Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17](O)=[O:18])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[OH:18][CH2:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
(2S)-1-{[(Phenylmethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (1.0 g, 3.798 mmol) in THF (5 mL) was cooled to −18° C. and borane-THF complex (3.798 mL, 3.798 mmol) was added over 10 min. The mixture was allowed to warm to room temperature with stirring overnight, then cooled to 0° C., and water (4 mL) was added, followed by K2CO3 (1.4 g). The phases were separated, and the aqueous phase was extracted with Et2O (3×25 mL). The combined organic phase was washed with brine (1×25 mL) and dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide phenylmethyl (2S)-2-(hydroxymethyl)-1-piperidinecarboxylate (815 mg, 86%). LCMS: (M+H)+: 250.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH2:26][OH:27])=[CH:23][C:22]=4[CH:28]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]>O1CCOCC1.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH:26]=[O:27])=[CH:23][C:22]=4[CH:28]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc4oc(CO)cc4c3)no2)cc1OCC
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C=O)cc4c3)no2)cc1OCC
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A suspension of the product of Step D (0.13 g; 0.34 mmol) and MnO2 (0.15 g; 1.7 mmol) in dioxane (4 ml) was refluxed for 1 h with stirring. After cooling to room temperature, the insoluble material was removed by filtration, washed with EtOAc (20 ml) and combined filtrates were evaporated to dryness to give the title compound (0.13 g; 100%), as greyish solid. 1H-NMR (CDCl3) 9.91 (s, 1H); 8.59 (s, 1H); 8.33 (dd, 1H, J=2, 9 Hz); 7.63-7.82 (m, 4H); 6.99 (d, 1H, J=9 Hz); 4.14-4.26 (m, 4H); 1.4-1.57 (m, 6H+H2O).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][NH:6][CH3:7])[CH3:2].Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][N:6]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])[CH3:7])[CH3:2]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: CCN(CC)CCNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of N1,N1-diethyl-N2-methylethane-1,2-diamine (9.1 g, 63.00 mmol, 1.50 equiv, 90%) in N,N-dimethylformamide (500 mL), 3-(bromomethyl)benzoic acid (10 g, 46.51 mmol, 1.00 equiv), potassium carbonate (7.8 g, 56.12 mmol, 1.20 equiv), and potassium iodide (1.55 g, 9.34 mmol, 0.20 equiv). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (10 g) was purified by reverse phase HPLC eluting with 0.05% TFA in a water/CH3CN gradient. The product was obtained as 6 g (46%) of a white solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.01 (m, 1H), 7.89-7.87 (m, 1H), 7.28-7.22 (m, 2H), 3.99 (s, 2H), 2.97-2.72 (m, 8H), 2.28 (s, 3H), 1.13-1.01 (m, 6H). MS (ES, m/z): 265 [M+H]+.
Reaction SMILES: COC([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH3:26])[C:17]([CH3:28])([CH3:27])[CH:16]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=O.C(N1C2C(=CC=CC=2)C(CS(Cl)(=O)=O)=[CH:33][C:32]1(C)[CH3:46])C.C(N)CCCCCCC.C(Cl)(Cl)Cl>C(O)C>[CH2:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([CH2:14][S:11]([NH:8][CH2:7][CH2:6][CH2:5][CH2:10][CH2:9][CH2:33][CH2:32][CH3:46])(=[O:12])=[O:13])=[CH:16][C:17]1([CH3:28])[CH3:27])[CH3:26]
Reactant: CCN1c2ccccc2C(CS(=O)(=O)Cl)=CC1(C)C
Reactant: CCN1c2ccccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Solvent: CCCCCCCCN
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCCCCNS(=O)(=O)CC1=CC(C)(C)N(CC)c2ccccc21
Yield: 81 %

Procedure:
(1-Ethyl-2,2-dimethyl-1,2-dihydroquinol-4-yl)-N-octyl-methanesulfonamide (12) is prepared similarly to compound (10) using compound (9) with n-octylamine. The product is isolated by column chromatography on silica gel with a gradient running from chloroform to ethanol.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[F:23])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)cc1
Temperature: 150 °C

