Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1C(=O)CCC1=O.C(OCC)(=O)C.ClCCl>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1COC(c2ccc([N+](=O)[O-])cc2)=N1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1coc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
α,α-Bisisobutyronitrile (66 mg, 0.4 mmol) was added to a solution of methyl 2-(4-nitrophenyl)-4,5-dihydro-1,3-oxazole-4-carboxylate (described in Kline, Toni; Andersen, Niels H.; Harwood, Eric A.; Bowman, Jason; Malanda, Andre; Endsley, Stephanie; Erwin, Alice L.; Doyle, Michael; Fong, Susan; Harris, Alex L.; Mendelsohn, Brian; et al., J. Med. Chem., 45, 14, 2002, 3112-3129, 1.95 g, 7.8 mmol) in benzene (30 mL). The mixture was heated to 80° C. and N-bromosuccinimide (1.53 g, 8.58 mmol) was added. The mixture was stirred at the same temperature for 1.5 hours and then ethyl acetate and dichloromethane were added, followed by sequentially washing with water and brine. This was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=100/0, 20/1, 10/1) to obtain 1.29 g of the title compound as a colorless solid (67%).
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:29]=[CH:28][C:10]2[S:11][CH2:12][CH2:13][N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:9]=2[CH:8]=1)=O.C([O-])(=O)C.[NH4+:40]>CN(C=O)C.C(=O)(O)[O-].[Na+].CCOC(C)=O>[C:30]1([C:2]2[NH:40][C:5]([C:7]3[CH:29]=[CH:28][C:10]4[S:11][CH2:12][CH2:13][N:14]([S:15]([C:18]5[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=5)(=[O:17])=[O:16])[C:9]=4[CH:8]=3)=[N:4][CH:3]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCS2)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCSc2ccc(-c3ncc(-c4ccccc4)[nH]3)cc21
Yield: 6.3 %

Procedure:
To a solution of N-(2-oxo-2-phenylethyl)-4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (20 mg, 38 μmol) in DMF (1 mL) was added ammonium acetate (30 mg, 380 μmol). The reaction mixture was subjected to microwave irradiation (150° C., 15 min). LCMS analysis of the reaction mixture indicated nearly complete conversion of the starting material. The reaction mixture diluted with saturated aqueous sodium bicarbonate (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (2 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography using a gradient elution of hexanes with 10-60% EtOAc to provide 6-(5-phenyl-1H-imidazol-2-yl)-4-(4-(trifluoro-methyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (1.2 mg, 2.4 μmol, 6% yield) as a yellow oil. LCMS (+ESI) m/z=502.5 [M+H]+; 1H-NMR (CDCl3) δ 8.10 (m, 2H), 7.90 (d, 2H), 7.80 (d, 2H), 7.4-7.5 (m, 4H), 7.25 (d, 1H), 7.00 (dd, 1H), 6.76 (d, 1H), 3.53 (t, 2H), 3.08 (t, 2H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 143 mg) in THF (dry) (15 mL) was added 2-chloroethanesulfonyl chloride (0.376 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-methoxyphenoxy)phenyl)pyridin-2-amine (348 mg) in THF (dry) (15 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 15 hr. The mixture was quenched with water at 0° C. carefully and water was added to form precipitates. The precipitate was crystallized from MeCN-THF-MeOH/IPE to give the title compound (304 mg) as colorless crystals.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].B(F)(F)F.[CH3:14][CH2:15]OCC.[CH2:19](O)[CH3:20]>>[NH:1]([CH2:6][C:7]([O:9][CH2:19][CH3:20])=[O:8])[CH2:2][C:3]([O:5][CH2:14][CH3:15])=[O:4]
Reactant: O=C(O)CNCC(=O)O
Reactant: CCOCC
Reactant: CCO
Agent: FB(F)F
Product: CCOC(=O)CNCC(=O)OCC
Yield: 92 %

Procedure:
To a magnetically stirred suspension of iminodiacetic acid (50 g, 0.376 mol) in absolute ethanol (1000 ml) under N2 was added boron trifluoride etherate (100 g, 1.127 mmol). The reaction mixture was refluxed for 3 days and concentrated in vacuo to a volume of 150 ml. A saturated NH4Cl solution (500 ml) was added and the reaction mixture was extracted with CH2Cl2 (3×250 ml). The combined organic layers were dried and concentrated in vacuo. The crude product was distilled at 10 mm Hg to give 65.2 g (92% yield) of iminodiacetic acid, diethyl ester as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]4)[CH2:10][CH:9]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:31]=[N:32][CH:33]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)COC1
