Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.Br[CH2:24][C:25]1[N:26]=[C:27]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:24][C:25]5[N:26]=[C:27]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:28][CH:29]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: COCCOCc1nc(CBr)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOCc1nc(COc2cc(OC)cc3oc(-c4cn5nc(OC)sc5n4)cc23)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.10 g, 0.315 mmol) and 4-(bromomethyl)-2-((2-methoxyethoxy)methyl)thiazole (Example 6E, 0.10 g, 0.376 mmol) in DMF (5 mL) was purged under vacuum and nitrogen for 10 minutes. The mixture was then treated with potassium carbonate (0.10 g, 0.724 mmol) and the reaction was stirred at RT for 2.5 hours. The reaction was then diluted with dichloromethane, washed with water (1×), brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 50% ethyl acetate/CH2Cl2) to give the title material which was crystallized in ethyl acetate and provided the desired title material (0.055 g, 35%) along with non-crystallized material (9 mgs, 6%). LC (Method F): 2.476 min. HRMS (ESI) calcd for C22H23N4O6S2 [M+H]+ m/z 503.1054. found 503.1066. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.82 (s, 1H), 7.35 (s, 1H), 7.05 (s, 1H), 6.68 (broad s, 1H), 6.39 (d, J=1.9 Hz, 1H), 5.28 (s, 2H), 4.86 (s, 2H), 4.19 (s, 3H), 3.82 (s, 3H), 3.74-3.77 (m, 2H), 3.58-3.61 (m, 2H), 3.39 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[O:16]1[C:25]2[CH:24]=[C:23]([CH:26]=O)[N:22]=[CH:21][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:16]1[C:25]2[CH:24]=[C:23]([CH2:26][NH:1][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]3)[N:22]=[CH:21][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(CNCc2cc3c(cn2)OCCO3)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.65 g of tert-butyl 3-(aminomethyl)piperidine-1-carboxylate in 5 mL of dichloromethane, 0.50 g of (2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 0.17 mL of acetic acid were added. Subsequently, 0.96 g of sodium triacetoxyborohydride was added thereto and the mixture was stirred at room temperature for 1 hour 15 minutes. The reaction mixture was charged with chloroform and adjusted to pH 8.6 with a saturated aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidine-1-carboxylate as a yellow oily substance.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][NH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CN(C)C=O>[CH3:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][N:7]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6]1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 30 °C
Reaction time: 18 h

Procedure:
Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (9.53 g, 41.6 mmol) and potassium carbonate (3.44 g, 25 mmol) were dissolved in N,N-dimethylformamide (140 mL) under nitrogen. The mixture was then treated with a solution of 1-bromo-2-(2-methoxyethoxy)ethane (9.90 g, 54 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 30° C. for 18 hours and then allowed to cool to room temperature. Additional 1-bromo-2-(2-methoxyethoxy)ethane (9.90 g, 54 mmol) and potassium carbonate (3.44 g, 25 mmol) were added and the reaction mixture allowed to stir at 30° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (200 mL) and water (200 mL). The aqueous was separated and washed with ethyl acetate (200 mL), the organics were combined and washed with water. The organic layer was dried over magnesium sulphate and concentrated in vacuo to yield the title product. 1H NMR (CDCl3, 400 MHz) δ: 3.25 (s, 3H), 3.38 (m, 2H), 3.50 (m, 2H), 3.80 (t, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 4.77 (t, 2H). MS APCI+ m/z 333 [MH]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N([CH2:29][CH3:30])CC)C.C(Cl)CCCCCCCCCCCCCCC.[OH2:48]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][C:29](=[O:48])[CH3:30])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: O
Reactant: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reactant: CCN(CC)CC
Agent: CCCCCCCCCCCCCCCCCl
Solvent: CN(C)C=O
Product: CC(=O)NCC(C)(C)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1

