Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
17.1 mg (18 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 22) was dissolved in 0.6 mL dioxane/water (1:1) and reacted with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride in a process similar to the synthesis process in Example 1. After lyophilization from dioxane, 14.8 mg (89% of the theoretical) of the title compound was obtained in the form of a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])[CH2:20][CH2:19]2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccccc1N1CCC(N2CCC(CNC(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1N1CCC(N2CCC(CN)CC2)CC1
Reaction time: 144 h

Procedure:
A suspension of 6 (100 mg, 0.232 mmol) and 10% Pd/C (30 mg) in 50 ml of ethyl acetate was hydrogenated at atmospheric pressure for 6 days. The suspension was subsequently filtered through celite and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][Cl:8])=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)CCCCl)cc1

Procedure:
53 ml of toluene and 70.5 g of 4-chlorobutyryl chloride are dissolved in 100 ml of dichloromethane, and the solution is added at 10° C. to a suspension of 74 g of aluminium chloride in 200 ml of dichloromethane. The temperature is then allowed to rise for a quarter of an hour and the mixture is treated with ice-cold water. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give 96.9 g of 4'-methyl-4-chlorobutyrophenone in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)/[CH:10]=[CH:11]/[CH3:12].Cl.O.N>>[OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:11]([CH3:12])[CH:10]=[C:9]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C/C=C/C(=O)c1ccccc1
Reactant: Nc1ccccc1O
Agent: Cl
Agent: N
Solvent: O
Product: Cc1cc(-c2ccccc2)c2cccc(O)c2n1
Yield: 55.7 %

Procedure:
A mixture of 2-hydroxyaniline (2 g), crotonoylbenzene (8.03 g) and concentrated hydrochloric acid (8 ml) was refluxed for 24 hours. The mixture was neutralized with concentrated ammonia water under ice-cooling, and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified according to a conventional manner to give 8-hydroxy-2-methyl-4-phenylquinoline (2.4 g) as an oil.
Reaction SMILES: [C:1]1([NH:11][CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](OCC)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[O:15]=[C:14]1[N:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]2=[N:11][CH:12]=[C:13]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CCOC(=O)C(=CNc1nccc2ccccc12)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c3ccccc3ccn2c1=O
Yield: 83 %

Procedure:
A stirred mixture of diethyl isoquinolylaminomethylenemalonate (32.0 g., 0.0986 mole) and diphenyl ether (125 ml.) under nitrogen was heated at a temperature of 235° for 15 minutes. The solid, m.p. 183°-184°, obtained upon cooling and dilution with Skellysolve B was recrystallized from ethanol to give salmon crystals (22 g., 83% yield), m.p. 189°-191°. An analytical sample, recrystallized from ethanol, had m.p. 190°-192°.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[CH:5]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0° C. was added a solution of 3-bromophenol 6-1 in DMF (40 mL) over 40 min. After the addition was complete, the solution was stirred for an additional 30 min. The solution was then treated with neat bromoacetaldehyde diethyl acetal (17.36 g, 115.6 mmol). The solution was heated at 100° C. for 8 h, cooled to room temperature, and extracted with Et2O (3×200 mL). The combined organic extracts were washed with 10% aq. NaOH (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated to give 6-2 as a yellow oil.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[C@@H:9]([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1.CCOC(C)=O>O.C1COCC1>[Cl:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[C@@H:9]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Yield: 1.7 %

Procedure:
LiOH (1.40 g, 58.3 mmol) was dissolved in water (50 mL) and added to (S)-ethyl {7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21a, 5.71 g, 11.7 mmol) in THF (50 mL). The reaction mixture was stirred at rt for 75 min EtOAc (150 mL) was added. Washed with HCl (1 M, 100+50 mL) and brine (50 mL). The organic phase was dried over Na2SO4 and after filtration the solvents were evaporated in vacuo to yield the crude the title compound (82 mg, 107%) which was used further in the synthesis of Example 5a.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:27]1[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=1[CH:34]([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:21][CH2:22][N:23]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[CH:34]([CH3:36])[CH3:35])[CH2:24][CH2:25]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)c1c(N)ncnc1Cl
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Temperature: 120 °C
Reaction time: 56 h

