Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.Cl[C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:27]=[CH:26][N:25]=1>CC(N(C)C)=O>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:24]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[N:27]=[CH:26][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1cc(C2CCOCC2)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc2[nH]c(C3CN(c4cc(C5CCOCC5)ncn4)C3)nc2c1
Temperature: 70 °C
Yield: 46.9 %

Procedure:
A mixture of cesium carbonate (0.83 g, 2.56 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.18 gg, 0.64 mmol), and 4-chloro-6-(tetrahydro-2H-pyran-4-yl)pyrimidine (0.13 g, 0.64 mmol) in DMA (1 mL) was heated to 70° C. for 18 h, then cooled to RT. The resulting suspension was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with water twice, brine once, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 5-chloro-2-(1-(6-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.11 g, 0.30 mmol, 47% yield) as a white solid. [M+1] 370. IC50 (uM) 1.283.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:25])([CH3:24])[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:24][C:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH3:25]
Reactant: CNC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (LC/MS): 332.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[Cl:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1nn(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 62 h
Yield: 79 %

Procedure:
The reaction was carried out using the same equipment as described in Example 1. The flask was charged with 53.9 g (0.143 mole, 82% assay) of 2-(5-amino-2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one and 24 grams of toluene. The mixture was heated to reflux and 15.6 mL (23 g, 0.20 mole) of methanesulfonyl chloride (Aldrich, 99.5%) added dropwise over 22 minutes. The solution was heated at reflux for 4.5 hours after the completion of the addition, and a further 3.9 mL (5.75 g, 0.05 mole) of methanesulfonyl chloride was added over 10 minutes. After an additional 2.5 hours at reflux, the reaction mixture was diluted with 75 mL of toluene, allowed to cool to room temperature, and stirred over the weekend (62 hours). The resulting slurry was warmed to dissolve the solids, transferred to a 1-L round bottomed flask equipped with a mechanical stirrer, and rinsed in with 200 mL of toluene. The mixture was warmed to 80° C. and washed twice with 150 mL portions of water, with the washes being removed via pipette. The solution was allowed to cool slowly to 40° C. and the resulting slurry then cooled in an ice bath for 2.5 hours. The product was collected by filtration and the filter cake washed with a total of 120 mL of cold toluene and dried in a vacuum oven to provide 48.6 g (79% yield) of 90% assay of N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl]methanesulfonamide as a tan solid.
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(F)(F)F)=[CH:18][C:17]=2[CH2:29][C:30]([O:32]C)=[O:31])(=[O:15])=[O:14])=[CH:10][C:5]2[B:6]([OH:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:11]2[C:2]([F:1])=[CH:3][C:4]3[CH2:8][O:7][B:6]([OH:9])[C:5]=3[CH:10]=2)=[C:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:18]=1
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a stirred solution of methyl 2-(2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (250 mg, 0.51 mmol) in 10 mL of MeOH and water (1:1, v/v) was added NaOH (1N solution, 2 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. After MeOH was removed in vacuo, the residue was dissolved in water and acidified with 0.5N HCl. The mixture was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a white powder (142 mg, yield 75%). MS calcd for (C15H14BFN2O6S): 380.1. MS found (ESI negative): (M−H)−=379.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.58 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.17 (d, J=10.4 Hz, 1H), 6.44 (d, J=2 Hz, 2H), 6.36 (dd, J=8.8, 2 Hz, 1H), 4.88 (s, 2H), 3.89 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](C#N)=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]#[N:20].ClC(Cl)(Cl)C(O)=O.Cl>CCOCC.C(Cl)Cl>[CH3:12][N:13]1[C:17]([C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]#[N:20]
Reactant: Cn1cccc1CC#N
Reactant: Cc1ccc(C(=O)C#N)cc1
Agent: Cl
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Reaction time: 72 h
Yield: 30 %

Procedure:
A solution of 0.16 g (1.1 mmole) of 4-methylbenzoylcyanide, 0.13 g (1.1 mmole) of 1-methylpyrrole-2-acetonitrile and 4 mg of trichloroacetic acid in 0.4 ml of ether was allowed to stand in the dark under nitrogen at 25°. After three days, a small amount of hydrogen chloride gas was admitted to the vessel. The mixture was allowed to stand for 14 days. It was diluted with methylene chloride and the solution washed with sodium hydroxide. The solution was dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed on 37 ml of silica gel. The fractions eluted with a mixture of 1,1,1-trichloroethane:hexane, 1:1 were discarded. The fractions eluted with 1,1,1-trichloroethaneihexane 3:1 were collected. The solvent was evaporated to give 0.80 g of dark solid 1-methyl-5-(4-methylbenzoyl)pyrrole-2-acetonitrile (30 percent yield). It was recrystallized from 1,1,1-trichloroethaneihexane to give brown solid, mp 103°-104°, undepressed by admixture with authentic material.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1

