Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[OH:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[N:33][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([O:28][C:2]2[CH:3]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=2)=[CH:34][N:33]=1
Reactant: Cc1ccc(O)cn1
Reactant: OC(CN(Cc1cccc(OC(F)(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2cccc(N(Cc3cccc(OC(F)(F)F)c3)CC(O)C(F)(F)F)c2)cn1
Temperature: 105 °C
Yield: 60.9 %

Procedure:
The 3-[(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (500 mg, 1.1 mmol) product from EX-633B and 5-hydroxy-2-methylpyridine (262 mg, 2.4 mmol) were dissolved in dimethylacetamide (6 mL). Cs2CO3 (10 g, 3.1 mmol) and (CuCF3SO3)2C6H6 (150 mg) were added, and the mixture was heated to 105° C. for 96 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that most of the starting materials had been consumed. After adding water, the reaction mixture was extracted with ether, and the ether extracts were washed with brine and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:12) to give 326 mg (61%) of the desired 3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 99% pure by HPLC analysis. 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.29 (t 1H), 6.99 (s, 1H), 7.02-7.15 (m, 5H), 6.46 (dd, 1H), 6.29 (t, 1H), 6.25 (dd, 1H), 4.88 (br s, 1H), 4.67 (ABq, 2H), 4.36 (m, 1H), 3.88 (dd, 1H), 3.56 (dd, 1H), 2.49 (s, 3H). 19F NMR (CDCl3) δ −58.2, (s, 3F), −79.1 (d, 3F). HRMS calcd. for C23H20N2O3F6: 487.1456 [M+H]+, found: 487.1425.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].O.[C:8]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([NH:15][C@H:16]([C:21]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:23])[CH2:17][CH:18]([CH3:19])[CH3:20])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CCN
Solvent: O
Product: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C

Procedure:
In substantially the same manner as working Example 2, isopentylamine (2.33 ml) was condensed with Boc-L-leucine monohydrate (5.00 g, manufactured by Peptide Institute, Inc.) to give N-(Boc-L-leucyl)isopentylamine (5.73 g) as a white powdery product (yield 95%). The Boc group was deprotected with TFA, and 667 mg of thus-produced compound was condensed, in substantially the same manner as Working Example 2, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 1.00 g) to afford the above-titled compound (Compound 11; 920 mg) as a colorless oily product (yield 58%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[CH3:22]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:19][CH2:20]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC12CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 2′-chloro-9′-cyclohexyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 271; 849 mg, 2.767 mmol) in DMA (60 mL) under nitrogen was added methyl iodide (190 μL, 3.044 mmol). The mixture was cooled on an ice/water bath and sodium hydride (60% mineral oil dispersion; 122 mg, 3.044 mmol) added in one portion. The reaction mixture was stirred on the ice/water bath for 1 hour, the cooling bath removed and allowed it to warm to room temperature. After 1.5 hours the solvent was evaporated and the residue treated with an excess of water. This afforded a solid, which was filtered off and washed well with water and then dried by dessication under high vacuum over P2O5 overnight. To yield the title compound as an off-white solid (887 mg, 100%)
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](O)=[O:8])[N:6]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7]([Cl:17])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1sc(Cl)nc1C(=O)Cl

Procedure:
2-Chloro-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (Intermediate 7, 1 g, 4.24 mmol) was dissolved in thionyl chloride (5 mL) and refluxed for two hours. It was then concentrated to give the desired product (light brown oil, 1 g). NMR (CDCl3): 1.37 (t, 3H), 4.39 (q, 2H).
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:40]=[CH:41][C:42]([CH3:47])=[C:43]([CH:46]=1)[C:44]#[N:45].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:40]=[CH:41][C:42]([CH3:47])=[C:43]([C:44]#[N:45])[CH:46]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(Br)cc1C#N
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)cc1C#N
Temperature: 85 °C
Yield: 78.6 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 200 mg) and 5-bromo-2-methylbenzonitrile (80 mg) in acetonitrile (8 mL) were treated with an aqueous solution of sodium carbonate (2M, 0.387 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was concentrated and purified by chromatography on silica eluting with 50 to 100% ethyl acetate/isohexane to afford the sub-titled compound (154 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][C:18]5[N:23]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)[N:22]=[CH:21][C:19]=5[C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[C:24]1([N:23]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[C:19]=3[CH:21]=[N:22]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCc2c-4cnn2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc(-n2ncc3c2CCc2cnc4[nH]ncc4c2-3)cc1
Yield: 19.2 %