Procedure:
A mixture of Example 74 (100.0 mg, 0.303 mmol), triethylamine (0.055 mL, 0.394 mmol), and cetyl chloride (0.024 mL, 0.334 mmol) in DMF (2.2 mL) was stirred at 0° C. for 60 minutes. Water was added slowly to the reaction mixture and a white suspension formed. The suspension was filtered, washed with water and diethyl ether, and oven-dried to give 45.0 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 0.87 (s, 6H), 1.89 (s, 3H), 2.96 (d, J=6.44 Hz, 2H), 3.13 (d, J=6.10 Hz, 2H), 6.86 (t, J=6.27 Hz, 1H), 6.90 (d, J=1.36 Hz, 1H), 6.98 (s, 1H), 7.22 (dd, J=7.80, 4.75 Hz, 1H), 7.79 (t, J=6.27 Hz, 1H), 8.15 (d, J=2.37 Hz, 1H), 8.27-8.40 (m, 2H), 12.16 (s, 1H). MS (ESI+) m/z 372.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=O)[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][CH2:19][C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)[CH2:26][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: COc1ccc2ncc(Cl)nc2c1
Product: COc1ccc2ncc(OCCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow viscous oil following Scheme 1 and in analogy to Example 9 using 2-chloro-7-methoxy-quinoxaline, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as starting materials.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1>CN(C)C(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[S:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Sc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.100 g, 0.230 mmol) and potassium carbonate (0.0668 g, 0.483 mmol) were stirred in N,N-dimethylacetamide (3 mL). 4-Methoxythiophenol (0.0322 g, 0.230 mmol) was added to the reaction mixture and stirred under a nitrogen atmosphere at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with a 1M aqueous solution of sodium hydroxide, then brine (×3). The organic layer was dried, filtered and concentrated in vacuo to afford the title compound as a solid (0.13 g, 100%), which was used without purification.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:7].O1CCCC1>O>[O:14]=[C:11]1[N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=[CH:12]1
Reactant: COC(=O)c1ccc(=O)n(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(=O)n(-c2ccccc2)c1
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Lithium hydroxide monohydrate (0.366 g, 8.73 mmol) was added to a mixture of methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (1.0 g, 4.37 mmol), tetrahydrofuran (9 mL) and water (6 mL) at 0° C. The mixture was stirred for 1 hour, diluted with water and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2 using 2 N hydrochloric acid and the precipitate was filtered to give the title compound as a brown solid (0.740 g, 79%). m.p. 256-263° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.53 (d, J=9.4 Hz, 1H), 7.40-7.49 (m, 5H), 7.87 (dd, J=2.5, 9.8 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H); IR (KBr) ν 3446, 1708, 1645, 1577, 1263, 1228 cm−1; MS 214 (M−1).
Reaction SMILES: [C:1](=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:3][C:1](=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)=C(C)CBr

Procedure:
Diethyl isopropylidenemalonate (4, 50 g, 0.25 mol) was refluxed with stirring with N-bromosuccinimide (44.3 g, 0.25 mol) and dibenzoyl peroxide (1.0 g, 4.1 mmol) in carbon tetrachloride (100 mL) with illumination using Kodak Ectagraphic slide projector lamp ELH (300 Watt) for 1.5 h. The reaction was completed as indicated by a negative starch-iodine test for N-bromosuccinimide. The resulting mixture was diluted with carbon tetrachloride (100 mL) and it was cooled in an ice-bath. The precipitated succinimide was filtered off and the filtrate was evaporated in vacuo at room temperature. The residual pale yellow oil of diethyl bromo-isopropylidene-malonate (5, 71.1 g) was used without purification in the Example 2.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C[Al]C.[C:9](Cl)([CH3:12])([CH3:11])[CH3:10]>ClC1C=CC=CC=1>[C:9]([C:2]1[CH2:1][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)Cl
Agent: C[Al]C
Solvent: Clc1ccccc1
Product: CC(C)(C)C1=CC=CC1