Yield: 7 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with 5-chloropyridin-3-ylboronic acid yielded the title compound (7% yield) as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][C@@H:7]1[CH2:11][N:10](CC2C=C(C3C=CC=C([N+]([O-])=O)C=3)C(OC)=CC=2)[C:9](=[O:30])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[H-].[Na+]>O>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][C@@H:7]1[CH2:11][NH:10][C:9](=[O:30])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesis of ((S)-4-(tert-Butyl-dimethyl-silanyloxy)-1-(6-methoxy-3′-nitro-biphenyl-3-ylmethyl)-pyrrolidin-2-one (I-213). Into a 250 mL round-bottomed flask with a stir bar was added I-212 (2.57 g, 11.95 mmol), THF (150 mL), and the solution was cooled to 0° C. NaH (0.56 g, 14.12 mmol) was added and the suspension was stirred at room temperature for 30 minutes. To this, I-70 (3.50 g, 10.86 mmol) was added and the reaction was stirred for 20 hours at room temperature after which time 50 mL of water was added and the product was extracted with ethyl acetate. The organics were concentrated to yield 8.9 g of I-213, which was used as is in the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][CH2:36][CH2:37][CH2:38][OH:39]>O1CCCC1.O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 4.5 g of 3-(3-pyridyl)acrylic acid, 3.5 g of N-hydroxysuccinimide, 6.8 g of dicyclohexylcarbodiimide, and 80 ml of dioxane is stirred at room temperature overnight. The reaction mixture is filtered, and the filtrate is concentrated to give a brown oil. The product is dissolved in 100 ml of tetrahydrofuran, and 2.3 g of 3-amino-1-propanol is added. The mixture is stirred at room temperature overnight and concentrated. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give 4.2 g of N-[3-(3-pyridyl)acryloyl]-3-amino-1-propanol. The product is converted into the hydrochloride with 35 w/v % ethanolic hydrogen chloride. To the hydrochloride is added 4.6 g of thionyl chloride, and the mixture is stirred at 100° C. for 2 hours. The remaining thionyl chloride is distilled off, and 50 ml of water is added. The resulting solution is neutralized with 10% aqueous sodium carbonate solution and extracted with three 50-ml portions of chloroform. The combined extracts are dried over magnesium sulfate, and the chlorofom is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give 3.2 g of N-[3-(3-pyridyl)acryloyl]-3-amino-1-chloropropane.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[S:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.IC.[CH3:20]CN(C(C)C)C(C)C.O>C(O)C>[CH3:20][S:16][C:14]1[S:15][C:11](=[CH:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[C:12](=[O:17])[N:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NC(=S)SC1=Cc1c[nH]c2ncccc12
Solvent: O
Solvent: CCO
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
The suspension of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxo-thiazolidin-4-one (2.2 g, 8.22 mmol), iodomethane (1.05 mL, 16.8 mmol) and DIEA (3.0 mL, 16.8 mmol) in anhydrous ethanol (110 mL) was stirred at 100° C. for 2 h. After adding water (200 mL), the solid was collected by filtration, washed with water and dried to obtain 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-thiazol-4-one (1.48 g, 60.8%) as a grey solid. LC-MS m/e 276 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([NH:49][C:50]([C:52]1[N:53]=[C:54]([C:61]([F:64])([F:63])[F:62])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][C:56]=12)=[O:51])[CH3:48].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH2:47]([NH:49][C:50]([C:52]1[N:53]=[C:54]([C:61]([F:63])([F:64])[F:62])[N:55]2[CH2:60][CH2:59][N:58]([C:4](=[O:5])[C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])[CH2:57][C:56]=12)=[O:51])[CH3:48]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CCNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 43.9 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (250 mg, 0.84 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (480 mg, 1.26 mmol), crude N-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 7a (242 mg, 0.92 mmol) and N, N-diisopropylethylamine (0.3 mL, 1.68 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H2O, and extracted with dichloromethane (50 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with saturated sodium bicarbonate solution (40 mL), saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-ethyl-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 7 (200 mg, yield 43.9%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][CH2:21][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: Oc1ccccc1S
