Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[C:17]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[N:32][N:31]=4)=[CH:25][CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:4][C:5]([NH:8]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:8][C:5]1[N:4]=[C:3]([C:16]2[C:17]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[N:32][N:31]=4)=[CH:27][CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[C:2]([F:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(F)c(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(F)c(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a RBF, tert-butyl 5-fluoro-4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylcarbamate (1.46 g, 2.43 mmol) was dissolved in DCM (4.86 ml, 2.43 mmol). TFA (749 μl, 9.72 mmol) was added at RT. The reaction was stirred at RT. After 20 min, LCMS showed mainly starting material. 1 mL of TFA was added and the reaction was allowed to stir at RT overnight. After 16 h, the reaction was concentrated and the residue dissolved in DCM. The solution was cooled to 0° C. and neutralized with 2N NaOH. At pH=5-7, the product as a white solid precipitated out. At pH>7, the product dissolves in DCM. The precipitate was filtered with aid of DCM. The solid product was set aside, while the filtrate was concentrated. The residue was diluted with a bit of DCM. Water was added. Ether was added and the whole solution was triturated to precipitate out additional product. The solid was filtered off with an aid of Et2O. This crop was combined with the first crop of solid. The product was purified by column chromatography on 120 g silica gel using 70:30 DCM:(90:10:1 DCM:MeOH:NH4OH). Fractions containing the product were combined, and concentrated, to afford an off white solid, which was triturated in Et2O. The resulting yellow solid was filtered off with an aid of Et2O and air dried. The solids were purified further via RPLC on the acidic Gilson Only fractions containing the product were combined, diluted with DCM, and washed with sat. NaHCO3. The organic was dried over MgSO4, filtered, and concentrated to afford N-(4-(3-(2-amino-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine. MS Calcd for C29H20FN7O: [M]+=501. Found: [M+1]+=502.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]([P:7]([CH3:14])(=[O:13])[O:8]CC(C)C)[CH3:6]>>[NH2:2][CH2:3][CH2:4][CH:5]([P:7]([CH3:14])(=[O:8])[OH:13])[CH3:6]
Reactant: CC(C)COP(C)(=O)C(C)CCN
Agent: Cl
Product: CC(CCN)P(C)(=O)O
Temperature: 25 °C

Procedure:
A solution of 21.5 g of isobutyl P-(4-aminobut-2-yl)-P-methyl-phosphinate 80 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 10 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated twice with 100 ml of water. The crude material is dissolved in water, washed with chloroform, and the aqueous layer treated with activated charcoal. The aqueous solution is filtered hot, evaporated to dryness, the crude product is dissolved in 50 ml of methanol and treated with 1-2 ml of propylene oxide. The hygroscopic solid is filtered and triturated with acetone. After drying, P-(4-aminobut-2-yl)-P-methyl-phosphinic acid is obtained as a hygroscopic solid, m.p. 68°-75°, 31P-NMR spectrum: δ=+46.5 ppm (D2O).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-:20]#[N:21].[Na+].[NH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1>C(#N)C.C(OCC)(=O)C.[Ni](Br)Br.[Zn]>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:20]#[N:21])=[CH:26][N:25]=1
Reactant: [C-]#N
Reactant: Nc1ccc(Br)cn1
Agent: Br[Ni]Br
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(N)nc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A solution of nickel(II) bromide (253 mg, 1.16 mmol), triphenylphosphine (1.15 g, 4.39 mmol), and zinc powder (113 mg, 1.73 mmol) in acetonitrile (11 mL) was stirred under argon at 60° C. for 1 h. The reaction turned dark brown in color. After such time, the reaction mixture was treated with sodium cyanide (578 mg, 11.8 mmol) and 2-amino-5-bromopyridine (2.00 g, 11.6 mmol), and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was then cooled to 25° C., diluted with ethyl acetate (50 mL), and then filtered through celite. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded 6-amino-nicotinonitrile (577 mg, 42%) as a white solid: mp 156.8-158.5° C.; EI-HRMS m/e calcd for C6H5N3 (M+) 119.0483, found 119.0480.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC/C=C/C(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Solvent: ClCCl
