Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Si:49]([O:56][CH2:57][C@@H:58](O)[CH3:59])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>O>[Si:49]([O:56][CH2:57][C@H:58]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:59])([C:52]([CH3:53])([CH3:54])[CH3:55])([CH3:51])[CH3:50]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2cccc(O[C@H](C)CO[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a solution of 2-methylquinolin-8-ol (0.40 g, 2.5 mmol) in tetrahydrofuran (2.1 mL, 2.5 mmol) was added triphenylphosphine (1.6 g, 6.3 mmol), diethyl azodicarboxylate (0.63 mL, 4.0 mmol), and (S)-1-(tert-butyldimethylsilyloxy)propan-2-ol (0.62 g, 3.3 mmol). The resultant mixture was allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.33 g, 40%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:30]([NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCc1ccc(NCc2ccccc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccccc2)C(=O)Nc2ccccc2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-octylphenyl)amine (2.0 g) and phenylisocyanate (0.91 mL) as starting materials, N-benzyl-N-(4-octylphenyl)-N′-phenylurea (1.9 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:30])([F:29])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][C:25](=O)[CH2:24][C:23](=[O:28])[CH2:22]2)=[CH:17][CH:16]=1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:25]1[CH2:26][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:30])([F:29])[F:13])=[CH:16][CH:17]=2)[CH2:22][C:23](=[O:28])[CH:24]=1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: O=C1CC(=O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: COC(=O)c1cccc(NC2=CC(=O)CC(c3ccc(C(F)(F)F)cc3)C2)c1Br
Temperature: 150 °C
Yield: 67.4 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (10.2 g, 44.3 mM) and 5-(4-trifluoromethylphenyl)-1,3-cyclohexanedione (1.77 g, 6.93 mM) was heated at 150° C. under a stream of nitrogen for 20 minutes. The resultant solid was triturated with 4:1 EtOAc/Et2O to afford 2.18 g (74%) of 3-(3-carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl)-cyclohex-2-en-1-one. 1H NMR (DMSO-d6) δ 8.9 (s, 1H), 7.75-7.5 (m, 7H), 3.9 (s, 3H), 3.5 (m, 1H), 2.9 (dd, J=14 and 9 Hz, 1H), 2.7 (dd, J=14 and 4 Hz, 1H), 2.55 (dd, J=14 and 9 Hz, 1H), 2.35 (dd, J=14 and 4 Hz, 1H). MS (ES) m/e 368, 370.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1)#[N:11]>C(#N)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[S:20])=[CH:16][CH:17]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccc(N=C=S)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC(=S)Nc1ccc(C#N)cc1
Reaction time: 12 h
Yield: 78.3 %

Procedure:
10.7 g (82 mmol) of glycine t-butyl ester are added to a solution of 13 g (82 mmol) of 4-cyanophenyl isothiocyanate dissolved in 100 cm3 of acetonitrile. After 12 hours of stirring, the precipitate formed is filtered off and is then washed with ethyl ether, to give 18.7 g (yield 78%) of the desired thiourea.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](C2C=CC=CC=2C(O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:25](F)(F)[C:26]([OH:28])=O.[Cl:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([S:42]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:44])=[O:43])[CH:36]=[CH:35]2>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:9]2[CH:14]=[CH:13][C:25]([C:26]([N:48]3[CH2:47][CH2:46][N:45]([S:42]([C:37]4[CH:36]=[CH:35][C:34]5[C:39](=[CH:40][CH:41]=[C:32]([Cl:31])[CH:33]=5)[CH:38]=4)(=[O:43])=[O:44])[CH2:50][CH2:49]3)=[O:28])=[CH:11][CH:10]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2C(=O)O)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cc1
Yield: 208.9 %

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-[4-(tert-butoxycarbonylamino)phenylbenzoic acid (150 mg) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate (203 mg) as the raw materials, the reaction was conducted, whereby the title compound (303 mg, 100%) was obtained.
