Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH3:39])[C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2].F[C:41](F)(F)[C:42]1C=C(C(C)(C)C(N(C)C2C(C3C=CC=CC=3C)=CC(NC(C3CC3)=O)=NC=2)=O)C=C(C(F)(F)F)C=1>>[F:24][C:22]([F:25])([F:23])[C:20]1[CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[C:12]([N:11]([CH3:31])[C:8]2[C:7]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[CH:6][C:5]([N:4]([CH3:39])[C:1]([CH:2]3[CH2:42][CH2:41]3)=[O:3])=[N:10][CH:9]=2)=[O:30])[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: Cc1ccccc1-c1cc(NC(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)N(C)c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Product: Cc1ccccc1-c1cc(N(C)C(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as a white foam in comparable yield according to the procedure described above for the preparation of N-[6-(acetyl-methyl-amino)-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide using cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-amide instead of N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([NH:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(CN)n1nnnc1S
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(CNC(=O)OC(C)(C)C)n1nnnc1S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 1-[1-(aminomethyl)ethyl]-1H-tetrazole-5-thiol hydrochloride (17 g) and triethylamine (19.33 g) in 50% aqueous dioxane (80 ml) was added a solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (21.4 g) in dioxane (50 ml) under cooling in an ice bath. The mixture was stirred for 1.5 hours at ambient temperature and concentrated to third volume. The aqueous solution was washed with diethyl ether and the washings were reextracted with aqueous solution of potassium carbonate. The two aqueous solutions were combined, washed with diethyl ether and mixed with ethyl acetate. The mixture was acidified with 10% hydrochloric acid and the organic layer was separated out. The solution was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with n-hexane to give 1-[1-{(N-t-butoxycarbonylamino)methyl}ethyl]-1H-tetrazole-5-thiol (19.15 g), mp 156° to 158° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([CH:15]=[CH2:16])[C:8]=1[O:17][CH3:18].[C:19](=[O:21])=[O:20].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:18][O:17][C:8]1[C:9]([CH:15]=[CH2:16])=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: C=Cc1c(SC)ccc(Br)c1OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1c(SC)ccc(C(=O)O)c1OC
Temperature: -100 °C
Reaction time: 0.33 h

Procedure:
At −100° C., n-BuLi (25 ml, 15% in n-hexane, 4.1 mmol) was added to a solution of 1-bromo-2-methoxy-4-methylsulfanyl-3-vinylbenzene (7 g, 31.3 mmol) in THF (300 ml), and the mixture was stirred at −100° C. for 20 min. At −100° C., CO2 was then introduced (exothermic reaction up to −60° C.). At −80 to −90° C., the mixture was then stirred for another 1 h, and NaOH (100 ml) was added dropwise at −40° C. The solution was stirred into EtOAc (400 ml), and the mixture was extracted 3× with 5% strength NaOH and acidified to pH=1 using 10% strength HCl. The H2O phase was extracted with EtOAc (300 ml), and the combined organic phases were dried over MgSO4 and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:39][CH3:40])[C:20]3[C:21]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CO>CO.O.C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:39][CH3:40])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCN(c1ncnc2[nH]ccc12)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 60 °C
Yield: 50.8 %

Procedure:
To a solution of (S)-2-(3,5-dichlorophenylamino)-1-(3-(ethyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl) ethanone (70 mg, 0.11 mmol) in MeOH:H2O (4:1, 10 mL), K2CO3 (48 mg, 0.35 mmol) was added and the reaction mixture was heated at 60° C. for 1 h, the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under vacuo to give a residue. The residue triturated with 10% MeOH in EtOAc (15 mL), the suspension was filtrated, the filtrate was evaporated under vacuo to give the crude compound that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (25 mg, 45%) of the titled compound. 1H NMR (400 MHz, DMSO-d6): δ 11.79 and 11.6 (2s, 1H), 8.106 (d, J=6.8 Hz, 1H), 7.18 and 7.13 (2s, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 6.62 (s, 1H), 6.49 and 6.43 (2s, 1H), 6.37 and 6.33 (2t, J=2.3 Hz, 1H), 4.74-4.69 (m, 1H), 4.46-4.39 (m, 1H), 4.13-3.88 (m, 4H), 3.76-3.70 (m, 2H), 3.20-3.16 (m, 1H), 3.00 (t, J=12.0 Hz, 1H), 2.86 (t, J=12.0 Hz, 1H), 2.62 (t, J=13.6 Hz, 1H), 1.98-1.81 (m, 3H), 1.65-1.49 (m, 1H), 1.19 (t, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=447. HPLC (254 nm): 97.68%. HPLC (210 nm): 98.20%.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([O-:11])=[O:10]>CCOC(C)=O>[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[N:14]=[C:4]=[O:3])([O-:11])=[O:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=C=Nc1ccccc1[N+](=O)[O-]

Procedure:
Method a (from 2-nitroanilines): To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0° C. was added a solution of the 2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 2-nitrophenylisocyanate as a yellow solid. This material was refluxed in a mixture of excess tert.-BuOH in CH2Cl2 for 2.5 h. Removal of the solvent left an orange solid which was purified by silica gel column chromatography with hexane/EtOAc to give the (2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
Reaction SMILES: ClC(S[CH2:5][CH3:6])=O.[CH3:7]C(SC1C=CC(SCCO)=CC=1)CC.[CH3:22][CH:23]([O:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33][OH:34])=[CH:29][CH:28]=1)CC.CC(C)=CCSC1C=CC(SCCO)=CC=1.CC(SC1C=CC(OCCO)=CC=1)CC>>[CH3:7][C:5]([CH3:6])=[CH:22][CH2:23][O:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33][OH:34])=[CH:29][CH:28]=1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Reactant: CCC(C)Sc1ccc(SCCO)cc1
Reactant: CCSC(=O)Cl
Agent: CC(C)=CCSc1ccc(SCCO)cc1
Agent: CCC(C)Sc1ccc(OCCO)cc1
Product: CC(C)=CCOc1ccc(OCCO)cc1

Procedure:
In the same manner, S-ethyl chlorothioformate is reacted with each of 2-[4(1-methylpropylthio)phenylthio]ethanol, 2-[4(1-methylpropoxy)phenoxy]ethanol, 2-[4(3-methyl-2-butenylthio)phenylthio]ethanol and 2-[4(1-methylpropylthio)phenoxy]ethanol to give, respectively, compounds 64, 65, 66, 67 and 84 under Table A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][C:25]([OH:27])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN(C)C=O.C(Cl)(=O)C([Cl:36])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][C:25]([Cl:36])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 10 g of product from Example 67, 0.0965 g of dimethylformamide and 150 ml of methylene chloride is added dropwise 3.46 ml of oxalyl chloride. The reaction is stirred at room temperature for 20 hours and the solvent concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 10.5 g of the desired product as colorless needles.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]1[N:14]=[C:13]([CH2:15][Cl:16])[CH:12]=[C:11]([OH:17])[N:10]=1)[CH3:7].O.[OH-].[Na+]>C(Cl)Cl>[CH2:6]([O:8][C:9]1[N:14]=[C:13]([CH2:15][Cl:16])[C:12]([Cl:4])=[C:11]([OH:17])[N:10]=1)[CH3:7]
Reactant: CCOc1nc(O)cc(CCl)n1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOc1nc(O)c(Cl)c(CCl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.8 ml (0.035 mol) of sulphuryl chloride are added dropwise to a solution of 6 g (0.032 mol) of 2-ethoxy-4-chloromethyl-6-hydroxy-pyrimidine in 90 ml of methylene chloride and the mixture is subsequently stirred at room temperature for 4 hours. The mixture is then treated with 100 ml of water and adjusted to pH 7 with 30% sodium hydroxide solution. The organic phase is separated and the combined organic phases are extracted with water, dried over anhydrous sodium sulphate and evaporated. There is obtained crystalline 2-ethoxy-5-chloro-4-chloromethyl-6-hydroxy-pyrimidine, 1H-NMR (CDCl3): 1.45 (t, OCH2CH3), 4.54 (q, OCH2CH3), 4.54 (s, CH2Cl), 9.80 (broad signal, OH).