Product: CC/C=C/C(=O)N1CCN(c2cc(C)[n+]([O-])c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
(E)-1-[4-(2-Methyl-4-quinolyl)piperazin-1-yl]pent-2-en-1-one (30.9 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane, meta-chloroperbenzoic acid (mCPBA) was added (44.6 mg, 0.2 mmol) and the mixture was stirred at room temperature for 15 minutes. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 6 mg of a solid (0.0185 mmol, 18.5%). MS (APCI): m/z=325.8 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].CCCCCC>C(O)(=O)C>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc2c1OCC2(C)C
Reactant: O=[N+]([O-])O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Temperature: 24 °C
Reaction time: 4 h

Procedure:
A solution of 7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan (10.0 g, 49.0 mmol) in glacial acetic acid 80 mL) is treated with 70% nitric acid (4.0 mL, 63.7 mmol) dropwise, and allowed to stir at 24° C. for 4 h. TLC (hexane) is used to monitor reaction progress. The reaction mixture is partitioned between Et2O (100 mL) and H2O (100 mL). The Et2O layer is washed with H2O (50 mL) and saturated Na2 CO3 (50 mL), dried (MgSO4), filtered and evaporated to a red solid (9.12 g). Crystallization from hexane provides 7-tert-butyl-3,3-dimethyl-5-nitro-2,3-dihydrobenzo[b]furan as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Subsequently, the resulting crude 1-(tert-butoxycarbonyl)-4-[(2-phthalimidylmethylphenyl)amino]piperidine (420 mg) was dissolved in ethanol (8 ml), added with hydrazine monohydrate (0.23 ml) and stirred at room temperature for 1 hour and at 40° C. for 1 hour. After insoluble matters were removed by filtration from the reaction mixture, the solvent was evaporated under reduced pressure. The residue was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The solvent was evaporated under reduced pressure to obtain 219 mg of 1-(tert-butoxycarbonyl)-4-[(2-aminomethylphenyl)amino]piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([OH:8])([CH3:7])[CH3:6])[CH3:2].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14].[Cl-].[NH4+]>CN(C)C=O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:9])[C:5]([O:8][CH2:14][CH:13]=[CH2:12])([CH3:7])[CH3:6])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC(C)(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
A solution of 2-hydroxy-2-methyl-propionic acid ethyl ester (2.64 g, 2.7 mL, 20 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. under nitrogen. Sodium hydride (60% dispersion in oil, 880 mg, 22 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. Allyl bromide (2.18 g, 1.6 mL, 18 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was cooled to 0° C. and saturated ammonium chloride solution was cautiously added to quench the reaction. Diethyl ether was added and the organic layer was separated, washed with water (3×) and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 12:1 to 4:1 to afford the title compound (2.33 g, 67%) as an clear oil. 1H NMR (300 MHz, CDCl3) δ 1.31 (t, J=7.1 Hz, 3H), 1.47 (s, 6H), 3.95-3.98 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 5.15-5.20 (m, 1H), 5.27-5.39 (m, 1H), 5.90-6.03 (m, 1H). LCMS (m/z) 195.2 [M+Na], Tr=2.24 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]1([CH3:37])[C:27]([CH3:29])([CH3:28])[O:26][B:25]([C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)[O:24]1>COCCOC>[CH3:28][C:27]1([CH3:29])[C:23]([CH3:22])([CH3:37])[O:24][B:25]([C:30]2[CH:35]=[CH:34][C:33]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)=[CH:32][CH:31]=2)[O:26]1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Solvent: COCCOC
Product: CC1(C)OB(c2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, using dry DME as the reaction solvent: 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 2H; AA′XX′), 7.67 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 6.99 (dd, J=8.9, 2.7 Hz, 1H), 6.84 (m, 2H; AA′XX′), 4.24 (t, J=5.2 Hz, 2H; partially overlapping 4.20), 4.20 (q, J=8.5 Hz, 2H; partially overlapping 4.24), 4.00 (t, J=5.1 Hz, 2H), 1.33 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].Cl>CCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([O:22][CH3:23])[CH:18]=1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccccc1OC
Agent: Cl