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCSc1ccccc1O
Reaction time: 0.33 h

Procedure:
2-Hydroxythiophenol (1.00 g, 8.70 mmol) was added to a mixture of DMF (10 mL) and Cs2CO3 (2.90 g, 8.90 mmol). To this was added 3-bromopropanol (0.80 mL, 9.16 mmol) and the mixture was stirred for 20 min. The mixture was added to into water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a clear oil (2.36 g, 100%). MS [M−H]− 183.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C:18](OCC)=[O:19])([CH3:17])[CH3:16])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[CH2:18][OH:19]
Reactant: CCOC(=O)C(C)(C)N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
2-Bromo-2-methylpropionic acid ethyl ester (155 μL, 1.06 mmol) was added to a solution of potassium carbonate (145 mg, 1.05 mmol) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in anhydrous acetonitrile (1 mL). The resulting mixture was heated at 80° C. for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 98:2) to give (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a pale brown oil. To a solution of (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (1 mmol) in anhydrous THF (5 mL) at 0° C., a solution of LiAlH4 (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a brown oil (168 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 3.37 (bs, 1 H); 3.31 (d, J=10.2 Hz, 1 H); 3.21 (d, J=10.2 Hz, 1 H); 3.15-3.00 (m, 2 H); 2.81-2.61 (m, 2 H); 2.45 (s, 2 H); 1.76 (d, J=10.0 Hz, 1 H); 1.56 (d, J=10.0 Hz, 1 H); 1.46 (t, J=5.02 Hz, 1 H); 1.03 (s, 3 H) and 1.00 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([OH:7])([CH3:6])[CH2:4][NH3+:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:9])([F:8])[C:3]([OH:7])([CH3:6])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:15]
Reactant: CC(O)(C[NH3+])C(F)(F)F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(O)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture comprising 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-ammonium (0.9 g), phthalic anhydride (1.039 g) and DIPEA (2.188 ml) in chloroform (30 ml) was heated at 70° C. for 5 hours. After cooling to RT, the mixture was washed with water and passed through a phase separator. The organic phase was reduced to dryness. The crude product was purified by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc removed to give the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.92 (2H, m), 7.85 (2H, m), 3.95 (2H, m), 1.36 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[CH2:36]([O:35][CH:34]([O:38][CH2:39][CH3:40])[C@@H:33]([N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16])[CH3:42])[CH3:41])[CH3:37]
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)-propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1.C(O[K])(C)(C)C.O>CN(C=O)C>[Cl:12][C:8]1[C:9]([Cl:11])=[N:10][C:2]([O:13][CH2:14][CH2:15][CH2:16][C:17]2([OH:20])[CH2:19][CH2:18]2)=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1Cl
Reactant: OCCCC1(O)CC1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Cl)c(Cl)nc1OCCCC1(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A mixture of compound 2,5,6-trichloronicotinamide (0.6 g, 2.7 mmol), 1-(3-hydroxypropyl)cyclopropanol (370 mg, 3.2 mmol) and tert-BuOK (363 mg, 3.2 mmol) in DMF was stirred at room temperature overnight and the reaction mixture was then poured into cold water, the mixture was extracted twice with ethyl acetate, the combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated, the residue was purified by column chromatography (silica gel, Petroleum ether: EtOAc=1:0 to 5:1) to give the 5,6-dichloro-2-(3-(1-hydroxycyclopropyl)propoxy)nicotinamide (0.72 g, 73%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 5.48 (s, 1H), 4.82 (t, 2H, J=6.4 Hz), 2.36 (m, 2H), 1.97 (m, 2H), 0.94 (t, 2H), 0.73 (t, 2H).