Reaction SMILES: [F-:1].[K+].[Cl-].C(CCCCCCCCCCCC[NH3+])C1C=CC=CC=1.[N+]([C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[C:29]#[N:30])([O-])=O>O.C1(C)C=CC=CC=1>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:27]([F:1])[C:28]=1[C:29]#[N:30]
Reactant: [F-]
Reactant: N#Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH3+]CCCCCCCCCCCCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c(F)cccc1Cl
Temperature: 105 °C
Yield: 22.5 %

Procedure:
A solution of 120 g (2 mols) of potassium fluoride in 100 ml of water was treated first with 30 ml of a 50% strength aqueous solution of benzyldodecyl-ammonium chloride and then with a solution of 186 g (1 mol) of 2-nitro-6-chloro-benzonitrile in 250 ml of toluene. The reaction mixture was heated to 105° C. for 8 hours. After cooling, the organic phase was separated off and the aqueous phase was extracted with chloroform. The organic phase and the chloroform extracts were combined and washed and then freed from the organic solvent by distillation. On distillation of the residue, 35 g of 2-chloro-6-fluoro-benzonitrile (boiling point: 105°-108° C./15 mm Hg) were obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:22][CH3:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[S:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([Cl:18])[N:17]=2)=[CH:7][CH:6]=1.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>C(#N)C>[Br-:1].[Cl:18][C:16]1[N:17]=[C:13]([N:12]=[N:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:22][CH3:23])[CH2:3][CH2:2][N:27]3[CH:28]=[CH:29][N+:25]([CH3:24])=[CH:26]3)=[CH:6][CH:7]=2)[S:14][C:15]=1[N+:19]([O-:21])=[O:20]
Reactant: CCN(CCBr)c1ccc(N=Nc2nc(Cl)c([N+](=O)[O-])s2)cc1
Reactant: Cn1ccnc1
Solvent: CC#N
Product: CCN(CCn1cc[n+](C)c1)c1ccc(N=Nc2nc(Cl)c([N+](=O)[O-])s2)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 30 %

Procedure:
1.20 g N-(2-bromoethyl)-4-[(4-chloro-5-nitro-1,3-thiazol-2-yl)diazenyl]-N-ethylaniline is dissolved in 20 ml acetonitrile followed by subsequent addition of 5.99 g 1-methyl-1H-imidazole. The reaction mixture is stirred under reflux for 3 days and allowed to cool to room temperature. The resulted precipitate is filtered off, washed with acetonitrile, and dried in vacuum at 40° C. 0.43 g 1-{2-[{4-[(4-chloro-5-nitro-1,3-thiazol-2-yl)diazenyl]phenyl}(ethyl)amino]ethyl}-3-methyl-1H-imidazol-3-ium bromide is obtained as a bordeaux red powder.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.Cl.[CH2:29]([N:31]([CH2:37][CH3:38])[CH2:32][CH2:33][C:34](O)=[O:35])[CH3:30].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:35])[CH2:33][CH2:32][N:31]([CH2:37][CH3:38])[CH2:29][CH3:30])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CCN(CC)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-(diethylamino)propionic acid hydrochloride (0.0032 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(diethylamino)-1-propanone (0.025 g, 0.00005 mol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.CN(C)CCN(C)C.Cl[CH2:25][C:26]1([CH2:30]Cl)[CH2:29][O:28][CH2:27]1>C1COCC1.O>[C:5]1([S:2]([CH:1]2[CH2:30][C:26]3([CH2:29][O:28][CH2:27]3)[CH2:25]2)(=[O:4])=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC1(CCl)COC1
