Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](Cl)=[N:10][N:9]=2)=[CH:5][CH:4]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2nnc(Cl)c3ccccc23)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
To 1,1′-bis(diphenylphosphoino)ferrocene-palladium dichloride (0.046 g, 0.063 mmol), 1-(4-methoxybenzyl)-4-chlorophthalazine (0.360 g, 1.3 mmol), and phenylboronic acid (0.39 g, 3.2 mmol) was added dioxane (4.0 mL) and sodium carbonate (2.0M, aq) (1.9 ml, 3.8 mmol). The resulting mixture was heated to 100° C. in a sealed tube for 1 hour. The reaction was diluted with EtOAc and extracted with water and brine. The organic layers were dried over sodium sulfate, filtered, concentrated, and the crude was purified by ISCO silica gel chromatography (10-100% EtOAc/hexanes, 40 g column). Concentrated the product fractions to yield 1-(4-methoxybenzyl)-4-phenylphthalazine as a light yellow solid. MS m/z=327 [M+1]+. Calc'd for C22H18N2O: 326.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Clc1cccc2cc[nH]c12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 7-chloroindole (0.70 g, 4.6 mmol) and 4-piperidone hydrochloride hydrate (1.4 g, 9.2 mmol). The product was isolated as a yellow solid. Yield 0.80 g (75%). mp 205°-208° C. FDMS m/e=234 (M+ of free base).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15]([NH2:20])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O>C(#N)C.CN(C1C=CN=CC=1)C>[C:32]([O:31][C:29]([N:20]([C:15]1[C:16]2[C:11](=[CH:10][C:9]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:19])[CH:17]=2)[CH:12]=[CH:13][N:14]=1)[C:29](=[O:28])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: Nc1nccc2cc(N(Cc3ccccc3)Cc3ccccc3)c(F)cc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N(Cc3ccccc3)Cc3ccccc3)c(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.2 %

Procedure:
To a solution of Intermediate 4A (1.73 g, 3.78 mmol) in acetonitrile (20 mL) was added BOC2O (1.229 mL, 5.29 mmol) followed by TEA (0.527 mL, 3.78 mmol) and DMAP (0.092 g, 0.756 mmol), then the suspension was stirred at rt for 1 h. Solvent was removed under vacuum and the residue purified on Isco (120 g) eluting with 0 to 75% EtOAc/hexanes to give Intermediate 4B (2.185 g, 3.92 mmol, 104% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.38 (s, 18H) 4.54 (s, 4H) 7.04 (d, J=8.53 Hz, 1H) 7.28-7.40 (m, 11H) 7.53 (d, J=14.05 Hz, 1H) 8.25 (d, J=5.77 Hz, 1H); MS (ESI) m/z: 558.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6](CO)[CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:15]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(CO)c1
Solvent: C1CCOC1
Product: Cl
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
The 4-nitro-2-hydroxymethylphenol is then converted to a 2-halomethyl-4-nitrophenol via a mild halogenation reaction such as a thionyl chloride in THF or is produced directly from 4-nitrophenol in a solution of concentrated HCl, a catalytic amount of H2SO4 and formaldehyde dimethylacetal solution by bubbling gaseous HCl through the solution at about 50 to 80° C. (preferably 70° C.) until a thick white precipitate is formed. The thionyl chloride conversion of the 2-hydroxymethyl group is shown process is shown as follows:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl.[OH:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N:18]1[C:17]([CH2:16][OH:15])=[CH:21][N:20]=[CH:19]1.[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N:20]1[CH:21]=[C:17]([CH2:16][OH:15])[N:18]=[CH:19]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1cn(Cc2ccc3ccccc3n2)cn1
Product: OCc1cncn1Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloromethyl-quinoline hydrochloride (2.24 g, 10.5 mmol), 4-(hydroxymethyl)-imidazole hydrochloride (1.35 g, 10 mmol) and K2CO3 (4.2 g, 30 mmol) are dissolved/suspended in anhyd. DMF (20 mL) and heated to 100° C. with rapid stirring overnight. The reaction is cooled to r.t. and poured into water (400 mL) and extracted with chloroform (3×150 mL). The organic fractions are pooled and washed with brine (2×200 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material is purified by flash chromatography (silica, 5% methanol in dichloromethane) to give (3-quinolin-2-ylmethyl-3H-imidazol-4-yl)-methanol and (1-quinolin-2-ylmethyl-1H-imidazol-4-yl)-methanol in a 2:3 ratio. The identity of each regioisomer was determined by NMR NOE experiments. MS (ESI) 240 (M+H)+ found for both regioisomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[OH:10].[CH3:11][O:12]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:10][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH:11]=[O:12])=[C:6]([CH3:9])[CH:5]=1
