-yl)-acetic acid ethyl ester (Intermediate TWENTYFOUR-2). Use of (4-chloro-indan-1-yl)-acetic acid ethyl ester (Intermediate TWENTYFOUR-2) in the applicable process steps described in Method SEVENTEEN and Method A produced 4-(4-chloro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 166).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a stirred solution of 2,4-dichlorobenzaldehyde (286 mmol) in diethyl ether (500 mL) was added 4-chlorophenylmagnesium bromide (1.0 M in diethyl ether, 286 mmol) dropwise at 0° C. over a period of 1 hour. The reaction was allowed to warm to ambient temperature, and stirred for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (500 mL) and extracted with diethyl ether (2×500 mL), the extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by trituration with iso-hexane (500 mL) to yield the product as a white solid (60.0 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>>[OH:34][C@@H:31]([CH2:32][OH:33])[CH2:30][NH:29][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:25]([F:27])([F:28])[F:26])=[N:14][C:15]=12)=[O:24]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Reactant: NC[C@@H](O)CO
Product: O=C(NC[C@@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Yield: 73 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation M) and (R)-3-aminopropane-1,2-diol. The crude material was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide the title compound (34 mg, 73% yield). MS (apci) m/z=468.1 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[N:14]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:13]=[CH:12]2)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[CH3:24][C:21]1[N:20]=[CH:19][C:18]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][N:14]3[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:10][C:9]=2[OH:8])=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of 5-(benzyloxy)-6-(6-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.44 g, 3.60 mmol) in EtOH (50 mL) and EtOAc (50 mL) is added Pd/C (500 mg, 10% wt) under N2. The resulting mixture is degassed by evacuation and backfilled with nitrogen. Then the reaction mixture is stirred at RT under H2 atmosphere overnight. The reaction mixture is filtered. The filtrate is concentrated to give the product (982 mg, 88.0% yield). MS (m/z): 310.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2)nc(Cl)n1
Yield: 58.5 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and pyrrolidine (469 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (9:1 to 7:3 v/v) as eluent to yield the title compound (694 mg, 58%) as white crystals. MS ISP (m/e): 198.1/200.1 (100/40) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.35 (s, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 2.29 (s, 3H), 1.94 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Si:18]([O:35][CH:36]1[CH2:39][C:38](=O)[CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[Si:18]([O:35][CH:36]1[CH2:37][C:38](=[CH:9][C:7]#[N:8])[CH2:39]1)([C:31]([CH3:33])([CH3:34])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](OC1CC(=O)C1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To 1.0 M of potassium tert-butoxide in tetrahydrofuran (1.2 mL) was added dropwise, at 0° C., diethyl cyanomethylphosphonate (0.19 mL, 0.0012 mol). The reaction was warmed to rt and 30 min later cooled to 0° C. again. To the reaction mixture was added a solution of 3-[tert-butyl(diphenyl)silyl]oxycyclobutanone (0.25 g, 0.00077 mol) in THF (5 mL). The reaction was allowed to warm up to rt gradually and stirred at rt for 2 h. The reaction was quenched with saturated aq. NH4Cl, extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, concentrated. The resultant residue was purified with Combiflash (silica gel, 0-20% EtOAc/Hex) to give the desired product (0.2 g) as colorless oil. LCMS calculated for C22H26NOSi(M+H)+: 348.1 Found: 348.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH2:19]O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N+:21]([C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(P(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH2:19][S:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S)c1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1CSc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a solution of (2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)methanol (E13, 20 mg) and 3-nitrothiophenol (17 mg) in tetrahydrofuran (1 mL), tributylphosphine (36 μL) and 1,1′-(azodicarbonyl)dipiperidine (28 mg) were added under ice cooling, and the mixture was stirred at room temperature for 6 hours and 30 minutes. To the reaction mixture, tributylphosphine (36 μL) and 1,1′-(azodicarbonyl)dipiperidine (28 mg) were added at room temperature, and the mixture was stirred at the same temperature for 8 hours and 30 minutes. The solvent was evaporated under reduced pressure, and then the obtained residue was purified by basic silica gel column chromatography (eluent, 88 to 40% hexane in ethyl acetate) to obtain N2-(3-fluorophenyl)-5-(((3-nitrophenyl)thio)methyl)-N4-propylpyrimidine-2,4-diamine (E19, 19 mg) as yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([CH:14]=[N:15][CH3:16])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[NH2:17])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC(S([CH:27]([N+:34]#[C-:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=O)=O)=CC=1.CN>CO>[CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([C:14]3[N:15]([CH3:16])[CH:35]=[N:34][C:27]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[NH2:17])[CH:2]([CH3:4])[CH3:3]
Reactant: [C-]#[N+]C(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CN=Cc1ccc2nc(N)n(CC(C)C)c2c1
Agent: CN
Solvent: CO
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C)cc21
Temperature: 25 °C

Procedure:
Heat a mixture of 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (504 mg, 2.19 mmol), α-(p-toluenesulfonyl)benzylisocyanide (1.48 g, 5.47 mmol), methanol (7 mL), and methylamine (5.5 mL, 2M in tetrahydrofuran) in a sealed tube at 80° C. for 20 hours. Cool to room temperature and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with a 1:1 mixture of acetonitrile and dichloromethane containing 5% methanol to provide the desired compound.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(C#Cc3ccccc3)nc2N1C1CCCC1

Procedure:
To a solution of Intermediate B (1.0 eq) in DMF, ethynylbenzene (compound III-139, 3.0 eq), Pd(PPh3)2Cl2 (0.2 eq), CuI (0.25 eq) and Et3N (5.0 eq) were added. The mixture was refluxed for 18 h under argon, extracted with EtOAc and purified by silica gel column to give (R)-8-cyclopentyl-7-ethyl-5-methyl-2-(phenylethynyl)-7,8-dihydropteridin-6(5H)-one (compound IV-139).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=[O:18])[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[C:43]4=[O:49])=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:50]1([N:60]=C=O)[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][CH:51]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:18])[NH:60][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=[CH:52][CH:51]=2)[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[C:43]4=[O:49])=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)n2)C1=O
Product: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)Nc4cccc5ccccc45)CCN3C(=O)OCc3ccccc3)n2)C1=O

Procedure:
The title compound was prepared from 2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)-piperazine-2-yl)-ethylamino]-4-[5-(3-ethyl-imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (35 mg) and naphthyl isocyanate (10 mg) according to the procedure described in EXAMPLE 14, Step F. Mass spectrum (ESI) 739.5 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH:12]([C:19]2[N:20]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:21]=[C:22]3[C:27]=2[CH:26]=[C:25]([F:28])[C:24]([F:29])=[CH:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH3:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=3[CH3:37])=[C:27]3[C:22]([CH:23]=[C:24]([F:29])[C:25]([F:28])=[CH:26]3)=[N:21]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(C)c(OC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1OC(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxy}-3,5-dimethyl-benzoic acid methyl ester (example 33) was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as yellow foam. MS: m/e=523.3 [M−H−].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[NH:7][CH2:6]1)=[O:4].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[CH2:6]1)=[O:4]
Reactant: BrCCCn1cccc1
Reactant: COC(=O)C1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(=O)N(CCCn2cccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-Oxo-pyrrolidine-3-carboxylic acid methyl ester (1 eq.) in dry DMF is added NaH (1.1 eq.) followed by 1-(3-bromo-propyl)-1H-pyrrole (1 eq.). The reaction mixture is stirred at room temperature overnight. Purification is by normal phase chromatography to yield 5-Oxo-1-(3-pyrrol-1-yl-propyl)-pyrrolidine-3-carboxylic acid methyl ester.