Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:16][CH2:17]1)=[O:29])[C:7]([N:44]1[CH2:43][CH2:42][N:41]([CH:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[CH2:46][CH2:45]1)=[O:8]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-(1-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[CH3:17][O:18]C(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[OH:15][C:14]1[C:2]([CH3:1])=[C:3]2[C:11](=[C:12]([CH:17]=[O:18])[C:13]=1[CH3:16])[O:10][C:6]1([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH2:4]2
Reactant: COC(Cl)Cl
Reactant: Cc1cc2c(c(C)c1O)CCC1(CCC1)O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(O)c(C)c2c(c1C=O)OC1(CCC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (1 g) in DCM (20 mL) was added TiCl4 (0.53 mL) which turned the solution a red color. To the solution was added dichloromethyl methyl ether (0.42 mL) and stirred at 0° C. for 30 min and then at room temperature for 30 min. The solution was poured into water and the DCM was separated, dried and evaporated. The residue was purified by silica gel column eluting with 20% ethylacetate in hexane to give 700 mg of 6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-8-carbaldehyde as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.C1C=CC=CC=1>O>[O:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:16]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: O=Cc1ccco1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1NC(=O)NN=C1c1ccc(N=Cc2ccco2)cc1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2 g), furfural (1.41 g), DMF (25 ml) and benzene (25 ml) was refluxed in an apparatus equipped with a Dean-Stark water separator for 3 hours. The reaction mixture was evaporated in vacuo and the resultant residue was triturated with diethyl ether to give 6-[4-(2-furylmethylenamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.47 g).
Reaction SMILES: CO.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)([OH:35])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:24][CH:23]=3)[OH:21])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[CH3:42][C:39]1[CH:38]=[CH:37][C:36]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)([OH:35])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:24][CH:23]=3)[OH:21])[CH2:13][CH2:12]2)=[CH:41][CH:40]=1
Reactant: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccc(C)cc3)c3ccc(C)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCN(CCCC(O)c3ccc(C(C)(C)C(=O)O)cc3)CC2)cc1

Procedure:
To 350 mL of methanol in a 1 L round bottom flask equipped with a mechanical stirrer was added 5.3 g (9.8 mmol) of methyl 4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate, 5.1 g (0.13 mol) of solid sodium hydroxide, and 100 mL of water. The mixture was heated to reflux for 3 hr. After cooling, the methanol was removed in vacuo, and 6 N hydrochloric acid was added dropwise until the solution was no longer basic (pH=7). The solution was extracted three times with ethyl acetate. The organic layers were combined, and precipitation is induced. The solid was washed with ether to provide 4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid, as the dihydrate.
Reaction SMILES: [C@H:1]1([O:12][C@@H:13]2[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16](Br)[C@H:15]([OH:22])[C@H:14]2[OH:23])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[N-:24]=[N+:25]=[N-:26].[Na+]>CS(C)=O>[C@H:1]1([O:12][C@@H:13]2[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16]([N:24]=[N+:25]=[N-:26])[C@H:15]([OH:22])[C@H:14]2[OH:23])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Br)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate (4) is reacted with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes followed by extraction in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate (6). The azide is hydrogenated at room temperature under pressure in dioxane-triethylamine solution using 10% palladium on carbon catalyst. The product is crystallized from dioxane-ethanol to provide 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester).