Reaction SMILES: [OH:1][C@H:2]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:16][CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[F:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44]Br>C(#N)C>[F:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44][N:24]1[CH:25]=[CH:26][N:27]=[C:23]1[CH2:22][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[CH:15][CH:16]=1)=[O:28]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)Cc2ncc[nH]2)cc1)C[C@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)Cc2nccn2Cc2ccccc2F)cc1)C[C@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
To a solution of 403 mg of tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(2-1H-imidazol-2-ylacetyl)amino]phenyl]ethyl]carbamate in 10 ml of acetonitrile were added 120 mg of potassium carbonate and 164 mg of 2-fluorobenzyl bromide successively at room temperature. The reaction solution was stirred at 50° C. for 12 hours. Insoluble matters were filtered off using Celite, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography to give 253 mg of tert-butyl (R)-N-[2-[4-[[2-[1-(2-fluorobenzyl)-1H-imidazol-2-yl]-acetyl]amino]phenyl]ethyl]-N-(2-hydroxy-2-phenylethyl)-carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH2:68]([S:75][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: SCc1ccccc1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(OC(c2cccc(SCc3ccccc3)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (200 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), Diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 24 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5) to afford 2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
Reaction SMILES: [CH3:1][O:2]/[C:3](/[CH2:9][CH3:10])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[Br:11]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:11][CH:9]([CH3:10])/[C:3](/[O:2][CH3:1])=[CH:4]\[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC/C(=C\C(=O)OC)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C(/OC)C(C)Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 379.6 %

Procedure:
A 500-ml 4-necked pear-shaped flask equipped with a mechanical stirrer, a thermometer, a cooler, an argon inlet and an oil bath was charged under argon with 31.2 g of crude methyl (E)-3-methoxy-2-pentenoate (ca. 0.217 mol), 10.45 g of N-bromo succinimide (58.7 mmol), 0.47 g of 2,2′-azobis(2-methylpropionitrile) (2.86 mmol) and 100 ml of carbon tetrachloride. The resulting yellow suspension was heated for 10 min with an 80° C. oil bath to give an almost colorless suspension. Then three additional portions consisting each of 10.45 g of NBS, 0.47 g of AIBN and 35 ml of carbon tetrachloride, in total 31.35 g of N-bromo succinimide (0.176 mol), 1.41 g of 2,2′-azobis(2-methylpropionitrile) (8.59 mmol) and 105 ml of carbon tetrachloride were added in 5 min time intervals at the same temperature. 20 min after the last addition of reagents (total reaction time was 45 min) the oil bath was removed and the reaction mixture cooled under stirring with an ice bath for ca. 30 min. The suspension was filtered with suction and the filter cake washed with a total of 90 ml of carbon tetrachloride. The filtrate was rotary evaporated to dryness (50° C., 10 mbar) to give 49.7 g of crude methyl rac-(E)-4-bromo-3-methoxy-pent-2-enoate (theor. amount 48.4 g) as an orange oil. This material was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:4]([CH:5]=[O:6])[CH:3]1[C:7]([O:9][CH3:10])=[O:8].[Cl:12][C:13]([Cl:19])([Cl:18])[C:14]([F:17])([F:16])[F:15].[C:20](OC(=O)C)(=[O:22])[CH3:21].O>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:11])[CH:4]([CH:5]([O:6][C:20](=[O:22])[CH3:21])[C:13]([Cl:19])([Cl:12])[C:14]([F:17])([F:16])[F:15])[CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:1][C:2]1([CH3:11])[CH:4]([CH:5]([OH:6])[C:13]([Cl:18])([Cl:12])[C:14]([F:17])([F:16])[F:15])[CH:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: COC(=O)C1C(C=O)C1(C)C
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Product: COC(=O)C1C(C(OC(C)=O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 50 °C
Reaction time: 10 h
Yield: 35 %
Yield: 43 %

Procedure:
To a solution of 156 mg (1.00 mmol) of methyl 2,2-dimethyl-3-formylcyclopropanecarboxylate in 1 ml of DMF, 78 mg (1.19 mmol) of zinc powder and 0.177 ml (1.50 mmol) of 1,1,1-trichlorotrifluoroethane were added at 0° C., and the mixture was stirred at 0° C. for 30 minutes and at 50° C. for 10 hours. Then, 0.5 ml of acetic anhydride was added at room temperature, and the mixture was stirred for 10 minutes. After an addition of 2 ml of water, the mixture was extracted with diethyl ether (2 ml×5 times). The extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=2/3) to isolate 122 mg (35%) of methyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate and 133 mg (43%) of methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[C:46]([C:50]1[CH:68]=[CH:67][C:53]([CH2:54][NH:55][CH2:56][CH2:57][CH:58]([C:63]([F:66])([F:65])[F:64])[C:59]([F:62])([F:61])[F:60])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]([CH2:56][CH2:57][CH:58]([C:63]([F:64])([F:65])[F:66])[C:59]([F:60])([F:61])[F:62])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:67][CH:68]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCC(C(F)(F)F)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCC(C(F)(F)F)C(F)(F)F)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a solution of 80 mg (0.41 mmol) 5-chloro-1H-indole-7-carboxylic acid and 128 mg of TBTU (0.41 mmol) in 6 ml DMF, were added 0.42 ml (2.45 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 155 mg (0.41 mmol) (4-tert-butyl-benzyl)-(4,4,4-trifluoro-3-trifluoromethyl-butyl)-amine hydrochloride was added. After stirring for 17 h at rt, the reaction mixture was diluted with 60 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 144 mg white foam (66%). MS (EI) 518.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][C:16]=3[CH:17]=2)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:35]([N:12]1[C:11]2[N:10]=[CH:9][C:8]([C:7]3[C:2]([Cl:1])=[C:3]([CH2:18][O:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]4)[CH:4]=[N:5][CH:6]=3)=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCC(OCc2cncc(-c3cnc4c(c3)CCCN4)c2Cl)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(OCc2cncc(-c3cnc4c(c3)CCCN4C(C)=O)c2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
1-{4-[4-Chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethoxy]-piperidin-1-yl}-ethanone (26 mg, 0.065 mmol) and pyridine (0.016 mL, 0.195 mmol) are dissolved in DCM (1.0 mL) and the mixture is cooled down to 0° C. Acetyl chloride (0.007 mL, 0.097 mmol) is added and the mixture is warmed up to room temperature and stirred for 1 hr. Then saturated NaHCO3 aqueous solution (10 mL) is added along with DCM (30 mL) and water (15 mL). The mixture is stirred for 15 min and the aqueous layer is separated, extracted with DCM (2×10 mL) and EtOAc (2×10 mL). All the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 17 mg of the titled product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH:17]([CH3:19])[CH3:18])([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]#[N:9].[CH2:20](CN)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:29][N:30](C)C=O.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH:17]([CH3:19])[CH3:18])([CH2:6][CH2:5][CH:4]([N:30]([CH3:29])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:3][CH3:2])[C:8]#[N:9])=[CH:11][CH:12]=1
Reactant: NCCc1ccccc1
Reactant: CN(C)C=O
Reactant: CC(C)C(C#N)(CCCCCCl)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC(CCC(C#N)(c1ccc(F)cc1)C(C)C)N(C)Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The product from Example 6, Step (a) (0,538 g, 1.91 mmol) was combined with N-benzylmethylamine (0.28 mL, 2.2 mmol), N,N-dimethylformamide (1.3 mL), diisopropylethylamine (0.33 mL, 1.91 mmol), and tetrabutylammonium iodide, and the mixture was then stirred at 70° C. overnight. Upon cooling, the reaction product was diluted with ethyl acetate (50mL) and washed with half-saturated sodium bicarbonate (30 mL). The aqueous layer was extracted with additional ethyl acetate (2×30 mL). The combined organic was dried over MgSO4, and the crude product was concentrated. Silica gel chromatography, using diethyl ether as the eluent, followed by concentration, afforded a product compound as an oil which was characterized by NMR as follows: NMR (free base) (CDCl3, 400 MHz, partial): 3.91 (s, 2H); 2.13 (s, 3H); 1.18 (d, 3H, J=6 Hz); 0.75 (d, 3H, J=6 Hz); Analysis calc'd. for C24H31FN2 : C, 78.64; H, 8.53; N, 7.64; Found: C, 78.54; H, 8.52; N, 7.84
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[CH:24]1([CH2:27][NH2:28])[CH2:26][CH2:25]1>C(O)C>[CH:24]1([CH2:27][NH:28][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH2:26][CH2:25]1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)n1cnc2c(NCC3CC3)nc(F)nc21
Yield: 83.1 %

Procedure:
6-Chloro-2-fluoro-9-isopropyl-9H-purine (0.3 g, 1.4 mmol), diisopropylethylamine (0.2 g, 1.55 mmol) and cyclopropylmethylamine (0.24 g, 2.7 mmol) were stirred together in ethanol (30 ml) at room temperature for 6 h. Volatiles were removed and the residue taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel flash column chromatography (ethyl acetate:hexane 3:2) to give the pure product (290 mg, 83%) as a colorless gum. δH (CDCl3, 500 MHz) 0.29-0.27 (2 H, m, CHHCHH of Cp), 0.56-0.54 (2H, m, CHHCHH of Cp), 1.13 (1 H, s, br, CH of Cp), 1.58 (6 H, d, J 7.5, CH[CH3]2), 3.44 (2 H, s, br, NHCH2Cp) 2.97 (1 H, s, br, CH of Cp), 4.74-4.72 (1 H, m, CHMe2), 6.22 (1 H, s, br, NH), 7.76 (1 H, s, ArH); δC (CDCl3, 500 MHz) 160.09 (C), 156.14 (C), 147.4 (C), 137.38 (CH), 118.26 (C), 47.14 (CH), 45.78 (CH2), 22.46 (2×CH3), 10.06 (CH), 3.5 (2×CH2)
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][CH3:21])[CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:20][CH3:21])[CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: CC[C@@H](COCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H](N)COCC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 2-(2-(tert-butoxycarbonylamino)butoxy)acetate (1 eq, from the previous step) in DCM (0.4 M) at room temperature was added a solution of 4 M HCl in dioxane (10 eq). The reaction was stirred for 2 hours, at which time more 4 M HCl in dioxane (3 eq) was added and stirred for 1 hour. The reaction mixture was concentrated en vaccuo to give the product as an oil. The material was carried onto the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][S:6][CH2:7][CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3].[P:16]([O-:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][P:16]([O:20][CH2:21][CH3:22])([C:9]([OH:15])([CH2:8][CH2:7][S:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:23])[CH3:19]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)C(=O)CCSCCN(C)C
Product: CCOC(=O)C(O)(CCSCCN(C)C)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 2.33 g (0.01 mole) of ethyl 4-(2-(N,N-dimethylamino)ethylthio)-2-oxobutanoate in 6.9 g (0.05 mole) of diethyl phosphite was stirred at 20°-30° for 4 days. The excess diethyl phosphite is removed under vacuum on a rotary evaporator, and the crude product is purified by flash chromatography on silica gel using chlorofomi/ethanol as eluant.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][C@H:27](OS(C)(=O)=O)[CH2:26]2)=[CH:21][CH:20]=1.O>CCCCCC.CS(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][C@@H:27]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:26]2)=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(Cl)cc2)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
60% sodium hydride (34 mg, 0.87 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (4 ml). After stirring at room temperature for 25 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (152 mg, 0.77 mmol) was added to the obtained suspension. They were stirred at room temperature for 25 minutes and then at 50° C. for 25 minutes. A solution of (S)-1-(4-chlorophenethyl)-3-methanesulfonyloxypyrrolidine (252 mg, 0.83 mmol) in dimethyl sulfoxide (2 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 90 minutes. The reaction liquid was poured into water in ice cooling bath. After the extraction with ethyl acetate, the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (2:1) and then with hexane and ethyl acetate (1:2) as the eluents. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5-[1-(4-chlorophenethyl) pyrrolidine-3-yl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (44 mg, 14%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1.O>CN(C)C=O>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
To a suspension of piperidin-4-ol (2.79 g, 28 mmol) and potassium carbonate (3.88 g, 28 mmol) in N,N-dimethylformamide (40 mL), 4-Fluoro-2-methoxy-1-nitro-benzene (4.0 g, 23 mmol) is added and stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is collected by a filtration. The resulting solid is dried in vacuo at 50° C. to afford 1-(3-methoxy-4-nitro-phenyl)-piperidin-4-ol (5.23 g) as yellow solids in 89% yield.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][NH:25][C:26](=[O:31])[CH2:27]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C1CNCCN1
Solvent: CCCCO
Product: Cc1nc(N2CCNC(=O)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 84 mg of piperazine-2-one in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-oxopiperazin-1-yl)nicotinamide. MS (Q1) 422.3 (M)+.