Solvent: CCCCC
Product: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1OC
Temperature: 150 °C
Yield: 77.7 %

Procedure:
2-Chloro-5-nitrobenzoyl chloride (11 g; 0.05 mole), 1,2-dimethoxybenzene (20 ml; 0.15 mole) and anhydrous ferric chloride (0.5 g) are successively introduced into a flask. The mixture is progressively heated to 150° C., and maintained at this temperature for 1 hour. After cooling, the reaction mixture is poured into 1N HCl (200 ml), then extracted with dichloromethane (3×200 ml). After washing with a sodium bicarbonate solution, the organic phase is dried over MgSO4 and then concentrated under reduced pressure to provide a brown oil. By trituration with pentane (300 ml), 2-chloro-3',4'-dimethoxy-5-nitrobenzophenone (12.5 g; yield: 78%) is isolated in the form of a beige solid of m.p. 138° C. (compound no. 171).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9](N2CCOCC2)[N:8]=[C:7]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[C:6]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38].C[Si]([C:43]#[N:44])(C)C>C(N(CC)CC)C>[C:21]([C:26]1[CH:25]=[C:24]([C:9]2[N:8]=[C:7]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:20])[C:6]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[C:5]([O:4][CH2:3][CH2:2][OH:1])[N:10]=2)[CH:23]=[CH:43][N:44]=1)#[N:22]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(N2CCOCC2)nc1OCCO
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(C#N)c2)nc1OCCO

Procedure:
reacting the product of step e) with trimethylsilylcyanide and triethylamine to form 5-isopropyl-pyridine-2-sulphonic acid 2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl-amide, and
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25]([O:27]C)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)Cc1cccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(CC(=O)O)c2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetate (0.5 g, 1.3 mmol) was dissolved in methanol, and 2N NaoH (3 mL) added. The reaction was stirred at 60° C. for 2 h, then the solution was adjusted to pH 6.5, the product was extracted into ethyl acetate and the organic phase was dried by MgSO4. Removal of solvent revealed 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetic acid (0.30 g). 1H NMR (500 MHz, CDCl3) δ 1.02 (m, 2H), 1.25 (m, 2H), 1.55 (m, 2H), 1.65 (m, 2H), 2.57 (m, 2H), 3.33 (m, 1H), 3.75 (s, 2H), 3.95 (m, 2H), 6.63 (m, 3H), 6.98 (m, 1H).
Reaction SMILES: Br.[C:2]([O:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:7]1[S:25]C(=N)N)(=[O:4])[CH3:3].C(Cl)(Cl)Cl.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[C:33]([S:25][C@@H:7]1[O:8][C@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:5][C:2](=[O:4])[CH3:3])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](SC(=N)N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,4,6-Tetra-O-acetyl-l-thio-β-D-glucopyranose, obtained from the hydrolysis of 29 g. of S-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiopseudourea hydrobromide as in "Methods in Carbohydrate Chemistry", Vol. II, page 436 (Whistler and Wolfrom editors, Academic Press Inc., 1963) was dissolved in 250 ml. of chloroform and cooled to 0°-5° C. in an ice bath. Anhydrous pyridine (20 ml.) was added, followed by 27.9 g. of trityl chloride. The mixture was stirred overnight at ambient temperature and the organic solution was extracted with dilute hydrochloric acid, washed with 5% aqueous sodium carbonate solution and with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether, then recrystallized from benzene-cyclohexane to give S-trityl-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose, m.p. 177.5°-179.5° C.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:31])[N:9]([CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:10]1[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[C:3]([O:7][C:8](=[O:31])[N:9]([CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccccc1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2 mL of a methanol solution containing 0.60 g of tert-butyl(3-phenylpropyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate, 0.4 mL of water was added, and 0.28 g of potassium carbonate was added under cooling with ice, and the mixture was stirred at the same temperature for 2 hours and 10 minutes and at room temperature for 2 hours and 15 minutes. Thereto was added 2 mL of methanol and 0.5 mL of water, and the mixture was left to stand at room temperature overnight. The solvent was removed under reduced pressure, and the residue thus obtained was added with ethyl acetate and water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.45 g of a colorless oily substance, tert-butyl(3-phenylpropyl)(piperidin-4-yl)carbamate.