Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:31]([O-])=O)=[C:18]([S:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)[CH:19]=1>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[C:18]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2cc(Cl)ccc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (48 mg, 0.27 mmol) was reacted in ethanol (2 ml) with the product from Example 231b (78 mg, 0.27 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt. (12 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.06 (s, 3H) 2.77 (s, 3H), 6.39 (d, J=7.35 Hz, 1H), 6.96 (d, J=1.84 Hz, 1H), 7.38 (d, J=8.82 Hz, 2H) 7.51 (s, 2H), 7.62 (d, J=8.82 Hz, 2H), 7.81 (d, J=8.82 Hz, 1H), 8.47 (d, J=7.35 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H), 10.15 (s, 1H), 11.01 (s, 1H), 14.48 (s, 1H); MS (DCI/NH3) m/z 435 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:13][CH3:14])([O:11][CH3:12])[CH3:10].C([Li])(C)(C)C.[F:20][C:21]([F:37])([F:36])[C:22]1[CH:35]=[CH:34][C:25]([CH:26]=[N:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:12][O:11][C:9]([O:13][CH3:14])([CH3:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:36])([F:37])[F:20])=[CH:35][CH:34]=1)[NH:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29]
Reactant: COC(C)(Cc1ccccc1Br)OC
Reactant: CC(C)(C)[S@@](=O)N=Cc1ccc(C(F)(F)F)cc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(Cc1ccccc1C(N[S@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Bromo-2-(2,2-dimethoxypropyl)benzene (4.00 g, 15.43 mmol) was dissolved in 150 mL THF and tert-butyllithium (18.160 mL, 30.871 mmol) was added dropwise at −78° C. After addition a solution of (R)—N-(4-(trifluoromethyl)-benzylidene)-2-methylpropane-2-sulfinamide (8.5608 g, 30.871 mmol) in THF (10 mL) was added and stirring was continued for 10 min in the cold. The reaction was hydrolyzed with 50 mL water and the mixture was warmed to RT. TLC showed a 1:1 mixture of the 2 diastereomers. No attempt was undertaken to separate the isomers. Glass column chromatography provided the title compound as a mixture of diastereomers. MS (ESI, positive ion) m/z: 412.0 (M+1; hydrolysis of the dimethyl acetal to the corresponding ketone).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1.[C:23]([N:31]=[C:32]=[O:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1)=[O:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1ccc2c(c1)OCC(C(O)CN1CCC(N)CC1)O2
Product: COc1ccc2c(c1)OCC(C(O)CN1CCC(NC(=O)NC(=O)c3ccccc3)CC1)O2

Procedure:
Using the procedure of Example 4 erythro 4-amino-1-[2-(6-methoxy-1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine may be reacted with benzoyl isocyanate to give the title compound.
Reaction SMILES: [C:1]1([C:7](=[O:21])[C:8](=[CH:17][N:18]([CH3:20])C)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:22][C:23]1[CH:29]=[CH:28]C(N)=[CH:25][CH:24]=1>CO>[C:1]1([C:7](=[O:21])[C:8](=[CH:17][NH:18][C:20]2[CH:28]=[CH:29][C:23]([I:22])=[CH:24][CH:25]=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: Nc1ccc(I)cc1
Solvent: CO
Product: O=C(C(=CNc1ccc(I)cc1)C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,3-diphenyl-2-[(dimethylamino)methylene]-1,3-propanedione (317 mg, 1.13 mmol) in 5.5 mL of MeOH was treated with solid 4-iodoaniline (245 mg, 1.12 mmol). The resulting solution was stirred at rt overnight. The resulting precipitate was isolated by filtration and washed with MeOH. The title compound was isolated as a light yellow solid.
Reaction SMILES: OO.[CH2:3]([C:5]1[N:6]=[N+:7]([O-:25])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:15]3)=[CH:11][C:9]=2[N:10]=1)[CH3:4].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:27].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:3]([C:5]1[N:6]=[N+:7]([O-:25])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[CH2:15]3)=[CH:11][C:9]=2[N+:10]=1[O-:27])[CH3:4]
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CN1CCOCC1)C3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(CN1CCOCC1)C3
Temperature: 20 °C
Reaction time: 7 h
Yield: 16.5 %