Procedure:
To 4-Hydroxy benzaldehyde (10 g) in acetone (200 ml), potassium carbonate (16.96 g) was added and stirred. To this, benzyl bromide (12.67 ml) was added and the reaction mixture was refluxed for 3 hours and then cooled. The reaction mixture was filtered and the filtrate was concentrated to obtain pale brown colored oil which got solidified at room temperature. Solid was crystallized from DCM-Petroleum ether to obtain the title compound as pale yellow solid. Yield: 13 g (74%); 1HNMR (CDCl3; 300 MHz): δ 9.91 (s, 1H), 7.87 (d, 2H), 7.33-7.43 (m, 5H), 7.12 (d, 21-1) 5.17 (s, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH2:6])=[S:5])[CH3:2].[CH2:7]=[C:8]1O[C:10](=[O:11])[CH2:9]1>C(O)(=O)C>[CH2:1]([N:3]1[C:8]([CH3:7])=[CH:9][C:10](=[O:11])[N:6]=[C:4]1[SH:5])[CH3:2]
Reactant: CCNC(N)=S
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)O
Product: CCn1c(C)cc(=O)nc1S

Procedure:
18 Grams of N-ethyl-thiourea were dissolved in 50 m. of glacial acetic acid, boiled to reflux and treated dropwise with 17.2 g of diketene. The mixture was then boiled at reflux for 20 minutes and subsequently evaporated to 50 ml. While cooling and stirring, the residue was treated with 50 ml of water. The yellowish crystals which precipitated were filtered off under suction and recrystallized from tetrahydrofuran to give 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxo-pyrimidine; melting point 190°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.CCN(CC)CC.[P:24](Cl)([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:14][C:12]([F:15])([F:13])[C:7]([C:4]1[S:3][C:2]([NH:1][P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])=[N:6][CH:5]=1)([OH:16])[C:8]([F:9])([F:10])[F:11]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of (2-amino-1,3-thiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (133 mg 0.5 mmol) from step 1 of example 1-1-1, DMAP (61 mg, 0.5 mmol), Et3N (100 μL, 0.72 mmol) and CH2Cl2 (5 ml) was added diethyl chlorophosphate (87 μL, 06 mmol). The reaction mixture was stirred at r.t. for 96 h. Solvent was removed and EtOAc was added. The solution was washed with water. After removal of solvent, the residue was purified by a short Ion Exchange Column (Dowex-50W, ethanol) to afford the title compound as a white solid (43 mg). 1H NMR (DMSO-d6) δ 1.20 (t, 6H), 3.89 (m, 4H), 7.46 (s, 1H), 9.18 (s, 1 H); ESIMS: m/z 401 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)[CH3:16])(=O)[CH3:12]>>[CH2:11]([O:14][CH2:15][C:16]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)[CH3:12]
Reactant: NC(=O)c1nccnc1N
Reactant: CC(=O)OC(C)=O
Product: CCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
A mixture of 8.3 g (0.060 mole) of 3-amino-2-pyrazinecarboxamide [prepared according to R. C. Ellingson et al., J. Am. Chem. Soc. 1945, 67, 1711], 49.5 g (0.24 mole) of triethyl orthoethoxyacetate [prepared according to S. M. McElvain and P. M. Walters, J. Am. Chem. Soc. 1942, 64, 1963] and 53 ml of acetic anhydride is refluxed under a nitrogen atmosphere for 3 hours. The temperature of this reflux falls with the passage of time from 124° to 96° C. and then remains constant at the latter temperature. After cooling, the precipitate formed is isolated by filtration. It is washed with ether and recrystallized from ethanol. Yld: 5.5 g (44%), m.p. 168°-169° C.
Reaction SMILES: [CH2:1]([C:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[CH2:5][O:4]1)[CH3:2].[NH2:14][CH2:15][CH:16]([OH:18])[CH3:17]>C(O)C>[CH2:1]([C:3]([CH2:5][NH:14][CH2:15][CH:16]([OH:18])[CH3:17])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[OH:4])[CH3:2]
Reactant: CC(O)CN
Reactant: CCC1(c2cccc(OC)c2)CO1
Solvent: CCO
Product: CCC(O)(CNCC(C)O)c1cccc(OC)c1