Procedure:
In runs 1 through 10, five ml. of 0.025M dimethylaluminum cyclopentadiene (Me2AlCPD) in chlorobenzene was dispensed by pipette into 20 × 150 mm test tubes. The tubes were then capped with screw caps fitted with self-sealing gaskets and TeflonR liners. The reaction tubes were placed in a constant temperature bath. After allowing sufficient time for the tubes and contents to attain bath temperature, 0.12 M tert.-butyl chloride solution in chlorobenzene (tBuCl) already at bath temperature was added by syringe fitted with hypodermic needle. After the desired time, the reactions were quenched by the addition of normal-butyl alcohol.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: COC(=O)C(C)n1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 from 4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromopropanoate: MS (APCI) m/z 297 (M+1).
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C[Si](C)(C)[C:10]([F:13])([F:12])[F:11]>C1COCC1.F.C([N+](CCCC)(CCCC)CCCC)CCC>[F:11][C:10]([F:13])([F:12])[CH:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Solvent: C1CCOC1
Product: C=CCCCC(O)C(F)(F)F
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a ice-bath cooled solution of hex-5-enal (500 mg, 4.331 mmol) and trimethyl(trifluoromethyl)silane (0.74 g, 5.13 mmol, 1.2 equiv.) in THF (10 mL) was added tetrabutylammonium hydrofluoride (10 mg, 0.04 mmol). The ice bath was removed and the reaction progress was monitored via GCMS and 1H NMR. Upon complete transformation of the starting material the reaction mixture was treated with 2M HCl and stirred for an additional 2 h. Then, 50 mL of Et2O was introduced and the layers were separated. The aqueous fraction was additionally extracted with Et2O and the combined organic phases were washed sequentially with a saturated aqueous NaHCO3 solution, water, and brine. After drying with MgSO4 and filtration the solvent was removed under reduced pressure and the resultant crude residue was purified by column chromatography (silica gel, pentane/Et2O, v/v=8/2). Fractions containing the pure compound were collected and concentrated in vacuo to give 1,1,1-trifluorohept-6-en-2-ol (225 mg, 31% yield) as a yellow oil.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[OH-].[Na+].O1C2CNCCC=2C=C1.[C:22](=O)([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.N1C=CC=CC=1>[C:35]1([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:22]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:23])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:24]1([OH:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCCCCc1ccccc1)Oc1ccccc1
Reactant: c1cc2c(o1)CNCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCCCCc1ccccc1)N1CCc2ccoc2C1
Product: Oc1ccccc1

Procedure:
4,5,6,7-Tetrahydrofuro[2,3-c]pyridine hydrochloride 0.280 g (1.754 mmol) was dissolved in water. The solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. A solution of the resulting crude 4,5,6,7-tetrahydrofuro[2,3-c]pyridine and 0.71 g (2.6 mmol) of phenyl 4-phenylbutyl carbonate in 10 ml of pyridine was stirred at 100° C. overnight. The solvent was distilled off under reduced pressure; the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield 6-(4-phenylbutoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine as a mixture with phenol.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:43][CH:42]=3)[C:37](O)=[O:38])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>>[C:48]([O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@H:36]([NH:35][C:33](=[O:34])[O:32][CH2:31][CH:29]2[C:30]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:37]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:15][CH2:16][CH3:17])[C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])=[O:38])=[CH:46][CH:45]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: CCOC(CN[C@H](C)c1ccccc1)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C)c1ccccc1)OCC
Yield: 87.7 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (R)-2,2-diethoxy-N-(1-phenylethyl)ethanamine (Compound IX-14) (50.0 g, 210 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (101.1 g, 220 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain the title compound (125.0 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:4][C:3]=1[CH2:16][OH:17].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[C:3]([CH2:16][O:17][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(OC2CCCCO2)cc(CO)c1Br
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.2 %