Procedure:
In step 6A-5, palladium tetrakis (25 mg, 0.02 mmol) was added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (77 mg, 0.23 mmol), sodium carbonate (85 mg, 0.81 mmol), and 4-cyanophenylboronic acid (60 mg, 0.41 mmol) in 2 mL of dioxane and 0.5 mL of water contained in a microwave reaction tube. The resulting solution was heated in a microwave for 25 minutes at 150° C. and the yellow slurry was cooled to room temperature and filtered through a 0.2 μm nylon frit. The solvent was removed from the mother liquor and the remaining residue was reconstituted in methanol and further purified by preparative LC/MS. The desired fractions were dried to yield the desired product as a racemic mixture, which was then purified by chiral LC to yield (R)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (6-7) as a chiral pure white solid along with (S)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile as a chiral pure white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([CH3:15])[S:14][C:10]=3[CH:9]=2)=[CH:6][C:5]([O:18]COCCOC)=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.Cl>>[F:1][C:2]1[N:3]=[C:4]([C:25]([F:28])([F:26])[F:27])[C:5]([OH:18])=[CH:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([CH3:15])[S:14][C:10]=2[CH:9]=1
Reactant: COCCOCOc1cc(-c2ccc3nc(C)sc3c2)c(F)nc1C(F)(F)F
Agent: Cl
Product: Cc1nc2ccc(-c3cc(O)c(C(F)(F)F)nc3F)cc2s1
Yield: 46 %

Procedure:
A 5 mL conical microwave vessel was charged with 6-(2-fluoro-5-((2-methoxyethoxy)methoxy)-6-(trifluoromethyl)pyridin-3-yl)-2-methylbenzo[d]thiazole (0.0186 g, 0.045 mmol), a spin vane and 1 mL TFE. The vessel was swept with Ar, treated with 2M hydrochloric acid (0.022 ml, 0.045 mmol) and sealed. The solution was irradiated using a Biotage microwave synthesizer to 120° C. for 15 minutes. The solution was concentrated using a stream of nitrogen. The crude was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 25% B; 5.0→35 min@20 mL/min, linear gradient to 55% B; 35→45@20 mL/min, isocratic at 55% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 25% B; 60 min end. A=water; B=2% TFE in ACN. A band that eluted from 26.4 to 28.7 minutes was isolated. The solvent was concentrated under a stream of nitrogen overnight, and then lyophilized to afford 6-fluoro-5-(2-methylbenzo[d]thiazol-6-yl)-2-(trifluoromethyl)pyridin-3-ol (0.0068 g, 46% yield). 1H NMR (400 MHz, DMF) δ ppm 2.88 (s, 3H) 7.78 (dt, J=8.46, 1.78 Hz, 1H) 7.89 (d, J=7.92 Hz, 1H) 8.07 (d, J=8.51 Hz, 1H) 8.39 (t, J=1.37 Hz, 1H) 11.89 (br. s., 1H). 19F NMR (376 MHz, DMF) δ ppm −82.30 (d, J=6.50 Hz, 1 F) −64.69 (s, 3 F). HPLC-MS: 2.14 min (>99%@215 nm; >99% @254 nm; m/z=329.0, calculated for C14H8F4N2OS+H+=328.0).
Reaction SMILES: O[N:2]1[C:11]2[C:10]3[CH:12]=[CH:13][N:14]=[CH:15][C:9]=3[NH:8][C:7]3[N:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[N:4]=[C:3]1[CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]#[N:28])[CH2:22][CH2:21]1.P(OC(C)C)(OC(C)C)OC(C)C>CN(C)C(=O)C>[N:4]1[C:5]2[C:6]3[CH:19]=[CH:18][CH:17]=[N:16][C:7]=3[NH:8][C:9]3[CH:15]=[N:14][CH:13]=[CH:12][C:10]=3[C:11]=2[NH:2][C:3]=1[CH:20]1[CH2:21][CH2:22][CH:23]([CH2:26][C:27]#[N:28])[CH2:24][CH2:25]1
Reactant: N#CCC1CCC(c2nc3c(n2O)-c2ccncc2Nc2ncccc2-3)CC1
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: CC(=O)N(C)C
Product: N#CCC1CCC(c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)CC1
Yield: 60.5 %