Procedure:
A solution of 3-(4-methoxybenzyl)-8-phenyl-3,6,7,8-tetrahydrodipyrazolo[3,4-c:4′,3′-f]isoquinoline (0.7 g, 1.72 mmol) in trifluoroacetic acid (4 mL) was heated at 100° C. for 2 hours. The reaction mixture was poured into water (50 mL) and basified with aqueous potassium carbonate to pH of 11. The reaction mixture was then extracted with dichloromethane (3×75 mL). The combined organic extract was dried using sodium sulfate and concentrated under reduced pressure to give dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to give a residue, which was further purified by crystallization from methanol and isopropanol to give the desired product (0.095 g, 18%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.43 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.64-7.55 (m, 4H), 7.45 (t, J=3.2 Hz, 1H), 3.12 (s, 4H); LCMS [M+H]: 288.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])=[CH2:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)[CH:8]=[CH:9][CH:10]=1)=[CH2:2]
Reactant: C=Cc1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=Cc1cccc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-ethenylbenzaldehyde from Step 1 (3.77 g) and ethylene glycol (1.8 mL) in benzene (40 mL) was added p-toluenesulfonic acid monohydrate (100 mg). The reaction mixture was heated to reflux for 6 hours. The water produced by the reaction was collected in a Dean-Stark trap. The reaction was allowed to cool to room temperature. The reaction was diluted with NH4OAc buffer and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. Flash chromatography of the residue using 15% diethyl ether in hexane afforded the title compound.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:22]Br>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:22][CH:18]([C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CCCCCCCCCCCCn1nnc(CC(=O)O)n1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCn1nnc(C(Br)C(=O)O)n1
Temperature: 45 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
The 2-dodecyltetrazoleacetic acid (4.7 g, 15.8 mmol) was suspended in carbon tetrachloride (5 mL) and warmed to 45° C. The solution was diluted by dropwise addition of bromine (2.6 g, 16.3 mmol), and the mixture was further heated to reflux with stirring for 5 hours. The solution was cooled to room temperature, diluted with 50 mL of ethyl acetate, washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to give α-bromo-2-dodecyltetrazoleacetic acid (5.3 g, 86%) as an orange colored liquid;
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:42])N(C)C)[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:43][CH3:44])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].[CH3:51][Mg]Br>C1COCC1>[C:19]([O:18][C:17](=[O:23])[N:16]([CH:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:42])[CH3:51])[CH:33]=3)[CH:29]=[CH:28][C:27]=2[O:43][CH3:44])[C:7]([C:6]2[S:5][C:4]3[C:45]([F:50])=[CH:46][CH:47]=[C:48]([F:49])[C:3]=3[C:2]=2[Cl:1])=[O:8])[CH2:15][CH2:14]1)[CH3:24])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[Mg]Br
Reactant: COc1ccc(-c2ccnc(C(=O)N(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(C(C)=O)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of dimethyl amide 163 (50 mg, 0.07 mmol) in dry THF (3 ml) at 0° C. was added a 3M solution of methyl magnesium bromide (0.18 ml, 0.55 mmol) in THF. After 1 h, the completed reaction was quenched with 1.2 M HCl, basified and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, reduced in vacuo and purified by chromatography with 70% EtOAc in heptane to give the title compound.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([NH:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8].O>C1COCC1>[N:10]1([N:9]2[CH2:4][CH2:5][CH2:6][C:7]2=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(CCCCl)NN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCN1N1CCCCC1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Add NaH (1 g, 25 mmol) into 4-chloro-N-piperidin-1-yl-butyramide (Preparation 10) (3.2 g, 16 mmol) in THF (100 mL) and stir for 1 hour. Add the reaction mixture into water and extract with ethyl acetate (100 mL). Wash the organic layer with brine (20 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure. Purify the residue by column chromatography to give the title product (2 g, 76%) as yellow oil: Mass spectrum (ion spray): m/z=169.1 (M+H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 42.6 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:1]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc(N3CCOCC3)cc2c1=O
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 20.3 %

Procedure:
To a solution of 7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.8 g, 0.0028 mol) in DMF (8 ml), was added potassium carbonate (2 g, 0.014 mol). After five minutes, bis (2-chloroethyl)ether (0.41 g, 0.0028 mol) was added and the solution was heated to 140° C. for 24 hours. After this time LC-MS indicated the complete consumption of starting material and the mixture was cooled, concentrated under vacuum and purified by flash column chromatography (elution: 70% heptane, 30% ethyl acetate) to give the title compound (0.2 g, 20% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:32]([O:31][C:29](=[O:30])[C:28]([O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:35])[CH3:34])[CH3:33]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(O)c2)n1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Reaction time: 2 h
Yield: 36.9 %

