Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([NH:27][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: NC1CCCC1
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)NC2CCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and cyclopentylamine (1 ml) was heated at 120° C. for 15 h to obtain 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N-cyclopentylacetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH2:42][OH:43])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH2:42][OH:43])[CH3:41]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-benzenesulfonamide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 616.2 [(M−H−]; mp 248° C.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:15]2[C:16]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[C@@H:20]([CH3:30])[CH2:19][CH2:18]3)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH:45]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:32]1([O:31][C:16]2[C:15]([C:5]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[C:2]([C:44]4[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH:45]=4)=[CH:3][N:4]=3)=[CH:24][CH:23]=[C:22]3[C:17]=2[CH2:18][CH2:19][C@H:20]([CH3:30])[N:21]3[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@H]1CCc2c(ccc(-c3ncc(Br)n3COCC[Si](C)(C)C)c2OC2CCC2)N1C(=O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(-c3ncc(C4=CCN(C(=O)OC(C)(C)C)CC4)n3COCC[Si](C)(C)C)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of ((S)-6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1 (2H)-yl)(cyclopropyl)methanone (0.0.091 g, 0.16 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.050 g, 0.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.013 g, 0.02 mmol), and cesium carbonate (0.159 g, 0.49 mmol) in water (3 mL) and 1,4-dioxane (10 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature and filtered through a short pad of celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1:2, ethyl acetate/petroleum ether) to afford tert-butyl 4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.094 g, 87%) as a light yellow solid. MS (ESI, pos. ion) m/z 663 [M+H]+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][OH:18].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:4]([Si:1]([O:18][CH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: OCCc1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Reaction time: 0.75 h

