Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:23](O)(=[O:34])[CH2:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:20][C:23]([CH2:24][NH:25][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Product: O=C(CNC(=O)c1ccccc1)NC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 1.1 from C,C-bis-(4-trifluoromethyl-phenyl)-methylamine (example 4.1) and hippuric acid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[O:22]C)=[O:8])C.B(Br)(Br)Br>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]([OH:24])=[O:3])=[O:8])=[C:10]([OH:22])[CH:11]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1ccc(-c2ccc(Cl)cc2)cc1O
Reaction time: 72 h
Yield: 40.9 %

Procedure:
To a solution of [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester (0.053 g, 0.152 mmol) in CH2Cl2 (2 mL) at room temperature under nitrogen is added BBr3 (1.52 ml of a 1M solution in CH2Cl2, 1.52 mmol) dropwise. The resulting mixture is stirred for 3 days after which time the reaction is quenched with H2O (0.5 mL) then acidified to pH 1 with conc. HCl. The mixture is extracted with EtOAc (×2), the organic phase separated, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material is purified by preparative HPLC to afford 0.019 g (41% yield) of the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (1H, s), 9.19 (1H, s), 7.96 (1H, d, J=8.3 Hz), 7.74 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz), 7.21 (1H, d, J=1.7 Hz), 7.26 (1H, dd, J=8.3, 1.8 Hz), 3.99 (2H, d, J=5.5 Hz). HPLC-MS: m/z 306 [M+H]+.
Reaction SMILES: [C:1]1(=[CH:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(OC)(C)C>[C:1]1([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(=O)CCC=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(=O)CCCC1=CCCC1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
A mixture of 5-cyclopentylidene-2-pentanone (9.92 g; 65 mmol) and p-TsOH (100 mg; 0.53 mmol) in toluene (150 ml) was heated at 90° C. for 8 hours, then cooled down to room temperature, diluted with MTBE (100 ml), washed with saturated NaHCO3 (50 ml), H2O (50 ml), brine (50 ml), dried over MgSO4 and concentrated in vacuo. Distillation under reduced pressure (48° C./0.065 torr) yielded 7.13 g of 5-(cyclopent-1-enyl)-2-pentanone (purity about 80%), which was further purified by flash chromatography to give 6.1 g (61% yield) of a 89% pure product containing 11% of 5-cyclopentylidene-2-pentanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:42])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][C:25]1[NH:26][C:27]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ClC1C=CC=C(C(OO)=[O:51])C=1.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:42])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24]([C:25]1[NH:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:27]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:26]=1)=[O:51])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCN(CCCCCS(=O)c1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea (0.59 g, 0.001 mol) in methylene chloride (50 mL) cooled to -78° was added, dropwise, a solution of metachloroperbenzoic acid (0.286 g, 0.0017 mol) in methylene chloride (10 mL). The reaction mixture was stirred at -78° for 1 hour and then allowed to warm to ambient temperature. The reaction mixture was then cooled to 0° and then added, dropwise, was a solution of saturated sodium bisulfite. The layers were separated and the organic layer was washed with saturated sodium bisulfite. The layers were separated and the sodium chloride solution dried over magnesium sulfate and concentrated under vacuum. The residue (0.76 g) was chromatographed with 1: 1 hexane-ethyl acetate to give the title compound (0.43 g, 0.00071 mol) as a yellow solid, mp 77°-79°.1H NMR (CDCl3) δ 8.1-7.9(m,1H), 7.6-7.2 (m,10H), 6.9-6.7(m,2H), 6.4(d,1H,J=3.3 Hz), 3.4-3.1(m,6H), 2.0-1.1(m,18H), 0.9 (t,3H,J=6.4 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](N(OC)C)=[O:16])(=[O:3])[CH3:2].[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.O1CCCC1>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: [Li]c1ccccc1
Reactant: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1NC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 3-acetylamino-7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 4, 321 mg, 1.08 mmol) in diethyl ether-tetrahydrofuran (1:1, 10 ml) was added phenyl lithium (1M solution in cyclohexane, 5.4 ml, 5.42 mmol) at −78° C. After stirring for 1 h, the mixture was allowed to warm to 0° C. and stirred for an additional 2 h. The mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with ether (150 ml). The organic layer was washed with water (50 ml) and dried (MgSO4). Removal of solvent gave an oily residue. Purification by flash column chromatography eluting with ethyl acetate/hexane (1:3) afforded yellow crystals. Recrystallization from ethyl acetate gave 87 mg, (26%) of the title compound. m.p.: 185-188° C. IR (KBr) ν: 3240, 1690, 1628, 1543, 1375, 1315, 1250, 725 cm1 1H-NMR (CDCl3) δ: 9.77 (1 H, br s), 8.36 (1 H, br s), 8.18 (1 H, d, J=8.6 Hz), 7.87-7.83 (2 H, m), 7.71-7.57 (3 H, m), 7.40 (1 H, dd, J=1.0, 7.6 Hz), 7.10 (1 H, dd, J=7.6, 8.4 Hz), 2.26 (3 H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385 mmol) and 2,5-dimethoxyaniline (59 mg, 0.385 mmol) similar to Example 13 and isolated as a greenish-yellow solid (24 mg, 17%). 1H NMR (CDCl3): 9.67-9.66 (m, 1H), 8.74-8.70 (m, 2H), 8.02 (s, 1H), 7.44-7.39 (m, 1H), 6.91 (s, 1H), 7.67 (s, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.65 (dd, J=3.0, 9.0 Hz, 1H), 3.86 (d, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]1[CH2:35][C:36](O)=[O:37].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:11]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:10])[CH2:8][NH:9][C:36](=[O:37])[CH2:35][N:19]2[CH2:20][CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18]2=[O:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(CN)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(CNC(=O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2-diphenylpropan-1-amine (0.21 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.09-7.33 (m, 20H), 5.72-5.77 (m, 1H), 3.95 (d, J=5.9 Hz, 2H), 3.91 (s, 2H), 3.23 (t, J=6.4 Hz, 2H), 2.58 (t, J=6.4 Hz, 2H), 1.57 (s, 3H); MS (DCI+) m/z 489 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C(C=P(CCCC)(CCCC)CCCC)#N>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[CH2:8]1