Reaction SMILES: N([CH2:3][C:4]([NH:6][C@H:7]([C:16]1[O:17][C:18]([CH3:21])=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:5])C.[CH2:22]([NH:29][C:30](=[O:54])[C@H:31]([CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:53])[NH2:52])[NH:32][C:33](=[O:46])[C@H:34]([CH3:45])[NH:35][CH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)(=O)C>>[C:4]([NH:6][C@H:7]([C:16]1[O:17][C:18]([CH3:21])=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)(=[O:5])[CH3:3].[CH2:22]([NH:29][C:30](=[O:54])[C@H:31]([CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:52])[NH2:53])[NH:32][C:33](=[O:46])[C@H:34]([CH3:45])[NH:35][CH:36]1[CH2:37][CH2:38][CH:39]([C:42]([OH:44])=[O:43])[CH2:40][CH2:41]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNCC(=O)N[C@@H](Cc1ccc(F)cc1)c1ncc(C)o1
Agent: C[C@H](NC1CCC(C(=O)O)CC1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NCc1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)N[C@@H](Cc1ccc(F)cc1)c1ncc(C)o1

Procedure:
Compound 9 was prepared by the method described for the preparation of compound 7 from AC2 (1.2 mmol) and acetyl chloride (1.2 mmol), and isolated as a white powder (0.10 g): mp 111-116° C.; FAB-MS m/e 705 (MH+). Anal. calcd. for C37H49N8O5F·1.0 TFA·1.0 anisole·1.0 H2O (901.78): C, 57.54; H, 6.35; N, 12.43; KF, 2.0. Found: C, 57.71; H, 6.27; N, 12.49; KF, 2.32.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([CH:27]([CH3:31])[C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH:27]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(Oc1ccccc1)C(=O)Cl
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CC(Oc1ccccc1)C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-phenoxypropionyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxypropanamide as a white powder, m.p. 85.0-87.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.07 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.43 (dt, J=7.5, 1.2 Hz, 1H), 7.28-7.16 (m,3H), 6.91-6.81 (m, 3H), 6.57 (s, 2H), 4.62-4.53 (m, 3H), 3.10 (q, J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.43 (quintet, J=7.1 Hz, 2H), 1.33 (d, J=6.6 Hz, 3H); MS (EI) m/e 403.2005 (403.2008 calcd for C23H25N5O2).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C@@:7]1(C)[C@H:13]2[C@H:11]([O:12]2)[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:19]=[N+:20]=[N-:21].[Na+]>CO.O>[N:19]([C@H:11]1[CH2:10][CH2:9][CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[C@@H:13]1[OH:12])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H]2O[C@H]21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCC[C@H](N=[N+]=[N-])[C@H]1O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl-dimethyl-[[(1R,5R,6R)-5-methyl-7-oxabicyclo[4.1.0]heptan-5-yl]oxy]silane, 50c, (0.05 g, 2.15 mmol) in methanol (5 mL) and H2O (0.6 mL) was added NH4Cl (0.23 g, 0.15 mL, 4.30 mmol), followed by portion wise addition of sodium azide (0.42 g, 1.26 mL, 6.45 mmol). The resulting reaction mixture was warmed to 60° C., stirred for 12 h, at which point TLC-analysis revealed traces of the starting material. The reaction mixture was cooled to ambient temperature, quenched with H2O (2 mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3×15 mL), washed with brine (10 mL), dried over MgSO4, filter and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2.5-10% ethyl ether in hexanes gradient) to afford 254 mg of (1R,2S,6R)-2-azido-6-[tert-butyl(dimethyl)silyl]oxy-cyclohexanol, 50d, as a clear oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[OH-].[Na+]>C(Cl)Cl.O>[CH3:25][S:26]([O:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=3)[CH2:9][C@@H:4]2[CH2:3]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of 1.00 g (4.20 mmol) of (7R,8aS)-7-hydroxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]-pyrazine (Preparation 6) and 0.644 mL (4.62 mmol) of triethylamine in 40 mL of methylene chloride was chilled to 0° C. and 0.34 mL (4.41 mmol) of methanesulfonyl chloride in 20 mL of methylene chloride was added slowly. After 30 min, water was added and the pH adjusted to 10 with 1M NaOH. The layers were separated, the organic phase was washed with water (2×), dried (magnesium sulfate), filtered and evaporated to give 1.15 g (86%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 317.