Procedure:
tert-Butyldimethylsilyl chloride (6.45 g) was added to a stirred solution of 2-(2-fluorophenyl)ethanol (5.00 g) and 1H-imidazole (7.29 g) in dry DMF (30 mL) cooled in an ice bath. After 45 min, the reaction mixture was diluted with ethyl acetate, washed three times with water and evaporated in vacuo. The resulting gum was dissolved in isohexane and applied to a silica gel column eluting with isohexane followed by 1:3 ethyl acetate:isohexane to collect the product as an oil. Yield 9.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33][CH:32]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:33][CH:32]=1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: COC(=O)c1ccc(N)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC3=C(Oc4cccc(OC)c4C3)C2=O)nc1
Yield: 18.3 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.54 mmol) (Example 7, Step 2c), commercially available 6-amino-nicotinic acid methyl ester (98 mg, 0.64 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (113 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (80 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionylamino]-nicotinic acid methyl ester (50 mg, 18.4%), as a white solid. 1H NMR (DMSO-d6) δ: 11.32 (br. s., 1H), 8.87 (br. s., 1H), 8.28 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.10 (br. s., 1H), 4.38 (d, J=18.6 Hz, 1H), 4.04 (d, J=19.1 Hz, 1H), 3.84 (d, J=15.7 Hz, 6H), 3.55 (br. s., 2H), 1.48-1.89 (m, 7H), 0.85-1.29 (m, 6H).
Reaction SMILES: C(C1N2C=CN=CC2=NC=1)#C.I[C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][C:33]=1C)[C:16]([NH:18][NH:19]C(=O)C1C(Cl)=CC(Cl)=CC=1Cl)=[O:17].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:16]([NH:18][NH2:19])(=[O:17])[C:15]1[CH:31]=[CH:32][CH:33]=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)NNC(=O)c2c(Cl)cc(Cl)cc2Cl)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#Cc1cnc2cnccn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-ethynylimidazo[1,2-a]pyrazine (0.09 g, 0.6 mmol), N′-(3-iodo-4-methylbenzoyl)-2,4,6-trichlorobenzohydrazide (0.3 g, 0.6 mmol), Pd(PPh3)4 (0.036 g, 0.03 mmol), CuI (0.008 g, 0.03 mmol) and diisopropylethylamine (0.75 ml, 0.9 mmol) in DMF (10 ml) was stirred at ambient temperature for 12 hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% methanol in dichloromethane) to provide 2,4,6-trichloro-N′-[3-[2-(2-imidazo[1,2-a]pyrazin-3-yl)ethynyl)]]-4-methylbenzoyl]benzohydrazide.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[N:7][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and [4-(pyrrolidin-1-yl)piperidin-1-yl][4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH3:9])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])CCC.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N:25]2[CH2:30][CH2:29][N:28]([C:31](OCC)=[O:32])[CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[OH-].[Na+]>C1COCC1.CCCCCC.O.C(O)(=O)C>[CH2:1]([O:3][P:4]([CH2:9][C:31]([N:28]1[CH2:29][CH2:30][N:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=[CH:16][CH:17]=2)[CH2:26][CH2:27]1)=[O:32])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOC(=O)N1CCN(c2ccnc3ccccc23)CC1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CCOP(=O)(CC(=O)N1CCN(c2ccnc3ccccc23)CC1)OCC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Diethylmethylphosphonate (302.8 mg, 2 mmol) was dissolved in anhydrous THF (2.5 ml), the mixture was cooled to −78° C. under argon, n-butyllithium (2.11 mmol, 846 μl of a 2.5 M solution in hexane) was added dropwise with stirring. After addition was complete, stirring was continued for 20 minutes, after which ethyl 4-(4-quinolyl)piperazine-1-carboxylate (284 mg, 1 mmol) dissolved in 0.5 μl THF was added dropwise. The mixture was allowed to reach room temperature overnight with continued stirring. Glacial acetic acid (0.25 ml) and water (2 ml) was added, after which the mixture was basified with 0.1 NaOH and extracted with diethylether (2×). The organic phases were combined, washed with 5% sodium bicarbonate and water. The aqueous phases were back-extracted with diethylether after basification with 0.1 N NaOH and the combined organic phases dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 271 mg (0.693 mmol, 69%). MS (ESI): m/z=392.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[CH:13][CH2:14][CH2:15][CH:9]3[CH:8]([CH3:16])[O:7][C:6]=2[C:5]([CH3:17])=[C:4]([C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH3:22])[CH2:19][CH2:20][CH3:21])[C:3]=1[CH3:30].[BrH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[BrH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([O:1][C:2]2[C:11]3[CH:10]4[CH:12]=[CH:13][CH2:14][CH2:15][CH:9]4[CH:8]([CH3:16])[O:7][C:6]=3[C:5]([CH3:17])=[C:4]([C:18]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)([CH3:22])[CH2:19][CH2:20][CH3:21])[C:3]=2[CH3:30])=[O:42])[CH2:34][CH2:33]1
Reactant: CCCC(C)(c1ccc(F)cc1)c1c(C)c(O)c2c(c1C)OC(C)C1CCC=CC21
Reactant: O=C(O)CCCN1CCOCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1c(C)c(OC(=O)CCCN2CCOCC2)c2c(c1C)OC(C)C1CCC=CC21