Reactant: O[C@H]1CC[C@H](c2ccccn2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](c2ccccn2)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A solution of trans-3-(2-pyridyl)cyclopentanol (957 mg, 5.86 mmol) in THF (25 mL) was cooled to 0° C. and treated with phthalimide (1.29 g, 8.77 mmol), cyanomethylenetri-n-butylphosphorane (2.12 g, 8.78 mmol). The reaction mixture was stirred at 70° C. for 8 h. The solvent was removed, and the crude product was purified by column chromatography (Hexane/EtOAc=3/1→1/1) and triturated with Hexane-EtOAc to yield cis-N-[3-(2-pyridyl)cyclopentyl]phthalimide (901 mg, 53%) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][C:6]=1[O:23][CH2:24][O:25][CH3:26])[CH3:2].[CH2:28]([O:35][C:36](=[O:41])[NH:37][CH2:38][CH2:39]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:39][CH2:38][NH:37][C:36]([O:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:41])[CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][C:6]=1[O:23][CH2:24][O:25][CH3:26])[CH3:2]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(O)cc32)cc1OCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(=O)OCc4ccccc4)cc32)cc1OCOC
Temperature: 50 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a solution of 4-(3-cyano-6-hydroxyindol-1-yl)-2-methoxymethoxybenzoic acid ethyl ester (0.37 g) in N,N-dimethylformamide (10 mL) were added (2-bromoethyl)carbamic acid benzyl ester (0.39 g) and potassium carbonate (0.28 g), and this mixture was stirred at 50° C. overnight. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This solid was washed with methanol, and dried to give the title compound (0.40 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:21]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[F:21][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH3:14])=[O:11]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)butyric acid (0.010 mol) dissolved in DCM (25 ml) was placed in a cooling bath at −10° C. Pyridine (0.010 mol) was added, followed by 2,4,6-trifluoro-1,3,5-triazine (0.0345 mol). The mixture was stirred under nitrogen. After one hour, ice cold water (75 ml) was added. More DCM (45 ml) was added, and the mixture was shaken. The organic phase was separated, washed with ice cold water again (100 ml), then the organic phase dried, filtered, and concentrated to yield 2.29 g of (S)-1,1-dimethylethyl [1-(fluorocarbonyl)propyl]-carbamate (intermediate 25).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]([N:13]1[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]1)=[O:12])[CH2:9][CH3:10])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][C@H:8]([CH2:9][CH3:10])[C:11]([N:13]1[CH2:14][CH:15]([C:17]#[N:18])[CH2:16]1)=[O:12]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(R)-1-(3-cyano-azetidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (200 mg, 0.67 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (1.8 ml, 23.4 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated to afford 1-((R)-2-amino-butyryl)-azetidine-3-carbonitrile trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][P:5]([O-:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].C1CCN2C(=NCCC2)CC1.[C:26]1([C:32]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:33]2[CH:37]=[C:36]([CH2:38]Cl)[N:35]=[CH:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][P:5]([CH2:38][C:36]1[N:35]=[CH:34][N:33]([C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:37]=1)(=[O:12])[O:6][CH2:7][C:8]([F:11])([F:9])[F:10]
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=P(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(OCC(F)(F)F)OCC(F)(F)F
Yield: 29.9 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)phosphite (0.11 ml, 0.6 mmol) in THF (1.5 ml) were added 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (0.09 ml, 0.6 mmol) and (1-triphenylmethylimidazol-4-yl)methyl chloride (71.8 mg, 0.2 mmol). The reaction mixture was refluxed under argon flow for 22 hours. The solvent was removed under reduced pressure, and water (10 ml) was added to the residue, which was then extracted 3 times with ethyl acetate (10 ml). The resultant organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained white solid was purified through chromatography on silica gel column using ethyl acetate-hexane (3:2) to give bis(2,2,2-trifluoroethyl)(1-triphenylmethylimidazol-4-yl)methylphosphonate (34 mg, 30%) as a white powder. This powder was recrystallized from a mixture of ethyl acetate and hexane to provide a white small needle crystal (m.p. 145-148° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:13][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[N:11][CH:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(-n2cncn2)c(F)c1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3cncn3)c(F)c2)n1