Reactant: CS(=O)(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)C1CC2(COC2)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of methylsulfonylbenzene (2.00 g; 12.8 mmol) in dry THF (40 mL) under nitrogen at 0° C. was added butyl lithium (25.6 mmol; 2.5M solution on hexane). The mixture was stirred for 1 hour and then cooled to −20° C. Tetramethylethylenediamine (1.93 mL; 12.8 mmol) was added followed by a solution of 3,3-bis(chloromethyl)oxetane (1.98 g; 12.8 mmol) in dry THF (10 mL). The mixture was allowed to warm to 0° C. and then slowly allowed to reach 15° C. over 12 hours. Water (100 mL) was added and the mixture was extracted into ethyl acetate (4×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified on silica gel (Biotage system, utilizing two 120 g columns in series) eluting with hexane/ethyl acetate (2:1 to 1:2 gradient). The desired product was obtained as an off white solid (700 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S([O-])(=O)(=O)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35]O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:35][CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: OCCCc1ccc(F)cc1
Agent: CS(=O)(=O)[O-]
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CCCc2ccc(F)cc2)c1=O
Yield: 90.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and the mesylate derivative of 3-(4-fluorophenyl)-1-propanol {J. Med. Chem., 19, 461 (1976)} were reacted to yield the title compound as a yellow oil (yield: 90.1%). The mesylate derivative was prepared in accordance with the procedure of Example 1(9).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21].C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[S:2]([N:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21])[S:2]([CH3:1])(=[O:4])=[O:3])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)N1CCC(=O)c2cc(N)ccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCC(=O)c2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc21
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of methanesulfonyl chloride (2.004 g) in methylene chloride (5 ml) was added dropwise to a solution of 6-amino-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.526 g) and triethylamine (2.121 g) in methylene chloride (15 ml) with ice cooling over a period of 15 minutes and stirred for further 1 hour. The mixture was diluted with chloroform, washed successively with 10% hydrochloric acid, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residual solid was washed with methanol and dried to give 6-(N,N-dimesylamino)-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.51 g).
Reaction SMILES: BrCC1C=C(Cl)SC=1Cl.[Cl:10][C:11]1[S:12][C:13]([Cl:19])=[CH:14][C:15]=1[C:16](O)=[O:17]>C1COCC1>[Cl:10][C:11]1[S:12][C:13]([Cl:19])=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: O=C(O)c1cc(Cl)sc1Cl
Agent: Clc1cc(CBr)c(Cl)s1
Solvent: C1CCOC1
Product: OCc1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-bromomethyl-2,5-dichloro-thiophene: Borane-THF complex (6.009 mL, 6.01 mmol) was added dropwise into a THF (5 mL) solution of 2,5-dichlorothiophene-3-carboxylic acid (296 mg, 1.502 mmol). The resultant solution was stirred at rt under argon overnight. The reaction was quenched with dilute HCl (12 mL) and stirred at rt for 1 h. The reaction was diluted with water and extracted with EtOAc (2×20 mL), washed with NaOH solution and brine, dried (Na2SO4), filtered and evaporated to provide (2,5-dichloro-thiophen-3-yl)-methanol, which was purified by flash chromatography. LCMS m/z 183.2 (M+H)+. To a solution of this intermediate (215 mg, 1.175 mmol) in DCM (7 mL) was added PBr3 (0.144 mL, 1.527 mmol) via syringe. The reaction mixture was stirred at rt under argon for 15 min, then quenched with water (18 mL) and stirred at rt for 1 h. The aqueous layer was extracted with DCM (2×10 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated yielding 103A (250 mg). 1HNMR (400 MHz, CD3OD) δ: 4.47 (s, 2 H), 7.02 (s, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:7]=1)=O)C.[NH3:23]>CO>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:8]1[N:7]=[C:6]([C:4]([NH2:23])=[O:3])[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]=12