Procedure:
3.54 g. (11.27 mmole) of 1-Hydroxy-3-(4-fluorophenyl-1-methylbutyl)-trimethyl-6a,7,8,10a-tetrahydrodibenzo[b,d] pyran, 2.86 g. (11.27 mmole) of γ-morpholinobutyric acid hydrobromide and 2.50 g. (12.12 mole) of dicyclohexylcarbodiimide are combined in 200 ml. of methylene chloride and stirred at room temperature for 24 hours. The reaction mixture is cooled and the by-product of dicyclohexylurea is removed by filtration. The volume of methylene chloride is removed by filtration. The volume of methylene chloride is reduced and 25 ml. of cyclohexane is added. The mixture is cooled and the small amount of solid which forms is removed by filtration. All solvents are removed on a rotary evaporator and the residue is dried in vacuo. The resulting material is dissolved in a mixture of benzene and ether and placed in cold storage to yield the crystalline product.
Reaction SMILES: NC1C=CC(/C(/C)=C/C(OCC)=O)=C(F)C=1.[CH3:17][Si:18]([CH3:49])([CH3:48])[C:19]1[CH:20]=[C:21]([CH:41]=[C:42]([Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:43]=1)[C:22]([NH:24][C:25]1[C:30](F)=[CH:29][C:28](/[C:32](/[CH3:39])=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:27]([F:40])[CH:26]=1)=[O:23]>>[CH3:47][Si:44]([CH3:45])([CH3:46])[C:42]1[CH:41]=[C:21]([CH:20]=[C:19]([Si:18]([CH3:17])([CH3:48])[CH3:49])[CH:43]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28](/[C:32](/[CH3:39])=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:27]([F:40])[CH:26]=1)=[O:23]
Reactant: CCOC(=O)/C=C(\C)c1cc(F)c(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Agent: CCOC(=O)/C=C(\C)c1ccc(N)cc1F
Product: CCOC(=O)/C=C(\C)c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Yield: 42 %

Procedure:
Using BTMB (1.0 g) and Compound 11a (1.01 g), Compound 11b (739 mg, 42%) was obtained as a light yellow solid in the same manner as Compound 10b was synthesized.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>C1COCC1>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=2)[CH2:2]1
Reactant: O[C@H]1CCOC1
Reactant: Nc1nccc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1nccc(O[C@H]2CCOC2)n1
Reaction time: 0.08 h

Procedure:
(S)-tetrahydrofuran-3-ol (612 mg, 6.95 mmol) was treated at room temperature with KHMDS (1 M in THF, 5.09 ml, 5.09 mmol). The reaction mixture was stirred for 5 min. Then, the mixture was added to a solution of 4-chloropyrimidin-2-amine (300 mg, 2.32 mmol) in THF (10 ml). The resulting brown solution was stirred at room temperature for 5 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted 2× with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 0.31 min; ESI-MS 182.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1>ClCCl>[Si:7]([O:4][CH2:3][C:2]([CH3:6])([NH2:1])[CH3:5])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a stirred solution of 2-amino-2-methylpropan-1-ol (1.78 g, 0.02 mol) in dichloromethane (25 mL) was added tert-butyldimethylsilyl chloride (5.4 g, 0.036 mol) followed by imidazole (3.4 g, 0.05 mol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with NaHCO3 aqueous, brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with EtOAc to give 1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-amine (3.1 g, 76%) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.26 (s, 2H), 1.02 (s, 6H), 0.88 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13][C:12]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[N:34]1>CN(C)C(=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([NH:39][CH2:38][C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:23][C:12]=2[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(Cl)c2CC1
Reactant: Cn1cc(CN)cn1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(NCc3cnn(C)c3)c2CC1

Procedure:
A solution of ethyl 2-benzyl-4-chloro-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylate of Step B (50 mg, 0.14 mmol), triethylamine (0.10 ml, 0.72 mmol) and C-(1-Methyl-1H-pyrazol-4-yl)-methylamine (50 mg, 0.45 mmol) in N,N-dimethylacetamide (2.0 ml) was stirred for 18 h at 60° C. The solvent was removed in vacuo and the crude product was deprotected without further purification. LRMS APCI m/z 421 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=[O:27])(C)(C)C>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]=1[NH:17][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=[O:27])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)c1

