Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]12.Br[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[N:3]1([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]12
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: c1cc2n(n1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN1CCn2nccc21
Temperature: 0 °C
Reaction time: 66 h
Yield: 30.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.3 g, 7.5 mmol) was added portion-wise to a stirred solution of 2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.68 g, 6.19 mmol) in anhydrous DMF (5 mL) at room temperature under a nitrogen atmosphere. The mixture was cooled to 0° C. and stirred for 15 min before a solution of tert-butyl 3-bromopropylcarbamate (1.47 g, 6.19 mmol) in DMF (5 mL) was added portionwise over 5 min. The reaction was warmed to room temperature and stirred for 66 hr at room temperature. Water (5 mL) was added dropwise and the mixture was concentrated under reduced pressure. More water was added and the mixture was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 3-(2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propylcarbamate as an orange oil (0.51 g, 31%). To a solution of this oil in conc. H2SO4 at 0° C. was added conc. HNO3 portionwise over 5 min. The reaction was warmed to room temperature and the mixture was stirred for 18 h. The mixture was re-cooled to 0° C., poured into ice water with stirring and basified with 40% aq. NaOH. The product was extracted into DCM and the combined organics were dried over MgSO4 and concentrated under reduced pressure to afford 3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propan-1-amine as a brown gum. This gum was dissolved in DCM (30 mL) and DIPEA (1 mL) and di-tert-butyl dicarbonate (0.5 g, 2.3 mmol) were added. The mixture was stirred at room temperature for 2 hr. The solvents were removed under reduced pressure and the residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propylcarbamate as a pale yellow gum (100 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 4.82 (s br, 1H), 4.26-4.16 (m, 2H), 4.12-4.00 (m, 2H), 3.84-3.72 (m, 2H), 3.23 (q, J=6.6 Hz, 2H), 1.89-1.78 (m, 2H), 1.44 (s, 9H)
Reaction SMILES: CO.[Na].CO[C:6](=[O:17])[C:7]1[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:9]([O:11]C)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1>C1C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:26]2[C:6](=[O:17])[C:7]3[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:9]2=[O:11])=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1C(=O)OC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: O=C(c1ccc(Br)cc1)C1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (8.5 ml) was treated with sodium (4.8 g) in benzene (90 mL). The reaction mixture was refluxed overnight, allowed to cool to room temperature, and treated with phthalic acid dimethyl ester (38.84 g) and 1-(4-bromophenyl)ethanone (39.81 g) in benzene (50 mL). Distillation of the reaction mixture was performed at 80° C. overnight to remove methanol. The reaction mixture was poured into diluted HCl and filtered. The filter cake was collected and recrystallized from ethanol to provide the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.CC(C)([O-])C.[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[C:5](=[CH:9][N:10]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CSc1ncnc2cn[nH]c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncnc2cn(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (500 mg) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (405 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Subsequently, 1-fluoro-4-nitrobenzene (465 mg) was added, and the mixture was stirred at 70° C. for 30 min. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title compound (860 mg) as brown crystals.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>CC#N.O>[C:1]1([S:7]([NH:10][NH:11][C:12](=[O:29])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NNS(=O)(=O)c1ccccc1)c1ccc(C#CC(O)C2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(NNS(=O)(=O)c1ccccc1)c1ccc(CCC(O)C2CCCCC2)cc1

Procedure:
Example 36 was synthesized in accordance with the methods of Example 33, except that 4-(3-cyclohexyl-3-hydroxy-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide (Example 35) was used instead of 4phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide. MS: 403 (M+1 for C21H26N2O4S1); mp 158-159° C.; TLC (SiO2) Rf=0.3 (50% EtOAc/hexanes); HPLC (C18 column, 7:3 CH3CN/H2O+0.1%TFA) 95%, RT=5.0 min. 1H NMR (DMSO-d6) δ 1.10-1.65 (m, 12H), 2.46-2.61 (m, 2H), 4.00 (s, 1H), 7.20 (d, 2 H, J=8.1 Hz), 7.46-7.57 (m, 5H), 7.78 (d, 2H, J=7.3 Hz), 9.93 (s, 1H, 10.56 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([I:19])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([I:19])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(I)cccc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(I)cccc3c21
Temperature: 40 °C
Yield: 74.9 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (450 mg, 1.18 mmol) was dissolved in toluene (10 mL). To the mixture was added activated manganese dioxide (4.95 g), followed by heating at 40° C. overnight. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was evaporated, and the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give the title compound (334 mg, 0.884 mmol) as a white oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([S:14]N=C=O)C.[C:18](#[N:20])[CH3:19]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:12]([NH:20][CH2:18][CH3:19])=[S:14])=[O:7])=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: NNC(=O)c1ccc(N)cc1
Reactant: CCSN=C=O
Product: CCNC(=S)NNC(=O)c1ccc(N)cc1
Temperature: 24 °C