Procedure:
A solution of [4-(3-hydroxy-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepin-2-yl)cyclohexyl]acetonitrile (7.0 g, 0.019 mol) and triisopropyl phosphite (20 mL, 0.08 mol) in N,N-dimethylacetamide (20 mL) was heated at 160° C. for 2 hours and was then concentrated in vacuo. The residue was purified by column chromatography on silica gel (5% trimethylamine 7.5% methanol and 87.5% ethyl acetate) yielding 4.10 g of product as a 9:1 mixture of the two diastereomers. The pure cis and trans isomers could be obtained by preparative HPLC. 1H NMR (300, DMSO-d6): δ 12.73 and 12.01 (br s, 1H), 7.83-7.99 (m, 4H), 7.70 and 7.46 (m, 1H), 6.77 (m, 1H), 2.54-2.63 (m, 1H), 2.49 (m, 2H), 1.84-2.02 (m, 4H), 1.50-1.79 (m, 3H), 1.09-1.24 (m,2H).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23](=O)[CH2:24]Br)=[CH:21][CH:20]=1)#[N:18].C(Cl)Cl>CC(O)C>[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]2[N:6]=[C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]3[CH:24]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: COC(=O)c1cccc(N)n1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)cn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
NaHCO3 (1.0 eq.) was added to a solution of (A1) in i-PrOH (0.5 M), then 4-cyanophenacyl bromide (1.2 eq.) was added and the resulting reaction mixture was stirred at RT for 18 h, then heated to reflux for another 18 h. After cooling down, the solvent was reduced in vacuo and the residue partioned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was triturated with hot EtOH and filtered to yield (31%) the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.31 (1H, s), 8.26 (2H, d, J=8.3 Hz), 8.00 (1H, d, J=9.0 Hz), 7.91 (2H, d, J=8.3 Hz), 7.85 (1H, d, J=7.0 Hz), 7.45 (1H, dd, J=9.0, 7.0 Hz), 4.00 (3H, s). MS (ES+) C16H11N3O2 requires: 277, found: 278 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37](OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][CH:37]=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4nnco4)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.023 g, 0.0443 mmol), triethylorthoformate (0.25 mL), and p-toluenesulfonic acid (5 mg) was stirred at rt for 2 h. Aqueous 1N HCl was added and stirring continued for 45 min. The reaction was quenched with saturated aqueous NaHCO3, and the product was extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography to afford the title compound. LC/MS: m/e 530.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.5 (1H, s), 8.28 (1H, d, J=2.1 Hz), 8.06 (1H, dd, J=8.7, 2.0 Hz), 7.64 (1H, d, J=7.6 Hz), 7.16 (1H, d, J=7.5 Hz), 7.13 (2H, d, J=8.5 Hz), 7.04 (1H, s), 6.95 (2H, d, J=8.4 Hz), 6.91 (1H, d, J=8.5 Hz), 4.70-4.59 (2H, br), 1.26 (9H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([CH3:45])([CH3:44])[CH2:10][C:11]([NH:13][C@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:18]2[CH:40]=[CH:41][CH:42]=[CH:43][C:17]=2[S:16][CH2:15]1)=[O:12].[CH:46](=O)[C:47]1[O:51][CH:50]=[CH:49][CH:48]=1>>[O:51]1[CH:50]=[CH:49][CH:48]=[C:47]1[CH2:46][NH:8][C:9]([CH3:45])([CH3:44])[CH2:10][C:11]([NH:13][C@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:18]2[CH:40]=[CH:41][CH:42]=[CH:43][C:17]=2[S:16][CH2:15]1)=[O:12]
Reactant: CC(C)(N)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Reactant: O=Cc1ccco1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O)NCc1ccco1

Procedure:
The title compound is prepared from 3-amino-3-methyl-N-[3,4-dihydro-4-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]butanamide trifluoroacetate (prepared by the method of M. Fisher, et al, U.S. Pat. No. 5,206,235) and furfuraldehyde by the procedures described in Example 1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([NH:12][C:13]([NH:15][CH2:16][C:17]1[C:18]([C:22](=[N:32][OH:33])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[N:19][O:20][N:21]=1)=[O:14])(C)(C)C>C(O)(C(F)(F)F)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:12][C:13]([NH:15][CH2:16][C:17]1[C:18]([C:22](=[N:32][OH:33])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[N:19][O:20][N:21]=1)=[O:14]
Reactant: CC(C)(C)NC(=O)NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Yield: 90.4 %

Procedure:
4-([(tert-Butylamino)carbonyl]aminomethyl)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide trifluoroacetate (10 mg, 0.02 mmol) was stirred in TFA (2.0 mL) for 2 hrs. The reaction was warmed gently with heat gun. Evaporation and purification by preparative LCMS gave the desired product (8 mg, 70%). MF=C1IH13ClFN6O3; LCMS calculated for C11H11ClFN6O3(M+H)+: m/z=329.0. 1H NMR (400 MHz, CD3OD): δ 7.01 (m, 2H), 6.85 (m, 1H), 4.59 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][C:22]1[CH:23]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)[S:20][CH:21]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: Cc1csc(OB([O-])[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3cc(C)cs3)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
In toluene/ethanol/water (10/1/1) (8.4 ml) was dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg), and to the mixture were added 4-methyl-2-thienyl borate (334 mg) and potassium carbonate (651 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (97 mg). The mixture was stirred at 100° C. for 24 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was purified with silica gel column chromatography (hexane/acetone=8/1) to give methyl 7-(4-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (432 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][CH2:32][C@@H:33]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:34][O:35][CH2:36][CH3:37]>CN(C=O)C.CCOC(C)=O>[C:41]([O:40][C:39]([NH:38][C@@H:33]([CH2:34][O:35][CH2:36][CH3:37])[CH2:32][NH:31][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1)=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(Nc2cccc(C)c2)n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (200 mg, 0.663 mmol) in DMF (5 mL) was added DIPEA (0.232 mL, 1.326 mmol) and (R)-tert-butyl 1-amino-3-ethoxypropan-2-ylcarbamate (174 mg, 0.795 mmol). The reaction mixture was stirred at RT overnight. Additional (R)-tert-butyl 1-amino-3-ethoxypropan-2-ylcarbamate (231.25 mg, 1.061 mmol) was added and the mixture was heated at 65° C. for 1 h. After cooling to RT, the reaction mixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL) and brine (20 mL). The combined organic layers were dried over Na2SO4 and concentrated to thick yellow oil. The crude product was used in the next step without further purification (415 mg). [M+H] calc'd for C25H33N5O5, 484; found, 484.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:31])[NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[CH:25][N:26]4[CH2:29][CH3:30])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.IC1C=CC(NC(C2C=CC(N3CCC(C(O)=O)CC3)=NC=2)=O)=CC=1C>>[CH2:29]([N:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([N:9]4[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]4)=[CH:17][CH:16]=3)=[O:31])[CH:28]=2)[CH:24]=[CH:25]1)[CH3:30]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(CC)c4c3)cc2)CC1
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)nc2)ccc1I
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCC(C(=O)O)CC4)cc3)cc21