Reactant: N
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)c2ncccn12
Solvent: CO
Product: NC(=O)c1nc(Cc2ccccc2F)c2ncccn12
Temperature: 150 °C
Reaction time: 1.33 h

Procedure:
8.200 g (27.40 mmol) of ethyl-8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxylate was distributed in 8 microwave vessels. Each vessel was charged with 10 ml of 7N solution of ammonia in methanol and stirred for 80 min at 150° C. in the microwave. After cooling, the contents of the vessels were combined, the resultant precipitate was filtered with suction, washed with a little methanol and dried under high vacuum. 8.42 g (quant.) of the target compound was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([CH3:14])[N:4]2[C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:16][N:17]=[C:3]12.[O:22]=[C:23]1[NH:31][C:26]2[N:27]=[CH:28][N:29]=[CH:30][C:25]=2[C@@:24]21[CH2:42][C:34]1=[N:35][CH:36]=[C:37]([C:39](O)=[O:40])[CH:38]=[C:33]1[CH2:32]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[OH:21][C:18]([C:15]1[N:4]2[C@H:5]([CH3:14])[C@H:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:7][C@H:2]([NH:1][C:39]([C:37]3[CH:38]=[C:33]4[CH2:32][C@@:24]5([C:25]6[CH:30]=[N:29][CH:28]=[N:27][C:26]=6[NH:31][C:23]5=[O:22])[CH2:42][C:34]4=[N:35][CH:36]=3)=[O:40])[C:3]2=[N:17][CH:16]=1)([CH3:20])[CH3:19]
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2ncc(C(C)(C)O)n21
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncncc32)c2ncc(C(C)(C)O)n21
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of 2-[(5R,6S,8S)-8-amino-5-methyl-6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl]propan-2-ol (6.7 mg, 0.023 mmol) in N,N-dimethylformamide (195 μL) was added (6S)-6′-oxo-5,6′,7,7′-tetrahydrospiro[cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylic acid (5.5 mg, 0.019 mmol), 1-hydroxy-7-azabenzotriazole (0.2 mg, 0.002 mmol), N-methylmorpholine (10.7 μL, 0.097 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 mg, 0.023 mmol). The mixture was stirred 2 h. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (1.4 mg). HRMS 550.2546 (M+1). NMR (500 MHz, CD3OD): δ 8.95 (s, 1H); 8.70 (s, 1H); 8.22 (s, 1H); 8.15 (s, 1H); 7.41−7.27 (m, 5H); 6.86 (s, 1H); 5.43 (dd, J=10.7, 7.5 Hz, 1H); 5.04 (dd, J=7.0, 4.8 Hz, 1H); 3.70−3.41 (m, 5H); 2.70−2.67 (m, 1H); 2.52−2.49 (m, 1H); 1.64 (d, J=13.6 Hz, 6H); 1.32 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1.ClC(Cl)C>[Br-].[Zn+2].[Br-].ClCCl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCc1ccc(F)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CCCCCC
Product: Oc1ccc(Br)cc1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
To a solution of 4-bromophenol (13.84 gm, 0.08 Mol), 4-fluorobenzyl alcohol (8.68 gm, 0.08 Mol), and 120 mL of dichloroethane was added zinc bromide (21 gm, 0.09 Mol). The reaction mixture was stirred at 60° C. for 24 h, filtered and concentrated under reduced pressure. Pure product was obtained by flash chromatography using SiO2, dichloromethane/hexane [1:1] as eluant to give 4-bromo-2-(4-fluorobenzyl)phenol (9.25 g, 41%) as colorless oil: 1H NMR (200 MHz, DMSO-d6): δ 9.79 (s, 1H), 7.16 (m, 5H), 6.74 (d, J=8.8 Hz, 1H), 3.82 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=methylene chloride-hexanes (1:1); Rf=0.38.