Procedure:
The title compound was prepared from 3-fluoro-4-[1,2,4]triazol-1-yl-phenylamine (81.4 mg, 0.46 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) in analogous manner to the procedure described in example 1e). Obtained as a light yellow wax (98 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:26])[CH:23](Br)[CH3:24])[CH3:20]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:26])[CH:23]([N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(Br)cc21
Temperature: 70 °C
Yield: 84.5 %

Procedure:
To a suspension of 6-bromo-4H-benzo[1,4]oxazin-3-one (27 g, 118.4 mmol) and K2CO3 (49.1 g, 355.2 mmol) in acetone (200 mL) was added 2-bromo-propionic acid ethyl ester (32.1 g, 177.6 mmol) and the reaction mixture was heated at 70° C. for 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo and the residue was dissolved in DCM (50 mL). The organic phase was washed with water (3×20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness and the residue was purified by chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a colorless liquid (32.5 g, 100 mmol, 84%). 1H NMR (CDCl3, 400 MHz): δ 7.09 (dd, J=8 Hz, J=2 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.28 (q, J=14.8 Hz, 1H), 5.21 (q, J=5.4 Hz, 1H), 4.55 (d, J=15.2 Hz, 2H), 4.17 (m, 1H), 1.63 (d, J=1.2 Hz, 3H), 1.22 (t, J=1.2 Hz, 3H).
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:12][O:13][CH:7]12)(=O)=O.[N:25]([Na])=[N+:26]=[N-:27]>CN(C=O)C.C(Cl)Cl>[N:25]([CH:6]1[CH:7]2[O:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH:8]2[O:9][CH2:10]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=N[Na]
Reactant: CS(=O)(=O)OC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Temperature: 140 °C

Procedure:
To a solution of 6-(1,3-dioxoisoindolin-2-yl)hexahydrofuro[3,2-b]furan-3-yl methanesulfonate (2.80 g, 7.9 mmol) in DMF (60 mL) was added azido sodium (2.16 g, 33.2 mmol). The reaction was allowed to warm to 140° C. for 23 h. The solution was diluted with CH2Cl2 (100 mL), washed with water (100 mL×3) and dried over anhydrous Na2SO4, and then concentrated in vacuo to give the crude product. The product was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[N:13]=[N:12][C:11](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][C:20]\2=[O:21])=[N:10]1)=[O:5])[CH3:2].[BH4-].[Na+].ClCCl>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[N:13]=[N:12][C:11](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][CH2:19][CH:20]\2[OH:21])=[N:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCCn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Yield: 37 %

Procedure:
(E)-3-({2-[3-(Ethoxycarbonyl)propyl]-2H-tetrazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (3.93 g) was reduced with sodium borohydride (281 mg) in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml) in a similar manner to that mentioned in Example 138 (c), and the crude product obtained by conventional extraction procedures was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (1:9 to 7:3) as the eluent to afford the title compound as a yellow oil (1.46 g, yield: 37%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH2:49])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9].C1([O:56][C:57](=O)[NH:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=2)C=CC=CC=1>CO>[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH:49][C:57]([NH:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=4)=[O:56])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NCc1cccc(O)c1)Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
(2S,3S,4R,5R)-5-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide trifluoroacetate (Intermediate E) and (3-Hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate UA) are dissolved in methanol and TEA. The reaction mixture is heated using microwave radiation at 100° C. for 30 minutes in the Personal Chemistry Emrys™ Optimizer microwave reactor. The reaction mixture is concentrated in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile:water (0.1% TFA) (gradient 0-100% acetonitrile) to afford the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)no1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: Cc1cc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)no1
Temperature: 150 °C
Reaction time: 24 h
Yield: 13.1 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide (200 mg, 0.590 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (591 mg, 2.95 mmol) in n-BuOH (5 mL) was stirred at 150° C. for 24 hours in a sealed tube. The reaction mixture was then concentrated in vacuo, and the liquid residue was purified by C-18 reverse phase flash chromatography (Biotage C-18 Flash 25M+) on Biotage SP4 unit eluting with 10-80% CH3CN/water gradient (24 CV). The product isolated was crystallized from MeOH/CH3CN to provide (R)-tert-butyl 1-(5-bromo-3-(5-methylisoxazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (40 mg, 13% yield) as a solid. LCMS (APCI+) m/z 519, 521 (M+H)+, Retention time=4.08 minutes (Method 2).