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C)cc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)c(C)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methoxy-5-methylphenol (50.0 g, 362 mmol) in CH2Cl2 (1000 mL) at −5° C. were added titanium (IV) chloride (80.0 mL, 724 mmol) slowly via syringe (internal temperature was kept below 0° C. during addition) and dichloromethyl methyl ether (52.9 mL, 593 mmol). After being stirred at room temperature for 3 h, the mixture was poured into ice water. The resulting precipitate was collected by filtration and then washed with EtOAc and Et2O to afford 4-Hydroxy-5-methoxy-2-methylbenzaldehyde. 1H NMR (CDCl3) δ 10.22 (s, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.14 (s, 1H), 3.96 (s, 3H), 2.62 (s, 3H); LC/MS: (IE, m/z) (M+1)+=16.0; tR=2.06 min.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C.C=O.C(O)(=O)C.[NH3:19]>CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH2:19])=[O:3])=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1ccc(O)cc1

Procedure:
Parahydroxybenzoic acid ethyl ester is dissolved in methanol, added with formalin and acetic acid to react overnight, added to NH3(aq) to obtain para-hydroxy benzoic amide. This product was added with formalin, acetic acid and N7-bromoethyl 3-isobutyl-1-methylxanthine processed through a Mannich reaction to obtain compound 33. Through purification and then dissolution into methanol, add NaOH and ethyl bromide to gain compound 34. Various substitutions can be made to produce other desired compounds. For example, by replacing ethyl bromide with propyl bromide, compound 35 can be obtained. By replacing theophylline with IBMX, compounds 36, 37, and/or 38 can be obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxyethyl)aminopurine (70 mg, 0.24 mmol) and bromine (0.5 ml) were dissolved in methylene chloride (50 ml). The solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (71 mg, yield 80%).
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[NH2:32][C:33]1[C:34]([O:47][CH3:48])=[CH:35][C:36]([CH3:46])=[C:37]([NH:39][C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH:38]=1.[CH3:49][NH2:50]>FC(F)(F)CO.C1COCC1.CCOC(C)=O>[CH3:43][N:42]([CH3:44])[CH2:41][C:40]([NH:39][C:37]1[C:36]([CH3:46])=[CH:35][C:34]([O:47][CH3:48])=[C:33]([NH:32][C:3]2[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]3=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=3[C:15]([NH:50][CH3:49])=[O:17])[N:16]=2)[CH:38]=1)=[O:45]
Reactant: COc1cc(C)c(NC(=O)CN(C)C)cc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc(NC(=O)CN(C)C)c(C)cc2OC)[nH]c2nccc1-2
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt (375 mg, 0.782 mmol) in 2,2,2-trifluoroethanol (10 mL) was added N1-[5-amino-2-methyl-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide (204 mg, 0.861 mmol). The resulting mixture was let stir at 60° C. for 45 min. Solvents were removed under reduced pressure to afford a green residue. Half of this material was dissolved in THF (10 mL) and a 2M solution of methylamine in THF (3.88 ml, 7.77 mmol) was added. After stirring at rt for 18 h, the reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure. The residue was dissolved in dioxane (6 mL) in a microwave safe vessel and 2N NaOH (3 mL) was added. The reaction was then heated in a microwave at 120° C. for 25 min. The reaction was diluted with EtOAc and the organic layer was washed with water and saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[5-[(N,N-dimethylglycyl)amino]-4-methyl-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (124 mg, 0.238 mmol) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 3 H) 2.31 (s, 6H) 2.79 (d, J=4.58 Hz, 3 H) 3.01 (s, 2 H) 3.83 (s, 3 H) 6.29 (dd, J=3.11, 1.83 Hz, 1 H) 6.83-7.02 (m, 3 H) 7.38-7.53 (m, 2 H) 8.16 (s, 1 H) 8.31 (d, J=8.24 Hz, 1 H) 8.55 (d, J=2.75 Hz, 1 H) 9.17 (s, 1 H) 10.16 (s, 1 H) 11.34 (s, 1 H). ESIMS (M+H)+=521.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:17])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C@H:10]([O:17][S:35]([CH3:34])(=[O:37])=[O:36])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)/C=C/[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