Procedure:
H2O2 (70%, 0.95 mL, ca 16 mmol) was added drop-wise (over 10 min) to a stirred solution of 1-oxide 143 (503 mg, 1.6 mmol), TFAA (2.56 mL, 16.0 mmol) and TFA (0.66 mL, 8.0 mmol) in DCM (60 mL) at 20° C. and the mixture was stirred at 20° C. for 7 h. Dilute Na2CO3 solution (40 mL) was added and the mixture was extracted with DCM (5×80 mL). The combined organic fraction was dried and the solvent evaporated to give an oil which was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give 1,4-dioxide 144 (87 mg, 21%) as a yellow solid: mp (MeOH/DCM) 164-165° C.; 1H NMR δ 8.31 (s, 1H, H-9), 8.25 (s, 1H, H-5), 3.72 (t, J=4.6 Hz, 4H, 2×CH2O), 3.17-3.34 (m, 4H, CH2), 2.80-2.95 (m, 3H, CH2, H-7), 2.45 (t, J=4.6 Hz, 4H, 2×CH2N), 2.38 (d, J=7.7 Hz, 2H, CH2), 1.43 (t, J=7.5 Hz, 3H, CH3); 13C NMR δ 155.7, 154.1, 149.5, 139.2, 134.0, 116.3, 114.3, 67.0 (2), 63.1, 53.9 (2), 37.7, 37.2, 36.6, 23.8, 9.2. Anal. calcd for C17H22N4O3: C, 61.8; H, 6.7; N, 17.0. Found: C, 62.1; H, 6.7; N, 16.8%.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>O1CCOCC1>[CH:3]1([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OC1CCCCC1
Reaction time: 1 h

Procedure:
To 40 ml of a dioxane suspension containing 0.92 g of 60% sodium hydride was added 2.5 ml of cyclohexanol at room temperature over a 15-minute period, and the mixture was stirred at the same temperature for 1 hour and then at 50° C. for 3.5 hours. The temperature of the reaction solution was returned to room temperature, 10 ml of a dioxane containing 3.2 g of 2-fluoronitrobenzene was added dropwise, and the mixture was stirred at room temperature overnight. The dioxane was evaporated, the residue was extracted with chloroform, and the chloroform layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated to give an oil, which was then distilled under reduced pressure to give 3.8 g of 2-cyclohexyloxynitrobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[OH-].[Na+].Cl[C:20]([O:22][CH3:23])=[O:21].Cl>O1CCOCC1.CCOC(C)=O>[CH3:23][O:22][C:20]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1)=[O:21]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of Example 119A (4.0 g, 17.76 mmol) in dioxane (40 mL) at 0° C. was added 2 M NaOH (29.3 mL, 58.6 mmol) followed by dropwise addition of methyl chloroformate (2.75 mL, 35.5 mmol). The solution was warmed to room temperature and stirred for 2 h. Diluted with EtOAc and added 1 N HCl until all solid had dissolved, separated the phases and washed the organic phase with 1 N HCl, H2O, brine, dried (Na2SO4), filtered and removed solvent in vacuo to give the title compound (4.69 g, 16.56 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ ppm 3.20-3.31 (m, 4H) 3.62-3.71 (m, 4H) 3.75 (s, 3H) 6.92 (t, J=8.8 Hz, 1H) 7.93 (dd, J=12.9, 2.6 Hz, 1H) 7.98-8.02 (m, 1H). MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Fc1cc(F)cc(CBr)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)cc(F)c2)c1
Yield: 49.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (205 mg, yield: 49.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH:35][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([CH3:17])=[CH:8][C:9]4=[O:16])[CH2:31][CH2:30]3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCNC3CCN(Cc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To 10 mL of a chloroform solution containing 120 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 165 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine, 30 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 176 mg of sodium triacetoxyborohydride was added and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=5:1], to give 150 mg of 1-(2-(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamino)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.Cl.[NH2:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16](=[N:19][OH:20])[CH2:17][OH:18].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16](=[N:19][OH:20])[CH2:17][OH:18])[N:7]=1
Reactant: CCC(N)(CC)C(CO)=NO
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(CC)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(CO)=NO
Yield: 48.8 %