Procedure:
2-Ethyl-2-(3-methoxyphenyl)oxiran (14 g, 0.079 mole) and 1-amino-2-propanol (100 g., 1.33 mole) wee refluxed with ethanol (50 ml) for 12 hours. The solvent and excess aminopropanol was removed under reduced pressure. The residue was dissolved in methanol (80 ml) and acidified with ethereal hydrogen chloride. The methanol was evaporated and the residue taken up in water (250 ml). Non-basic material was extracted by shaking the aqueous solution with three portions of 100 ml of ether. The aqueous layer was neutralised with a large excess of 0.880 ammonia, and reextracted with ether (3×100 ml). The ether layers were washed with water and dried (MgSO4). Removal of solvent left the title compound in 98% purity (12.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].ClC1C2C(=CC=C([CH:25]([C:27]3[N:31]([CH3:32])[C:30](C)=[N:29][CH:28]=3)O)C=2)N=C(OC)C=1CC1C=NC(C(F)(F)F)=CC=1.N1C=C(C=O)C=NC=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:25][C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=Cc1cncnc1
Solvent: CCO
Solvent: c1ccncc1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Cc1cncnc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a dark solution of 6-bromo-4-hydroxyquinolin-2(1H)-one (3.92 g, 16.31 mmol, Intermediate 45: step a) and pyrimidine-5-carbaldehyde (1.94 g, 17.95 mmol) in pyridine (29 mL) was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.13 g, 16.31 mol). The resulting mixture was warmed with stirring in a 100° C. oil bath for a period of 5 hours. After cooling to room temperature, the mixture was diluted with ethanol. The tan precipitate was isolated by filtration, rinsing further with EtOH then acetonitrile and dried to provide the title compound that was carried to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([OH:17])=O)[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.ClCCl>[F:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[C:5]=1[C:15](=[O:17])[CH2:14][CH:9]2[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CC(CC(=O)O)c1cc(F)cc(F)c1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)CC1CC(=O)c2c(F)cc(F)cc21
Yield: 23.1 %

Procedure:
This compound was prepared in an analogous manner to that of Example 25d with the replacement of 3-(3-fluorophenyl)glutaric acid with 3-(3,5-difluorophenyl)glutaric acid (9.02 g, 36.9 mmol) and an increase of the heating time from 10 min to 30 min. Chromatography of the collected product on a column of Silica Gel 60 (51×450 mm) with methanol: dichloromethane (4:96) gave a material which was recrystallized from water to give 1.93 g (23%) of 2-(4,6-difluoro-3-oxo-1-indanyl)acetic acid: m.p., 170°-172° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[F:16].[NH3:17]>O1CCCC1.CO>[NH2:17][C:11]1[CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([NH2:1])=[C:3]([F:16])[CH:4]=2)[N:8]=[CH:9][N:10]=1
Reactant: N
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1F
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Oc2ccc(N)c(F)c2)ncn1
Temperature: 25 °C
Yield: 35 %

Procedure:
After dissolving 4-(4-amino-3-fluorophenoxy)-6-chloropyrimidine (2.25 g) in tetrahydrofuran (25 ml) and a 7N ammonia solution in methanol (50 ml), the mixture was heated in a sealed tube for 3 days at 130° C. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and 1N aqueous sodium hydroxide. The separated organic layer was washed with brine. The aqueous layer was then re-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:3, then ethyl acetate) to provide the title compound (0.73 g, 35%) as a purple solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:4]=1)[C:12](=[O:11])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:1]=2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(I)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(I)cn2c1=O
Temperature: 25 °C
Yield: 32 %