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20]([O:22]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:3]1=[O:32].CN(C)C=O.[NH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][CH2:42]2.C(N(CC)CC)C>O>[CH2:44]1[C:45]2[C:41](=[CH:40][C:39]([NH:38][C:20]([NH:19][C@@H:4]3[N:5]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:2]([CH3:1])[C:3]3=[O:32])=[O:22])=[CH:47][CH:46]=2)[CH2:42][CH2:43]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C(=O)[C@H](NC(=O)Nc2ccc3c(c2)CCC3)N=C(c2ccccc2)c2ccccc21
Reaction time: 4 h

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (200 mg. 0.46 mmole) was dissolved in 2 ml of freshly degassed, dry N,N-dimethylformamide (DMF) and treated with 1 ml of DMF containing 74 mg (0.50 mmole) of 5-aminoindane and 97.4 μl of triethylamine. The resulting solution was stirred under nitrogen for four hours. The reaction mixture was poured into 75 ml of water and extracted with ethyl acetate (3×40 ml). The combined organic extracts were washed with 1N sodium hydroxide solution (4×100 ml), 10% citric acid solution (2×100 ml), and brine. The organic extracts were then dried and the residue was plug-filtered through a six inch silica gel column. The eluate was concentrated and the residue was crystallized from a methylene chloride-ether mixture to give the title compound: mp 156°-158° C. NMR: Structure is consistent with the spectrum.
Reaction SMILES: CS([C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1)(=O)=O.[CH3:30][NH2:31].O1CCCC1>CN1CCCC1=O>[CH3:30][NH:31][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reactant: CN
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3ncn(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 79 %

Procedure:
In the same manner as in Example 433 and using 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[3-(trifluoromethoxy)phenyl]-1H-benzimidazole instead of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole, using 2M methylamine-tetrahydrofuran solution instead of sodium methoxide, and using 1-methyl-2-pyrrolidone instead of N,N-dimethylformamide, the title compound (yield 79%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([OH:29])=O)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>ClC(Cl)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:29])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:31][CH:32]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)Nc1cccnc1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloroethane. 5 mg (0.055 mmol) of 3-aminopyridine, 11 mg (0.055 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: B1C2CCCC1CCC2.[F:10][C:11]([F:28])([F:27])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=2)[CH:13]=1.[OH-:29].[Na+].OO>C1COCC1>[F:10][C:11]([F:27])([F:28])[C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:29])=[CH:21][CH:20]=1
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
9-BBN (277 mL, 139 mmol) was added to a solution of 1-(trifluoromethyl)-3-(4-vinylphenoxy)benzene (24.4 g, 92 mmol) in THF (200 mL) at 0° C., and the resulting reaction mixture was stirred at room temperature overnight. To the mixture was added 3M NaOH solution (140 mL) and 30% hydrogen peroxide (123 mL) slowly at 0° C., and the reaction mixture was stirred at 50° C. for 2 h. Purification via column chromatography then afforded the title compound as a colorless oil (17 g, 63.8% yield). LCMS: rt=1.79 min, [M−OH]+=265
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C(N(CC)C(C)C)(C)C.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[NH2:1][C:2]1[C:3]([C:7](=[N:17][O:18][C:36]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nonc1C(=NOC(=O)NCc1ccccc1)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 24.7 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (50 mg, 0.18 mmol) and N,N-diisopropylethylamine (64 μl, 0.37 mmol) in dichloromethane (2 mL) was treated with benzyl isocyanate (29 mg, 0.22 mmol) and stirred for 3 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (18 mg, 24%). LCMS for C17H15ClFN6O3 (M+H)+: m/z=405.0.