A solution of 0.44 g (1.3 mmol) of the resultant compound of Example 6 and 0.91 ml (5.2 mmol) of diisopropylethylamine in 20 ml of anhydrous dichloromethane was cooled under N2 atmosphere to -20° C. and treated with 0.2 ml (2.6 mmol) of methanesulfonyl chloride. After 20 minutes, the mixture was treated with 10 % aqueous citric acid, extracted with methylene chloride, dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography provided the desired product. 1H NMR (CDCl3) δ 1.36 (s, 9 H), 2.73 (m, 1 H), 2.93 (dd, J=14, 5 Hz, 1 H), 3.06 (S, 3 H), 3.77 (s, 3 H), 4.18 (m, 1 H), 4.62 (s, 1 H), 5.47 (m, 1 H), 6.17 (dd, J=16, 2 Hz, 1 H), 6.90 (dd, J=16, 6 Hz, 1 H), 7.15-7.35 (m, 5 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:19]=1[C:20]#[N:21]>>[CH3:27][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([NH:17][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[C:19]=1[C:20]#[N:21]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COc1cccc(N)c1C#N
Product: COc1cccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1C#N
Yield: 87 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 113 using Compound 83 (100 mg, 0.43 mmol) and 2-amino-6-methoxy-benzonitrile (77 mg, 0.52 mmol) to provide 157 (128 mg, 86% yield) as a yellow solid. LC-MS (M+H=343, obsd.=343).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([NH2:14])=[CH:4][CH:3]=1.CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.[OH-].[Na+]>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([N:14]2[CH:17]=[CH:21][CH:20]=[CH:19]2)=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: CN1CCc2c(N)ccc(Cl)c2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCc2c(Cl)ccc(-n3cccc3)c2CC1
Product: Cl
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-amine (633 mg, 3 mmol) in acetic acid (6 ml) was treated with 2,5-dimethoxytetrahydrofuran (396 mg, 3 mmol) and stirred at 110° C. for 1.5 hours. The mixture was poured into ice, basified with 10% sodium hydroxide and extracted with ethyl acetate. The organic phase was dried, concentrated and treated with hydrogen chloride to give 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-yl)-1H-3-benzazepine hydrochloride (methanol-acetonitrile); mp 262°-264° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH2:6][C:7](F)([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:9][CH:10]=1)[NH2:4].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[CH:36]=[C:35]([C:37](O)=[O:38])[NH:34][C:30]2=[N:31][C:32]=1[CH3:33])=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[CH3:33][C:32]1[N:31]=[C:30]2[NH:34][C:35]([C:37](=[O:38])[NH:4][CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=3)[C:2]([F:17])([F:16])[F:1])=[CH:36][C:29]2=[CH:28][C:27]=1[CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: NC(C1=CC=CC(F)(C(F)(F)F)C1)C(F)(F)F
Reactant: Cc1nc2[nH]c(C(=O)O)cc2cc1CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1nc2[nH]c(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
2,2,2-Trifluoro-1-[3-fluoro-3-(trifluoromethyl)phenyl]ethanamine (726 mg, 2.98 mmol) was dissolved in N,N-dimethylformamide (10 ml), and 5-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (730 g, 2.39 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (907 mg, 2.39 mmol) and 4-methylmorpholine (725 mg, 7.17 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous phase was extracted three times with ethyl acetate and the extract was dried over sodium sulphate, adsorbed on silica gel and chromatographed with ethyl acetate. 420 mg (33% of theory) of tert-butyl {[6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}carbamate were obtained. HPLC-MS: log P=3.49; mass (m/z): 531.2 (M+H)+; 1HNMR (D6-DMSO): δ 1.40 (s, 9H), 3.30 (s, 3H), 4.20 (m, 2H), 6.29-6.32 (m, 1H), 7.35 (s, 1H), 7.71 (m, 1H), 7.82-7.84 (m, 1H), 8.03 (d, 1H), 8.17 (s, 1H), 9.43 (m, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[O:15]
Reactant: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2N)cc1
Temperature: 40 °C
Reaction time: 13 h
Yield: 70.1 %

Procedure:
To a mixture of 4-methoxybenzyl (1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate (2.2 g) and methanol (11 ml) was added p-toluene sulfonic acid hydrate (1.2 g) at room temperature, followed by stirring at 40° C. for 13 hours. Further, p-toluene sulfonic acid hydrate (0.24 g) was added thereto, followed by stirring at 40° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid and diethyl ether were added to the residue. The aqueous layer was separated, and the organic layer was extracted with 1 M hydrochloric acid. The aqueous layer was combined, and sodium hydrogen carbonate was added thereto under ice-cooling to adjust the pH to about 7. The reaction mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-methoxybenzyl (1R,2S)-2-aminocyclopentanecarboxylate (1.1 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH2:17]([C:24]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:26]([CH2:35][CH3:36])[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:37]([C@@H:39]1[C@@H:43]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=2)[CH2:42][N:41]([C@@H:51]2[C:55]([CH3:57])([CH3:56])[CH2:54][O:53][C:52]2=[O:58])[CH2:40]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:17]([C:24]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:37][C@@H:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=4)[CH2:42][N:41]([C@@H:51]4[C:55]([CH3:57])([CH3:56])[CH2:54][O:53][C:52]4=[O:58])[CH2:40]3)[CH2:31][CH2:30]2)[N:26]([CH2:35][CH3:36])[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)COC(=O)[C@@H]1N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Reactant: CCn1nc(Cc2ccccc2)cc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCn1nc(Cc2ccccc2)cc1C1CCN(C[C@H]2CN([C@H]3C(=O)OCC3(C)C)C[C@@H]2c2cccc(F)c2)CC1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
Diisopropylethylamine (0.018 mL, 0.1 mmol) was added to a solution of 4-(3-benzyl-1-ethyl-(1H-pyrazol-5-yl))piperidine trifluoroacetate (37 mg, 0.1 mmol, from Example 1, Step C) in 0.5 mL of 1,2-dichloroethane (DCE). A solution of dihydro-3-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-4,4-dimethyl-2(3H)furanone (25 mg, 0.082 mmol, from Step D) in 0.5 mL of DCE was then added, followed by a slurry of sodium triacetoxyborohydride (30 mg, 0.144 mmol) in 0.5 mL of DCE. The reaction mixture was mixed well, then allowed to stand at room temperature for 2 h. The mixture was concentrated and purified by preparative HPLC (column: YMC combiprep ODS-A 20×50 mm, gradient: 10% acetonitrile/water w/0.1% TFA to 100% acetonitrile/water w/0.1% TFA over 8 min, then ramp to 10% acetonitrile/water w/0.1% TFA over 2 min, flow: 20 mL/min), followed by conversion to the free base by solid phase extraction (column: Varian SCX, loading: methanol, elution: 2.0M ammonia in methanol) to afford 17.2 mg (37% yield) of the title compound. ESI-MS. M/z; (M+H)=559.7; HPLC A: 2.34 min.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:51]([NH:53][CH3:54])[CH3:52]>C(Cl)(Cl)Cl>[CH2:51]([N:53]([CH2:27][CH2:26][NH:25][C:24]([O:23][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29])[CH3:54])[CH3:52]
Reactant: CCNC
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCBr
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCN(C)CC
Reaction time: 8 h
Yield: 81.7 %

Procedure:
In 3 ml of chloroform was dissolved 131 mg (0.170 mmol) of 1,3-O-dioleoyl-2-O-(2-bromoethyl) carbamoylglycerol followed by addition of 470 mg (7.951 mmol) of N-ethylmethylamine and the reaction was conducted in a sealed tube at 80° C. overnight. This reaction mixture was then washed with 5% sodium dihydrogen phosphate-H2O, dried and concentrated. The residue was subjected to column chromatography silica gel/methylene chloride-methanol) to provide 104 mg (81.5%) of the title compound of the invention.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[CH2:9]([O:13][C:14]1[C:17](=O)[C:16](=[O:19])[C:15]=1[O:20]CCCC)[CH2:10][CH2:11][CH3:12]>CO>[CH2:9]([O:13][C:14]1[C:15](=[O:20])[C:16](=[O:19])[C:17]=1[NH:6][CH2:5][CH2:4][CH2:3][Br:2])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: NCCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1c(NCCCBr)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Solid 3-bromopropylamine hydrobromide (31.0 g, 0.1416 mole) was added with stirring to a solution of sodium hydroxide (5.77 g, 0.140 mole) in methanol (152 mL) and stirred at ambient temperature for 15 minutes. The solution was cooled to 0°-5° C. and then added with stirring to the solution of Step A. The mixture was stirred at 22° C. for 1.5 hours then concentrated under reduced pressure (40° C.) to about 120 mL volume. Toluene (120 mL) was added and the mixture was washed with water (240 mL). The organic layer was dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give 38.64 g (95.0 % yield) of the title compound as an off-white solid. The product was used without further purification in the subsequent reaction.