Procedure:
In a 3-necked round-bottom connected to a Dean-Stark trap, a solution of 2-amino-5-iodopyridine (Preparation 1, 500 mg) and diethyl ethoxymethylenemalonate (0.92 mL) is heated at 130° C. for 2 h. The reaction is cooled to room temperature. Diphenyl ether (5 mL) is added and the reaction is heated at 250° C. for 1 h. Upon cooling the mixture to room temperature, a solid precipitates and is filtered and washed with hexanes. The crude solid is adsorbed onto silica and chromatographed eluting with CH2Cl2 (2 L). Product-containing fractions are combined and concentrated to afford a solid. The crude product is recrystallized from CH2Cl2/hexanes to yield 251 mg (32%) of the title compound as a yellow solid. Physical characteristics: m.p. 166-168° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.24, 8.85, 8.38, 7.62, 4.27, 1.30; IR (drift) 1747, 1611, 1558, 1506, 1473, 1355, 1345, 1291, 1266, 1258, 1152, 1140, 1118, 840, 796 cm−1; MS (ESI+) m/z 345; Anal. found: C, 38.37; H, 2.48; N, 8.11.
Reaction SMILES: [CH3:1][CH:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([CH3:13])[CH2:11][O:12][C:8]=2[CH:7]=1.[OH-].[BH4-].[Na+].[OH-].[Na+].[CH2:27]([OH:29])[CH3:28]>>[CH2:27]([O:29][C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][CH:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH:10]([CH3:13])[CH2:11][O:12][C:8]=2[CH:7]=1)[CH3:28]
Reactant: CC(C)=CCCC(C)CCOc1ccc2c(c1)OCC2C
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCOC(C)(C)CCCC(C)CCOc1ccc2c(c1)OCC2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.48 g. of 6-[(3,7-dimethyl-6-octenyl)-oxy]-3-methyl-2,3-dihydrobenzofuran in 15 ml. of absolute ethyl alcohol is slowly added dropwise at room temperature to a suspension of 3.81 g. of mercuric acetate in 30 ml. of absolute ethyl alcohol. The mixture is thereupon stirred for one hour at room temperature, cooled by means of an ice bath and 12.8 ml. of 10% by weight aqueous hydroxide followed by 0.24 g. of sodium borohydride in 12.8 ml. of 10% by weight aqueous sodium hydroxide are added dropwise. After stirring for 30 minutes at room temperature, the mixture is filtered through diatomaceous earth, the aqueous phase saturated with sodium chloride and subsequently extracted with pentane. The extracts are washed neutral with aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel there is obtained pure 6-[(7-ethoxy-3,7-dimethyl-octyl)-oxy]-3-methyl-2,3-dihydrobenzofuran which is distilled in a bulb-tube at 132° C./0.01 mmHg; nD 22 = 1.4976.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[C:10]([N:5]1[CH2:6][C@H:7]([O:9][C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH2:8][C@H:4]1[C:3]([O:2][CH3:1])=[O:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N(C)C)CN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester (Example 1, part b) in chloroform is treated dropwise with an equivalent quantity of dimethylcarbamyl chloride. The mixture is stirred for two hours, washed with water and the organic phase is dried over MgSO4. The solution is filtered and solvent evaporated to give trans-N-carbobenzyloxy-4-[[(dimethylamino)carbonyl]oxy]-L-proline, methyl ester.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]3[CH2:22][C@H:21]([OH:23])[C@@H:20]([CH2:24][OH:25])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.Cl[S:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:44])=[O:43]>C(#N)C>[C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@@H:18]3[CH2:19][C@H:20]([CH2:24][O:25][S:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])(=[O:43])=[O:44])[C@@H:21]([OH:23])[CH2:22]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A neat mixture of (1S,2R,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-(hydroxymethyl)cyclopentanol (100. mg, 0.294 mmol) and 2,6-di-tert-butyl-4-methylpyridine (181 mg, 0.881 mmol) was dissolved in ACN (5.00 mL) before tert-butyl (chlorosulfonyl)carbamate (95.0 mg, 0.441 mmol, as prepared in Example 21c) was added. The reaction was stirred for 2 h before being quenched via addition of MeOH (2 mL). The resulting mixture was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 10 to 20% MeOH in DCM to afford the title compound as an amorphous solid (50.0 mg, 33%). LC/MS: Rt=1.24 min, ES+ 520. (AA standard).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=1>CO.C1COCC1>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c2ccccc12
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)c2ccccc12

Procedure:
Method C1 was used with tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)naphthalen-1-ylcarbamate (3.0 g, 7.6 mmol) with solvent mixture MeOH:THF 1:1 to afford the title compound in quantitative yield (2.4 g).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=1.[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1>CS(C)=O.CCOC(C)=O>[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:2]2[O:6][C:5]([C:7]3[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=3)=[CH:4][C:3]=2[C:18]2[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=2)[CH2:34]1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(Br)o2)c(C)cn1
Reactant: CN(C)C1CCCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(N3CCCC(N(C)C)C3)o2)c(C)cn1
Temperature: 120 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a solution of N-{-4-[5-bromo-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.19 g, 0.38 mmol) in DMSO (3 mL) was added N,N-dimethylpiperidin-3-amine (0.25 g, 1.9 mmol). The mixture was allowed to stir at 120° C. for 48 h. The reaction mixture was diluted with EtOAc and washed with water. The organic solution was separated, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-{5-[3-(dimethylamino)piperidin-1-yl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.15 g, 72%). LCMS (FA): m/z=540.7 (M+H).