Procedure:
The mixture of 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine (162.8 mg; 0.47 mmol; 1.0 eq.), 6-chloro-5-isopropyl-pyrimidin-4-ylamine (81.6 mg; 0.47 mmol; 1.0 eq.) and potassium carbonate (82.1 m g; 0.59 mmol; 1.25 eq.) in DMSO (3 ml) was stirred 120° C. for 56 hr. The crude was purified by prep HPLC to afford the title compound. LC-MS (M+H=478, obsd=478). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.66-7.59 (m, 1H), 7.54 (ddd, J=7.7, 4.9, 2.1 Hz, 1H), 7.48 (s, 1H), 7.08 (t, J=9.1 Hz, 1H), 6.13 (s, 2H), 3.87 (t, J=6.2 Hz, 2H), 3.11 (t, J=6.9 Hz, 4H), 2.93-2.80 (m, 3H), 2.68 (t, J=6.2 Hz, 2H), 2.30-2.21 (m, 3H), 1.92 (dtd, J=24.6, 12.8, 12.1, 4.0 Hz, 5H), 1.30 (d, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15]C(C)=O>>[C:1]([O:14][CH3:15])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CC(C)=O
Product: CCCCCCCCCCCC(=O)OC

Procedure:
As internal standard, 0.06 g of methayl laurate and 2 g of a sample were prepared and dissolved in 4 g of acetone, and the obtained solution (2 μL) was introduced to a device. An analytical curve was formed from the peak area of the internal standard, and the peak area obtained when the concentration of methyl laurate was changed, and an amount of an unreacted component contained the sample was determined.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (5.85 g) was dissolved in methanol (20 ml), 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (4.40 g).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CS(C)=O>CCOCC>[Br:19][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCC(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Product: BrCCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
4,4-Diphenyl-1-butanol (22.41 g, 0.099 mol) was dissolved in ether (250 mL). CBr4 (41.07 g, 0.123 mol) was added and the reaction cooled to 0° C. Triphenylphosphine (38.96 g, 0.148 mol) in ether (400 mL) was added dropwise to the reaction. The reaction was then allowed to warm to room temperature overnight. DMSO (3.51 mL) was added, and the reaction allowed to stir for 8 hours. The white precipitate was filtered and washed with ether (100 mL). The ether was removed in vacuo, and the residue washed with hexanes and filter. The hexanes were removed in vacuo, and the residue chromatographed on silica gel eluting with hexanes to give 20.72 g (72%) of desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (2.5 g, 5.89 mmol) and 10% palladium on activated carbon (900 mg) in methanol (600 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb for 5 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (1.7 g, 68%) as a white solid which was used without further purification: LC/MS m/e calcd for C23H26N2O4S [M+H]+ 427.54, observed 426.8; 1H NMR (400 MHz, CDCl3) δ ppm 10.81 (br. s., 1H), 8.79 (br. s., 1H), 8.56 (s, 1H), 7.88-7.93 (m, J=8.3 Hz, 2H), 7.48-7.53 (m, J=8.1 Hz, 2H), 6.48 (s, 1H), 5.31 (s, 1H), 4.30 (t, J=7.7 Hz, 1H), 3.99 (s, 3H), 3.03 (s, 3H), 2.12-2.33 (m, 2H), 1.59-1.86 (m, 4H), 1.45-1.56 (m, 2H), 1.15-1.29 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[NH:3]/[C:4](=[N:17]\[NH2:18])/[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[N:10]=1.[CH:19]([O-])([O-])OCC>>[Cl:1][C:2]1[N:3]2[CH:19]=[N:18][N:17]=[C:4]2[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[N:10]=1
Reactant: N/N=c1\[nH]c(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCOC([O-])[O-]
Agent: NNc1nc(Cl)nc2c1ncn2C1CCCCO1
Product: Clc1nc2c(ncn2C2CCCCO2)c2nncn12

Procedure:
A mixture of (6Z)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-6H-purin-6-one hydrazone [which is a tautomeric form of 2-chloro-6-hydrazino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine; 0.1 g, 0.5 mmol] and ethyl orthoformate (3 g, 20 mmol) was stirred at 98° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide the product. LCMS calculated for C11H12ClN6O (M+H): 279.1. found: 279.0.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[N:44][CH:45]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:42]4[CH:43]=[N:44][CH:45]=[C:40]([O:39][CH3:38])[CH:41]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: COc1cncc(B(O)O)c1
Product: COc1cncc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)c1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (5-methoxypyridin-3-yl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=528, obsd.=528).
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=[O:2].C(CN1C2C(=CC=CC=2)C[C@@H](NC(C2NC3C(C=2)=CC(Cl)=CC=3)=O)C1=O)(O)=O.C(CN1C2C(=CC=CC=2)C[C@@H](NC(C2NC3C(C=2)=CC(Cl)=CC=3)=O)C1=O)(OC)=O>>[C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([OH:3])=[O:2]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: O=C(O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21