Procedure:
1-[4-(1-Ethyl-1H-indol-6-ylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid was prepared by the hydrolysis of 1-[4-(1-ethyl-1H-indol-6-ylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid ethyl ester with LiOH monohydrate in a manner similar to the one described in the synthesis of 5′-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid above. HRMS m/z calcd for C23H25N3O3 [M+H]+; 392.1969. Found: 392.1968
Reaction SMILES: [C:1](Cl)#[C:2][CH3:3].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:28])([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[OH2:36]>C1COCC1>[F:28][C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:36])[CH2:2][CH3:3])[CH:11]=[CH:10][CH:9]=2)=[CH:17][CH:16]=1)([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22]
Reactant: CC#CCl
Reactant: O
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
Into a 100 mL single-neck flask, 58 mg of propynyl chloride was added dropwise to 200 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine (prepared in example 5) and 63 mg of triethylamine in THF (25 mL) while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature for 2 h. The mixture was then poured into H2O and the desired product was extracted into ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 256 mg as a foam. This material was purified via silica gel chromatography employing the Chromatotron, using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 1:1 to yield the title compound (130 mg, 56%) as a white foam. Ion spray M.S. 405.5 (M*−1).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[C:11]([O:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=2[CH3:35])[N:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH:23]([C:12]1[C:13](=[O:15])[NH:14][C:9](=[O:8])[NH:10][C:11]=1[O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[CH3:35])([CH3:25])[CH3:24]
Reactant: Cc1cc(C)c(C)c(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C)c(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 59 %

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-6-(2,3,5-trimethyl-phenoxy)-pyrimidine was dissolved in 6 mL ethyl acetate and 6 mL ethanol mixture. 10% Pd/C (52 mg) was added to the mixture. Then hydrogen balloon was applied. The reaction was stirred at room temperature for 40 minutes. The reaction crude was filtered through celite. The filtrate was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) followed by reverse phase HPLC (MeCN/water) to give white solid (94 mg, 59%). LC-MS shows 289.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.6 (br, 1H), 8.9 (br, 1H), 6.88 (s, 1H), 6.58 (s, 1H), 3.12 (m, 1H), 2.18 (s, 6H), 2.12 (s, 3H), 1.22 (d, 6H).
Reaction SMILES: [N+:1]([O-:4])([O-:3])=O.[NH4+].[N+:6]([C:9]1[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[CH:11][C:10]=1[CH3:18])([O-:8])=[O:7].[N+](C1C=CC=C([N+]([O-])=O)C=1C)([O-])=O.[Al]>>[N+:1]([C:14]1[C:9]([N+:6]([O-:8])=[O:7])=[C:10]([CH3:18])[CH:11]=[CH:12][CH:13]=1)([O-:4])=[O:3]
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])[O-]
Agent: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Al]
Agent: [NH4+]
Product: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
Eighty-five (85) parts of porous prill ammonium nitrate (average particle size, 1.7 mm; oil absorbency, 17%) preheated to 70° C., and 14 parts of a liquid dinitrotoluene mixture which was prepared by mixing 2,4-dinitrotoluene with 2,6-dinitrotoluene and heating at 70° C. were thoroughly mixed using a horizontal kneader equipped with a sigma wing, thereby obtaining a granular explosive of the present invention. After cooling, the granular explosive and 1 part of flake-shaped aluminium (P-0100; manufactured by Toyo Aluminium) were mixed using a horizontal kneader. The thus obtained explosive was recovered from the kneader and packed in a paper shell.