Procedure:
A suspension of 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal=Cl) (2.3 g) in dry ethanol was treated with 3-amino-1-hydroxy-3-spirocyclohexylpropan-2-one oxime hydrochloride (IV) (2.5g) and dry triethylamine (2.7 g) and the mixture was refluxed for 7 h. The reaction mixture was filtered and the solid washed with hot ethanol. The solvent was removed from the filtrate and the resulting yellow oil was triturated with cold water giving a yellow solid which on recrystallisation from water in the presence of charcoal gave the nitropyrimidine (II) (1.85 g; yield 47.4%) as an off-white powder, m.pt >300° (decomp.).
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[CH2:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=O>C(O)C>[CH:13]1[N:4]2[C:5]3[C:10]([N:11]=[CH:12][C:3]2=[N:2][C:14]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CCOC(=O)C(=O)C[n+]1c(N)cnc2ccccc21
Agent: [Br-]
Solvent: CCO
Product: CCOC(=O)c1cn2c(cnc3ccccc32)n1
Yield: 88.1 %

Procedure:
A suspension of 0.4 g of the product of Step A in 15 ml of ethanol was refluxed for 2 hours and the resulting clear orange solution was concentrated to half its volume. The mixture was filtered to obtain 0.25 g of ethyl imidazo-[1,2-a]-quinoxaline-2-carboxylate as a pale yellow solid which were crystallized from an ether-methanol mixture to obtain the product in the form of soft-white needles melting at 184°-187° C. with decomposition.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)C(C)C)(C)C.[C:21]([NH:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH2:25][NH:24][C:21](=[O:23])[CH3:22])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(=O)NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (15.5 mmol) 2,6-dichloro-3-nitropyridine in 50 mL of THF at −78° C. under Ar atmosphere was added 2.7 mL (15.5 mmol) of N,N-diisopropylethylamine followed by 1.6 mL (15.5 mmol) of N-acetylethylenediamine. The mixture was stirred at −78° C. for 30 min, allowed to warm to room temperature, and stirred for 72 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with MeOH/dichloromethane gradient (1→10%) to provide N-(2-(6-chloro-3-nitropyridin-2-ylamino)ethyl)acetamide as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.N[C:13](N)=[O:14].C.Cl>[OH-].[Na+]>[O:14]=[C:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1
Reactant: NC(N)=O
Reactant: Nc1cccnc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2cccnc2S(=O)(=O)N1
Temperature: 25 °C

Procedure:
An intimate mixture of 5 g of 3-aminopyridine-2- sulfonamide (Preparation 1) and 1.91 g of urea is progressively brought to a temperature of 200° C. (melting). After gas has ceased to be given off and the mass has solidified, the reaction mixture is cooled to ambient temperature. The solid mass is redissolved in 1N NaOH and the solution obtained, optionally decolored with absorbing charcoal, is then adjusted to a pH of 2 using 1N HCl. The white precipitate corresponding to the title compound is collected on a filter, washed with water and dried.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([Cl:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyloxyacetic acid (4.6 g, 28.0 mmol, 4.0 mL) in DCM (52 mL) was added oxalyl chloride (7.7 g, 61 mmol, 5.3 mL) and a drop of DMF. The reaction mixture was stirred at room temperature for 4 h. Excess of oxalyl chloride was removed in vacuo to give benzyloxy-acetyl chloride. The crude acyl chloride was diluted into DCM (100 mL) and triethylamine (5.3 mL, 41.6 mmol, 4.2 g) was added followed by 4-fluoroaniline (3.5 g, 32 mmol, 3.0 mL). The reaction mixture was stirred at RT overnight. The reaction was then quenched with 1 M aqueous HCl (100 mL), dried and concentrated in vacuo to give 7.1 g (95%) of 2-benzyloxy-N-(4-fluoro-phenyl)-acetamide (33) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 69.2, 73.5, 115.4 (d, JCF=22 Hz), 121.4 (d, JCF=7 Hz), 127.9, 128.2, 128.5, 132.5 (d, JCF=3 Hz), 136.3, 157.6, 160.8, and 167.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[C:18](=[O:23])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1>>[NH:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[C:18](=[O:23])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:37]=[N:36]1
Reactant: CC(C)n1c(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n[nH]c1=O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)n1c(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n[nH]c1=O