Procedure:
The title compound was prepared from (S)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 8) by the procedures described for the preparation of (R)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 9) from (R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril. HPLC/MS [M+H]+, 398.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)[CH:7]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cn(-c2cc(F)ccc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.4 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (50 g, 314 mmol), 4-methyl-1H-imidazole (25.7 g, 314 mmol) and potassium carbonate (100 g, 725 mmol) in dichloromethane (600 mL) was stirred at room temperature for 4 days. The mixture was washed with water then dried over magnesium sulfate. Solvent was removed under reduced pressure and the residue was recrystallized in ethyl acetate to provide product 1A as a yellow solid (35 g, 50% yield). EIMS 221.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]([OH:20])([CH3:19])[CH3:18].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH:17]([CH3:19])[CH3:18])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: CC(C)O
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(C)Oc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, isopropanol and DBU in DME. EI-MS m/e (%): 254 (M+, 41), 212 ([M—C3H6]+, 55), 184 (35), 170 (100).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1.[NH4+].[Cl-]>C1COCC1>[I:8][C:4]1[CH:3]=[C:2]([C:16]2([OH:19])[CH2:17][CH2:18][O:14][CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Ic1cccc(I)c1
Reactant: O=C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cccc(I)c2)CCOC1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A solution of 1,3-diiodobenzene (3.0 g, 9.09 mmol) in dry THF (40 mL) was cooled to −78° C. under a nitrogen before addition of n-butyl lithium (1.6 M in hexane, 5.6 mL, 9.09 mmol) dropwise over 10 min. The reaction mixture was stirred for 30 min and then a solution of dihydrofuran-3(2H)-one (782 mg, 9.09 mmol) in THF (3 mL) added over 5 min. The reaction mixture was stirred for 1 h at −78° C. then poured into saturated NH4Cl solution. The mixture was extracted with ethyl acetate and the organic layer dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give 3-(3-iodophenyl)tetrahydrofuran-3-ol (2.0 g, 76%) as a colorless liquid: 1H NMR (CDCl3, 300 MHz) δ 7.87 (t, J=1.8 Hz, 1H), 7.64 (td, J=7.8 Hz, 1H), 7.45 (td, J=7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 4.26-4.06 (m, 2H), 3.98-3.82 (m, 2H), 2.46-2.32 (m, 1H), 2.30-2.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].N1C2C(=CC=CC=2)C2(COC3C=[C:36]4[C:40](=[CH:41][C:31]2=3)[CH2:39][CH2:38][O:37]4)C1=O>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:39][CH:38]1[CH2:31][CH2:41][CH2:40][CH2:36][O:37]1)[C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 6-methoxy-5-methyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ 7.28 (dd, J=7.8, 7.8 Hz, 1H), 7.13-6.97 (m, 3H), 6.47 (s, 1H), 6.43 (d, J=4.3 Hz, 1H), 4.91 (dd, J=8.9, 2.1 Hz, 1H), 4.66 (dd, J=8.9, 3.3 Hz, 1H), 4.02-3.59 (m, 4H), 3.79 (s, 3H), 3.43-3.31 (m, 1H), 1.99 (s, 3H), 1.92-1.77 (m, 1H), 1.71-1.26 (m, 5H); MS (ES+) m/z 380.4 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])[C:17]([O:19][CH2:20]C)=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[C:8]([Br:29])=[N:9][NH:10]2)(=O)C.C[O-].[Mg+2].C[O-]>CO>[Br:29][C:8]1[C:7]2[C:11](=[C:12]([Br:28])[CH:13]=[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]([O:19][CH3:20])=[O:18])[C:6]=2[CH2:5][OH:4])[NH:10][N:9]=1
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1COC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-3,7-dibromo-1H-indazol-5-yl)methyl)succinate (540 mg, 1.011 mmol) was dissolved in methanol (12 mL). 6-10% Magnesium methoxide solution in methanol (2.7 mL, 2.041 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 5 mL 1N hydrochloric acid. Mixture stirred at room temperature for 30 minutes. Methanol was removed from the mixture by roto-vap. Residue was dissolved in water and then made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white foam in 99% yield. 1H NMR, MS (M−H)−=463.1, 461.1, 465.1.