Procedure:
A mixture of 4.5 g (29.8 mmol) of 4-aminobenzoic acid hydrazide and 2.6 mL of ethylthioisocyanate in 15 mL of acetonitrile was heated at reflux for 3 hours. The solution was cooled to 24° C., and the precipitate was collected by filtration and dried under vacuum to afford 7.0 g of 1-(4-aminobenzoyl)-4-ethylthiosemicarbazide, mp 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Br)CCC2=O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-6-methoxy-2, 3-dihydro-1H-inden-1-one 11 (250 mg, 0.1037 mmol) in benzene was added 4-((trifluoromethyl)thio)benzaldehyde 72 (213 mg, 0.103 mmol). PTSA (395 mg, 0.207 mmol) was added, the reaction mass was stirred at 120° C. for 6 h, then diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 104 and was purified through flash chromatography by using 100-200 mesh silica gel. The compound 104 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11](=[N:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([O:25][CH3:26])[CH:16]=2)SC)=O)[CH:5]=[C:4]([CH3:27])[N:3]=1.[NH:28]([CH2:30][C@@H:31]([OH:34])[CH2:32][CH3:33])[NH2:29]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]([CH2:30][C@@H:31]([OH:34])[CH2:32][CH3:33])[N:29]=[C:11]([NH:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([O:25][CH3:26])[CH:16]=3)[N:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: COc1cc(N=C(NC(=O)c2cc(C)nc(Cl)c2)SC)cc(C(F)(F)F)c1
Reactant: CC[C@H](O)CNN
Solvent: CCO
Product: CC[C@H](O)Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(Cl)c1
Reaction time: 8 h

Procedure:
A mixture of intermediate D6 (8.356 g, 0.020 mol) and intermediate D3 (2.083 g, 0.020 mol) in ethanol (200 ml) was stirred overnight at reflux. Subsequently, the solvent was evaporated to yield intermediate D7 (S-enantiomer) as a yellow oil that was used as such in the next reaction step.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=O)[CH2:7][CH2:6]1.C([O:15][C:16]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)(=O)C.Cl.[N+](C)([O-])=[O:26]>>[O:26]=[C:21]1[CH2:22][CH2:23][C:16](=[O:15])[CH:20]1[CH2:19][CH2:18][CH2:17][CH2:8][CH2:7][CH2:6][C:5]([OH:10])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)OC1=CCCCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCCCCCC1C(=O)CCC1=O
Reaction time: 4 h

Procedure:
To a solution of 2.7 g of aluminum chloride in 15 ml of nitromethane, 1.0 g of succinic anhydride was added, and then 1.7 g of 1-cyclooctenyl acetate was added dropwise under cooling. The resultant mixture was stirred at room temperature overnight and refluxed with stirring for four hours. The mixture was cooled, poured into 50 ml of 1N hydrochloric acid containing ice, and extracted four times with 30 ml of ethyl acetate. The organic layer was extracted twice with 30 ml of a saturated aqueous sodium bicarbonate solution. The aqueous layer was washed with ethyl acetate at pH 7. The aqueous was adjusted to pH 2 with 6N hydrochloric acid, and again extracted four times with 30 ml of ethyl acetate. The extract was dried and concentrated. The residue was washed with water to give 0.2 g of 7-(2,5-dioxocyclopentyl) heptanoic acid. This product had a melting point of 105° to 122° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([C@H:10]([NH:12][C:13]2[C:14]3[N:15]([CH:22]=[C:23]([C:25]4[O:26][C:27](SC)=[N:28][N:29]=4)[CH:24]=3)[N:16]=[CH:17][C:18]=2[C:19]([NH2:21])=[O:20])[CH3:11])[CH2:9][CH2:8]1>CN1C(=O)CCC1>[CH:7]1([C@H:10]([NH:12][C:13]2[C:14]3[N:15]([CH:22]=[C:23]([C:25]4[O:26][C:27]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[N:28][N:29]=4)[CH:24]=3)[N:16]=[CH:17][C:18]=2[C:19]([NH2:21])=[O:20])[CH3:11])[CH2:9][CH2:8]1
Reactant: CSc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(N4CCOCC4)o3)cc12)C1CC1
Temperature: 200 °C
Yield: 44.9 %