Procedure:
A mixture of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol [945 mg, 2.42 mmol, Example 35(i)], PS-TBD (3.38 g, 5 mmol), ethyl 2-bromoisobutyrate (888 mL, 605 mmol) and acetonitrile (20 mL) is heated to reflux and stirred for 2 hours. The heating is turned off and the mixture is stirred overnight at ambient temperature. The reaction mixture is filtered to remove the resin and the resin is washed with MeOH (20 mL) and with acetonitrile (20 mL). The combined filtrate and washings are concentrated by rotary evaporator. The residue is subjected to flash column chromatography on silica (40 g) eluting with 20 to 50% EtOAc in heptane gradient to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester [450 mg, 37%, Example 42] as a solid. LCMS: RT=2.9 minutes, MS: 504 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[N:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[C:16]([CH3:17])[C:3]=12.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CN1C(=O)CCC1>[CH3:17][C:16]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:15]=1
Reactant: C1CNCCN1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(Cl)c12
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Temperature: 200 °C
Yield: 100 %

Procedure:
4-Chloro-3-methyl-5-phenyl-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.300 g, 0.784 mmol) and piperazine (0.675 g, 7.84 mmol) were placed in NMP (1 mL) and heated to 200° C. in a microwave for 1 hour. The reaction was then poured into water and extracted with MTBE. The combined organic fractions were dried, filtered, and concentrated to give the crude product 3-methyl-5-phenyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.339 g, 100% yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 23.3 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(ethylamino)piperidine-1-carboxylate obtained in Example (207a) (22.0 mg, 0.055 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (17 mg, 0.066 mmol) and sodium carbonate (58 mg, 0.55 mmol), to obtain 6 mg of the title compound (23%) as a colorless solid.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: OO
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
An aqueous solution (10 ml) of sodium dihydrogenphosphate (12.0 g, 0.100 mol), an aqueous solution (30 ml) of sodium chlorite (5.19 g, 0.0577 mol) and aqueous hydrogen peroxide (1.701 ml, 30%) were added to an acetonitrile solution (30 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (5.60 g, 0.0128 mol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (5.20 g, 0.0115 mol, 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][OH:35])=[CH:32][CH:31]=1>>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:35][CH2:2][C:3]2[N:4]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:5]=[C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])[N:7]=2)=[CH:32][CH:31]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccc(Br)cc2)n1
Yield: 15 %

Procedure:
As described for Example 153, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 4-bromobenzyl alcohol instead of 4-methylbenzyl alcohol, was converted to the title compound (21 mg, 15%) which was obtained as a light yellow solid. MS: m/e=545.3/547.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: Cc1ccc2c(c1)CCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3cc(C)ccc32)CC1
Reaction time: 20 h
Yield: 47.7 %

Procedure:
A 4 mL vial was charged with crude 1-(3-chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH14) (0.128 g), 4-butylpiperidine (0.076 g, 0.54 mmol), KI (0.166 g, 1.00 mmol), and K2CO3 (0.138 g, 1.00 mmol) in MeCN (2 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-1) (0.088 g, total yield 41%). 1H NMR (CD3OD) δ 7.07-7.01 (m, 3H), 3.94 (t, J=7.4 Hz, CH2), 2.90-2.80 (m, 4H), 2.57-2.53 (m, 2H), 2.39-2.33 (m, 2H), 2.27 (s, 3H, CH3), 1.95-1.90 (m, 2H), 1.85-1.79 (m, 2H), 1.66 (d, J=9.8 Hz, 2H), 1.30-1.17 (m, 9H), 0.89 (t, J=6.8 Hz, CH3); 13C NMR (CD3OD) δ 172.4, 137.9, 134.1, 129.8, 129.0, 128.0, 116.3, 57.1, 55.0, 41.3, 37.4, 36.8, 33.1, 32.8, 30.1, 26.2, 25.5, 23.9, 20.7, 14.4; HPLC-MS (ammonium acetate) [M+H+]=343.33.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]=[C:12]=[O:13])[CH2:8]2.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:15]>CCOCC>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([NH:11][CH:2]1[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)=[O:13])[CH3:15]
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
2-Adamantyl-isocyanate (CAS 71189-14-5, made from 2-aminoadamantane according to Eur. J. Med. Chem. 28 (1), 1993, 37-45, 500 mg) and commercially available benzylamino-acetic acid ethyl ester (572 mg) were dissolved in absolute ether (25 mL) under argon and stirred at RT for 12 hours. A colorless precipitate was formed. The reaction mixture was concentrated in vacuo and the residue was triturated with hexanes (30 mL) for one hour. The suspension was filtered and the solid was dried in vacuo to give (3-adamantan-2-yl-1-benzyl-ureido)-acetic acid ethyl ester (823 mg). MS (ESI): 371.2 (MH+).