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl.[CH:23]1[CH:28]=[CH:27][CH:26]=[CH:25]C=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[C:25]1[CH2:26][CH2:27][CH2:28][C:23]1=[O:9]
Reactant: COc1cccc(C=O)c1
Reactant: c1ccccc1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: COc1cccc(C=C2CCCC2=O)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 27.2 g (0.20 mol) of 3-methoxybenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under refluxing for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 66.0%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)c1[nH]c2cc(Cl)ccc2c1N
Product: CC(=O)Nc1c(C(=O)C(C)(C)C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-trimethylacetylindole (Example 89) and acetyl chloride. m.p.: 190-193° C. 1H-NMR (CDCl3) δ: 10.46 (1H, br s), 8.40 (1H, br s), 8.22 (1H, d, J=9.2 Hz), 7.29 (1H, s), 7.05 (1H, d, J=9.2 Hz), 2.29 (3H, s), 1.42 (9H, s)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(#N)C.ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:18]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1cc[nH]n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: O=C(Nc1cc[nH]n1)c1ccccc1Cl
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a solution of 1H-pyrazol-3-amine (166 mg, 2 mmol, Aldrich) in acetonitrile (8 ml) was added triethylamine (0.558 ml, 4.0 mmol, Aldrich) and the stirred solution was cooled in an ice-water bath. To the mixture was added a solution of 2-chlorobenzoyl chloride (0.253 ml, 2.0 mmol, Aldrich) in acetonitrile (7 ml). The mixture was stirred under nitrogen and allowed to warm slowly to ambient temperature overnight. The mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (approximately 30 ml) and water (approximately 30 ml). The layers were separated and the aqueous phase was washed with further ethyl acetate (2×20 ml). The combined organic layers were filtered through a hydrophobic frit and the filtrate concentrated in vacuo to give the crude material (0.47 g). The sample was loaded in dichloromethane and purified on silica 50 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a colourless solid (0.198 g); LCMS: (System 4) MH+=222, tRET=1.54 min.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[C:20]([C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[CH:19][C:18](I)=[CH:17][CH:16]=3)=[O:7].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[CH:16]=[CH:17][CH:18]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH2:19][C:20]=3[C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccn2c(=O)c3cc(I)ccc3nc12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3c(nc12)C=CC(c1cccnc1)C3
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A mixture of N-[2-(dimethylamino)ethyl]-2-iodo-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide (100 mg), 3-pyridinyl-boronic acid (225.41 mg), tetrakis(tri-phenylphosphine)palladium(0) (66.22 mg) and sodium carbonate (0.57 ml of 2 M (1.15 mmol)) was heated in an oil bath at 120° C.-125° C. for 45 minutes. The reaction mixture was cooled to room temperature, diluted with water (30 ml), and extracted with CH2Cl2 (3×30 ml). Combined organic phases were washed with brine (50 ml), dried with MgSO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (50 g; gradient elution with 10-30% MeOH/CHCl3) to give the desired product (66 mg).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[C@H:20]1([NH:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:40])[CH:36]=3)[N:31]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>>[C@H:20]1([NH:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:40][C:1]([NH:13][CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[O:12])[CH:36]=3)[N:31]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCOCC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCOCC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 4-aminotetrahydropyran and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=403.5 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1>CN(C=O)C>[CH3:20][S:19][C:15]1[N:16]=[C:17]([N:2]2[CH:3]=[C:4]3[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]3)=[N:1]2)[CH:18]=[CH:13][N:14]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cc3ccccc3n2)n1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
A solution of 1H-indazole (2.36 g, 20.0 mmol) in anhydrous DMF (100 mL) was treated with NaH (60% dispersion in mineral oil, 1.60 g, 40.0 mmol) at RT for 10 min. 4-Chloro-2-methylthiopyrimidine (2.55 ml, 22.0 mmol) was then added in one portion at RT, and the resulting mixture stirred at 70° C. for 2.5 h. The reaction mixture was cooled to RT, quenched with aqueous HCl (1 M), and extracted with EtOAc. The layers were separated, the organic layer washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was absorbed onto silica gel and purified by flash chromatography (ethyl acetate/hexane, gradient from 5:95 to 25:75) to afford a mixture of 1-(2-methyl-sulfanyl-pyrimidin-4-yl)-H-indazole and 2-(2-methylsulfanyl-pyrimidin-4-yl)-2H-indazole (3.77 g, 78% yield) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([OH:10])=O.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Na].Cl>C(O)C.O>[C:13]([C:12]1[C:11](=[O:18])[NH:1][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]=1[OH:10])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: NC1=C(C(=O)O)CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Reaction time: 30 h

Procedure:
A mixture of a 60:40 mixture of the ethyl and methyl esters of 2-amino cyclohex-1-ene carboxylic acid (47.2g; 0.29 mole) and diethyl malonate (46.4g; 0.29 mole) were added to a solution of sodium (7.2g; 0.29 mole) in ethanol (145 ml) stirred at ca 110° C for 30 hrs. in an autoclave. The product was acidified with 5N HCl to pH 4.0 and diluted with water. The precipitated ester was filtered off and recrystallised from ethanol with charcoalisation, m.p. 236° -7° (d).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:25]([NH:28][CH2:29][CH2:30][NH2:31])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:31][CH2:30][CH2:29][NH:28][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)NCCN
Reactant: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCNC(C)C)cc3)cc2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester (intermediate 64) (66 mg, 0.180 mmol), N-isopropylethylenediamine (55.2 mg, 0.540 mmol) and cesium carbonate (58.6 mg, 0.180 mmol) in 2 ml of dimethyl sulfoxide in a test tube, equipped with a magnetic bar, is stirred overnight at 80° C. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is then washed with water, dried over magnesium sulfate and evaporated. The residue, purified by LC/MS, gives 43 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester (white powder) in a yield of 53%.