Procedure:
Morpholine (13 mg, 0.14 mmol) was added in one portion to a solution of (R)-4-(1-cyclopropylethylamino)-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 127, 10 mg, 0.028 mmol) in NMP (0.1 mL). The resulting mixture was heated in the CEM microwave at 200° C. for 1 hour before purifying by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded the title compound (5 mg, 45% yield). HPLC (condition B): retention time=0.73 min. LCMS (condition B): MH+ m/z 398.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.84 (1 H, br. s.), 8.28 (1 H, s), 8.15 (1 H, d, J=1.39 Hz), 7.22 (1 H, d, J=1.39 Hz), 3.99 (1 H, d, J=1.39 Hz), 3.68-3.82 (4 H, m), 3.44-3.53 (4 H, m), 1.34 (3 H, d, J=6.38 Hz), 1.11 (1 H, d, J=6.94 Hz), 0.44-0.56 (1H, m), 0.39 (1 H, br. s.), 0.31 (2 H, br. s.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH3:21][N:20]([CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])[CH3:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(OC(=O)c2ccccc2Cl)ccc2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 and 6 from 2-naphthol, benzylidene-dimethyl-ammonium chloride and 2-chlorobenzoyl chloride.
Reaction SMILES: CO[CH:3](OC)[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([O:16][CH3:17])=[C:6]([O:18][CH3:19])[C:5]=1CO.[CH3:24][O:25][C:26](=[O:33])/[CH:27]=[CH:28]\[C:29]([O:31][CH3:32])=[O:30].[CH3:34]S(O)(=O)=O.O>C(O)(=O)C.C1(C)C=CC=CC=1>[N:13]1[CH:12]=[CH:11][C:10]([C:9]2[C:4]3[C:3](=[CH:8][C:7]([O:16][CH3:17])=[C:6]([O:18][CH3:19])[CH:5]=3)[CH:34]=[C:27]([C:26]([O:25][CH3:24])=[O:33])[C:28]=2[C:29]([O:31][CH3:32])=[O:30])=[CH:15][CH:14]=1
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: COc1cc(-c2ccncc2)c(C(OC)OC)c(CO)c1OC
Reactant: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 3,4-dimethoxy-6-(4-pyridyl)hydroxymethylbenzaldehyde dimethyl acetal (18.4 g) in a mixture of acetic acid (50 ml) and toluene (50 ml) is added maleic acid dimethyl ester (8.64 ml), and the mixture is refluxed for one hour. To the mixture is added methanesulfonic acid (9.33 ml), and the mixture is refluxed for 8 hours while the generated water is removed by using a Dean-stark apparatus. The mixture is cooled to room temperature and concentrated. The residue is dissolved in chloroform, and the pH value thereof is adjusted to pH 8 with an aqueous potassium carbonate solution. The mixture is extracted with chloroform, and the extract is washed, dried, concentrated, and the residue is crystallized from ether to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (13.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=O)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.[NH4+:36]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:36][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:16][N:15]=2)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Yield: 72.3 %

Procedure:
The mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g, 4 mmol), acetic acid (24 μl), and ammonium acetate (1.54 g, 20 mmol) in xylene (20 ml) was heated at 140° C. for 20 hours. The mixture was quenched with saturated sodium carbonate solution, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.21 g). m/z: 417.9 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12]>N1C=CC=CC=1.N1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:10][C:11]([OH:13])=[O:12]
Reactant: O=Cc1ccccn1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNC1
Product: O=C(O)C=Cc1ccccn1
Temperature: 25 °C