Procedure:
To a solution of (2-bromo-3-methyl-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol (2.54 g, 8.43 mmol) and 3,4 dihydro-2H-pyran (0.92 mL, 10.12 mmol) in CH2Cl2 (8 mL) was added camphorsulfonic acid (40 mg, 0.17 mmol), and the mixture was stirred at room temperature for 21 h. The reaction mixture was then quenched with equal volumes of 0.2 M NaOH and EtOAc (1:1, 20 mL) before the layers were separated. The water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-(4-bromo-3-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (2.93 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Yield: 82.7 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-2 using ethyl 3-chloro-6-(pivalamidomethyl)picolinate (1.00 g, 3.35 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (268 mg, 6.71 mmol) to afford 750 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.85 (br s, 1H), 8.25 (br t, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H), 1.19 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C(Cl)(Cl)Cl>CN(C)C=O>[N:28]([C@@H:11]1[CH2:10][C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:14]2[CH2:15][O:16][C@@H:12]1[O:13]2)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](OCc3ccccc3)[C@H]3CO[C@@H]2O3)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Temperature: 150 °C
Reaction time: 72 h
Yield: 89.7 %

Procedure:
To a solution of 1,6-anhydro-4-O-benzyl-3-deoxy-2-O-p-toluenesulphonyl-β-D-arabino-hexopyranose (See Preparative Example 3) (0.50 g) in N,N-dimethylformamide (10 ml) was added sodium azide (0.25 g) and the mixture was heated with stirring at 150° C. for 3 days. Chloroform was added and the mixture was washed with water (×4), dried (MgSO4) and concentrated to a syrup. Purification by flash chromatography gave the title compound (0.30 g), [α]D -14.8°; 13C-nmr data: 100.8 (C-1), 55.8 (C-2), 24.6 (C-3), 71.0 and 70.6 (C-4 and PhCH2O), 74.7 (C-5), 65.7 (C-6), 137.8, 128.4, and 127.7 (aromatic).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[C:3]=1[N+:15]([O-:17])=[O:16].C(N(C(C)C)CC)(C)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][CH:37]=[N:36][N:35]=2)=[CH:30][C:29]=1[NH2:39]>CCCCO>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:8]([CH3:9])[C:4]1[C:3]([N+:15]([O-:17])=[O:16])=[C:2]([NH:39][C:29]2[CH:30]=[C:31]([C:34]3[NH:38][CH:37]=[N:36][N:35]=3)[CH:32]=[CH:33][C:28]=2[CH3:27])[N:7]=[CH:6][N:5]=1
Reactant: CN(CC(C)(C)C)c1ncnc(Cl)c1[N+](=O)[O-]
Reactant: Cc1ccc(-c2nnc[nH]2)cc1N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1ncnc(N(C)CC(C)(C)C)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
A solution of (6-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-methyl-amine (185 mg, 0.72 mmol), diisopropylethylamine (0.13 mL, 0.72 mmol) and 2-Methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamine (126 mg, 0.72 mmol) in 3 mL of n-BuOH was heated with stirring at 80° C. for 18 h. The solvent was then evaporated in vacuo and the crude product was purified by flash chromatography to afford 87 mg of the product (30%). MS (m/z) calcd for C19H24N8O2 (MH+), 397.2, found, 397.3.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[N:19]([CH2:32][C:33](=[O:39])[NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:18]3=[O:40])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C(O)=O>>[C:35]([NH:34][C:33](=[O:39])[CH2:32][N:19]1[C:18](=[O:40])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)[CH:16]=2)[N:21]=[C:20]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCNCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
4-[3-(tert-Butylcarbamoylmethyl)-2-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE VIII.1) (38.9 mg, 0.068 mmol) was treated with TFA:DCM (1:1 (v/v), 1 mL) and the solution stirred at room temperature for 40 min. The volatiles were removed in vacuo and the residue partitioned between DCM and 1 M NaOH (aq.). The organics were dried (Na2SO4) and concentrated in vacuo to yield N-tert-butyl-2-[2-(3-chlorophenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 1a) (27 mg, 0.046 mmol, 68%) as the trifluoroacetic acid salt.