Procedure:
Following the procedure of Example 44, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 264. MS: (ESI+) 394.2
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:31][CH2:30]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[N:2]1[NH:32][N:33]=[N:34][C:1]=1[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2cccc(-c3ccc(OCc4ccc(-c5nn[nH]n5)nc4)cc3)n2n1)C1CC1
Reaction time: 16 h
Yield: 5.7 %

Procedure:
A solution of cyclopropanecarboxylic acid{5-[4-(6-cyano-pyridin-3-ylmethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide (143 mg, 0.35 mmol, 1 equiv), sodium azide (46 mg, 0.7 mmol, 2 equiv), ammonium chloride (38 mg, 0.7 mmol, 2 equiv) was stirred at 0° C. under nitrogen for 30 minutes. Afterwards the mixture was subjected for 100° C. for 16 hours. The crude of the reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4, filtered, and dried under vacuum. The crude was diluted with DMSO and submitted for preparative HPLC purification: HPLC system (XBridge™ Prep C18, 5 μm, 19×100 mm column); 8 min LC; flow: 20 mL/min; gradient: from 30% to 70% acetonitrile in water 0.1% TFA; to afford the final pure product (9 mg, 6% yield).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:24]1[CH2:30][CH:29]2[NH:31][CH:26]([CH2:27][CH2:28]2)[CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23]>CCCCCCC.CCOC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][C@H:3]([CH3:18])[CH2:2][N:31]3[CH:26]4[CH2:27][CH2:28][CH:29]3[CH2:30][CH:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25]4)[C:10]=2[CH:11]=1
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(OC)cc21
Yield: 43.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.226 g, 0.63 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.101 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF41) (0.101 g, 39%). 1H NMR (CDCl3) d 6.89 (d, J=8.8 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.60-4.46 (m, 2H), 4.01 (d, J=6.8 Hz, 2H), 3.77 (s, 3H), 3.15-3.02 (m, 2H), 2.32-2.26 (m, 1H), 2.20-1.79 (m; 7H), 1.68-1.51 (m, 3H), 1.42-1.16 (m, 10H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) d 168.4, 155.6, 139.8, 129.8, 117.0, 106.9, 103.8, 68.0, 60.6, 59.1, 58.1, 56.0, 45.3, 39.4, 36.6, 36.4, 32.2, 31.5, 28.4, 28.4, 28.0, 27.3, 22.8, 16.8, 14.2; HPLC-MS (ammonium acetate) [M+H]+=415.3.
Reaction SMILES: CO.C([O:10][C@@H:11]1[C@@H:16]([O:17]CC2C=CC=CC=2)[C@H:15]([O:25]CC2C=CC=CC=2)[C@@H:14]([CH2:33][O:34]CC2C=CC=CC=2)[CH2:13][C:12]1(OC(=O)C)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[CH:43]=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].C1COCC1>[OH:34][CH2:33][C@H:14]1[CH2:13][C@@H:12]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)[CH:43]=2)[C@H:11]([OH:10])[C@@H:16]([OH:17])[C@@H:15]1[OH:25]
Reactant: COc1ccc(Cc2cccc(C3(OC(C)=O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cc2cccc([C@@H]3C[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a methanol (0.2 mL)-THF (0.2 mL) solution of acetic acid [2R,3S,4R,5R]-2,3,4-trisbenzyloxy-5-benzyloxymethyl-1-[3-(4-methoxybenzyl)phenyl]cyclohexyl ester (4.2 mg), a 20% palladium hydroxide-carbon (3 mg) was added and the mixture solution was stirred under a hydrogen atmosphere for three hours. The reaction mixture was filtered and the filtrate was concentrated and the obtained residue was purified by preparative TLC [developing solution=dichloromethane:methanol (9:1)] to obtain the title compound (1.7 mg) as a single diastereomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>CO.[C].[Pd]>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:4]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccc1F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl {2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (14.2 g, 49.5 mmol) in methanol (200 mL)/ethyl acetate (200 mL) was added palladium carbon (50% water-containing product, 1.50 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (9.69 g, 75%) as a white solid.