Procedure:
A mixture of pyridine-2-carboxaldehyde (32.1 g 0.30 mmol), malonic acid (62.4 g, 0.60 mmol) in pyridine (200 mL) and pyrrolidine (2 mL) was stirred under reflux for 16 hours. The reaction mixture was allowed to cool to room temperature and poured into ice water (200 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layer was concentrated in vacuo and the crude material obtained was purified by flash column chromatography on silica using a gradient system of solvents: 1) ethyl acetate (100%); 2) methanol/ethyl acetate (10%). The title product was obtained (6.28 g, 14%) as a grayish-green solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1)(C)(C)C.[F:31][CH2:32][C:33]1[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:18])([F:19])[F:20])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:39]([C:36]3[CH:35]=[N:34][C:33]([CH2:32][F:31])=[CH:38][N:37]=3)=[O:40])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1
Reactant: O=C(O)c1cnc(CF)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-(fluoromethyl)pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (dd, J=13.6, 3.8 Hz, 1 H), 3.19 (dd, J=13.6, 3.0 Hz, 1 H), 3.43 (dd, J=7.5, 3.4 Hz, 1 H), 3.86-3.99 (m, 1 H), 4.39-4.67 (m, 3 H), 4.74 (quin, J=7.1 Hz, 1 H), 5.76 (d, J=45.5 Hz, 2 H), 8.10 (ddd, J=11.4, 6.8, 2.8 Hz, 1 H), 8.77 (s, 1 H), 9.46 (s, 1 H), 9.69 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([OH:13])=[CH:8][CH:7]=2.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]O)[CH2:23][CH2:22]1)(C)(C)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36]1[O:40][N:39]=[C:38](C(O)=O)[CH:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH2:28][CH2:27][N:24]1[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:38]3[CH:37]=[C:36]([C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)[O:40][N:39]=3)=[O:30])[CH2:26][CH2:25]1)=[CH:8][CH:7]=2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O=C(O)c1cc(-c2cccs2)on1
Reactant: COc1cnc2ccc(O)cc2c1
Product: COc1cnc2ccc(OCCN3CCC(NC(=O)c4cc(-c5cccs5)on4)CC3)cc2c1

Procedure:
The title compound is prepared as a brown solid following Scheme 1 and in analogy to Example 2 using 3-methoxy-quinolin-6-ol, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 5-thiophen-2-yl-isoxazole-3-carboxylic acid as starting materials.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:18][CH2:17][CH2:16]3)[NH:14][C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4].CS(O[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])(=O)=O.O>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:16][CH2:17][CH2:18]3)[N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:46])([F:47])[F:48])[C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4]
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: O=C1NC2(CCC2)C(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C2(CCC2)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Yield: 33 %

Procedure:
NaH (to 60%) (44 mg, 1.1 mmole) is added under argon to a solution of 7-[4-nitro-3-(trifluoromethyl)phenyl]-5,7-diazaspiro[3.4]octane-6,8-dione (329 mg, 1 mmole) in anhydrous DMF (9 ml). A release of gas accompanies the change in colour of the reaction medium which becomes orange. Stirring is maintained for 1 hour at 23° C. before adding 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate (prepared according to an experimental protocol described in WO 2005077968) (332 mg, 0.8 mmole). After reaction for 15 hours, the reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on an RP18 silica column (eluent: ACN/H2O: 8/2 to 100). The expected compound is obtained in the form of a colourless oil with a yield of 33% (214 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[N:16]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]3)[C:7]=2[N:16]=1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
[6-(Methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (0.250 g, 1.14 mmol) was combined with 1,1-dimethylethyl 4-piperidinylcarbamate (0.229 g, 1.14 mmol) in a 1:1 MeOH/DCM solution. Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature overnight. NaBH(OAc)3 (0.724 g, 3.42 mmol) was added and the reaction was stirred an additional 2 h. The solution was concentrated onto silica gel under vacuum and the crude residue purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired compound (0.271 g, 59%).