Procedure:
Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G47) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a light brown solid (183 mg).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH2:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26].O>C(O)(=O)C>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]2[N:21]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C1CCc2c(cc(-c3ccccc3)n2-c2cccc(C(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of 4-tert-butyl-2-(2-oxo-2-phenylethyl)-cyclohexanone (0.219 gm) in glacial acetic acid (3.0 mL) in a 25-mL round-bottomed flask, under nitrogen, was fitted with a heating mantle and reflux condenser. To this solution was added 3-aminobenzoic acid (0.138 gm), which was then heated at 110 C for 3 hr. The solution was cooled to ambient temperature, 8 mL water was added, and the suspension was stirred 18 hr under nitrogen. The solid was filtered, washed with water, and recrystallized in acetonitrile to provide 0.123 gm of the pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane (590 mg, 2.38 mmol) in THF (20 mL) was added 6N HCl (1.2 mL). The reaction was stirred at room temperature for 4 hours and then diluted with EtOAc (50 mL) and washed with water (2×40 mL) and saturated NaHCO3/brine (2×40 mL, 1:1). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) afforded 4-(4-methoxyphenyl)cyclohexanone. 1H NMR (600 MHz, CDCl3) δ 7.15-7.18 (m, 2H), 6.85-6.88 (m, 2H), 3.80 (s, 3H), 2.99 (m, 1H), 2.46-2.54 (m, 4H), 2.17-2.22 (m, 2H), 1.87-1.95 (m, 2H).
Reaction SMILES: C(C1(CC)CCN(C)C(=O)C1(C)C)C.[CH3:15][C:16]1([CH2:29][CH2:30][CH3:31])[CH:21]([CH2:22][CH3:23])[C:20](=O)[CH2:19][C:18]([CH3:28])([CH2:25][CH2:26][CH3:27])[NH:17]1>>[CH3:15][C:16]1([CH2:29][CH2:30][CH3:31])[CH:21]([CH2:22][CH3:23])[CH2:20][CH2:19][C:18]([CH3:28])([CH2:25][CH2:26][CH3:27])[NH:17]1
Reactant: CCCC1(C)CC(=O)C(CC)C(C)(CCC)N1
Agent: CCC1(CC)CCN(C)C(=O)C1(C)C
Product: CCCC1(C)CCC(CC)C(C)(CCC)N1

Procedure:
If instead of diethyl-trimethyl-oxopiperidine the equivalent amount of 2,6-dimethyl-2,6-dipropyl-3-ethyl-4-oxopiperidine is used in this procedure there is obtained 2,6-dimethyl-2,6-dipropyl-3-ethylpiperidine (Compound No. 2), boiling at 90°-95° C. at 2 mm Hg.
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23].C(OCC)(=O)C>O1CCCC1>[C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([CH3:12])([CH3:13])[O:10][C:9]1=[O:14])(=[O:24])/[CH:21]=[CH:22]/[CH3:23]
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Reactant: C/C=C/C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)N1C(=O)OC(C)(C)[C@H]1c1ccccc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Reaction of the auxiliary (15) (0.416 g, 2.19 mmol) in solution in tetrahydrofuran (10 ml) at -78° C. with butyllithium (1.3M, 1.69 ml, 2.20 mmol) and crotonyl chloride (0.229 ml, 2.40 mmol) for 30 minutes and then at room temperature for 2 hours, with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (25) as a solid (0.564 g, 100%) ; mp 104° C.; νmax (CDCl3) 1687 and 1769 cm-1 ; [α]D24 (c 1 in CDCl3)=-82.6; (Found: C, 69.60; H, 6.64; N, 5.35. C15H17NO3 requires C, 69.48; H, 6.61; N, 5.40%); δH (CDCl3 ; 200 MHz) 0.99 (3H, s, C(CH3)2), 1.60 (3H, s, C(CH3)2), 1.93 (3H, d, J=5.4, CH3CHCH), 5.13 (1H, s, CHPh), 7.02-7.40 (7H, m, ArCH and CH3 CH=CH); δC (125 MHz; CDCl3) 18.39 (CH3), 23.60 (CH3), 28.81 (CH3), 67.09 (CH), 82.87 (C), 122.14 (CH), 126.08 (CH), 126.19 (CH), 128.71 (CH), 129.08 (CH), 136.61 (C), 147.31 (CH), 153.50 (CO), 165.07 (CO); m/z (CI+, NH3) 260 (M+ +1).