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#N.[OH2:12].[OH-].[Na+].[CH2:15]([OH:17])[CH3:16]>C(Cl)Cl>[CH3:11][N:9]([CH3:10])[C:6]1[N:5]=[N:4][C:3]([C:1]([O:17][CH2:15][CH3:16])=[O:12])=[CH:8][CH:7]=1
Reactant: O
Reactant: CN(C)c1ccc(C#N)nn1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N(C)C)nn1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Ethyl (6-dimethylaminopyridazin-3-yl)carboxylate can be obtained by heating, at a temperature of about 70° C. for 4.5 hours, a suspension of 3-cyano-6-dimethylaminopyridazine (52.7 g) in a mixture of distilled water (600 cc), 10N aqueous sodium hydroxide solution (200 cc) and ethanol (400 cc). After cooling to a temperature of about 20° C., methylene chloride (200 cc) is added to the reaction mixture, which is then left to stand for 12 hours at a temperature of about 20° C. The aqueous phase is removed by decantation, acidified by addition of 12N hydrochloric acid (150 cc) and evaporated to dryness under reduced pressure. Ethanol (360 cc), 1,2-dichloroethane (360 cc) and pure methanesulphonic acid (76 g) are added to the residue thus obtained. The resulting mixture is then heated under reflux for 20 hours. After cooling to a temperature of about 20° C., the insoluble matter which has formed is filtered off and washed with methylene chloride (3 × 20 cc). A saturated aqueous sodium carbonate solution (720 cc) is added to the filtrate thus obtained. The insoluble product which forms is filtered off and washed with methylene chloride (2 × 200 cc). The aqueous phase is removed by decantation and is washed with methylene chloride (2 × 100 cc). The combined organic fractions are dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. Ethyl (6-dimethylaminopyridazin-3-yl)carboxylate (50.81 g), melting at 112° C., is thus obtained.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]5[NH:39][C:38]([C@@H:40]6[CH2:45][C@@H:44]7[C@@H:42]([CH2:43]7)[N:41]6C(OC(C)(C)C)=O)=[N:37][CH:36]=5)=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)=[CH:17][N:18]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C(Cl)Cl>[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54].[C@@H:9]12[CH2:10][C@@H:11]1[CH2:12][C@@H:13]([C:14]1[NH:18][CH:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]5[N:39]=[C:38]([C@@H:40]6[CH2:45][C@@H:44]7[C@@H:42]([CH2:43]7)[NH:41]6)[NH:37][CH:36]=5)=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)[N:15]=1)[NH:8]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)ccc1-c1ccc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (1R,3S,5R)-tert-butyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (275 mg) in DCM (10 mL) was added TFA (2 mL, 26.0 mmol). The mixture was stirred for 2 h at room temperature. The volatiles were removed under vacuum and the crude residue was purified by a reverse phase HPLC (water/MeOH/TFA) to afford a TFA salt of (1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (106 mg) as tan solid. LC-MS retention time 1.153 min; m/z 499.36 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.33 (s, 1H), 8.19 (s, 1H), 7.99-8.05 (m, 2H), 7.85-7.95 (m, 6H), 7.83 (s, 1H), 7.76 (s, 1H), 4.78 (q, J=9.4 Hz, 2H), 3.47-3.54 (m, 2H), 2.65-2.74 (m, 4H), 2.02-2.12 (m, 2H), 1.18-1.25 (m, 2H), 0.97-1.05 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:13](O)([C:15](F)(F)F)=O.[C:20](OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC(C)=O>[CH3:20][C:13]1([CH3:15])[O:5][C:4](=[O:6])[CH:3]=[C:2]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[O:1]1
Reactant: O=C(O)CC(=O)c1ccncc1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: CC1(C)OC(=O)C=C(c2ccncc2)O1

Procedure:
Prepared from 3-oxo-3-pyridin-4-yl-propionic acid [prepared from 4-acetylpyridine, magnesium methylcarbonate and CO2 in DMF at 120° C. according to Journal of Antibiotics 1978, 31, 1245] by treatment with acetone, TFA and TFAA according to general procedure J (method b). Obtained as a white solid (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]2.C(N(CC)CC)C.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH:12][C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:7]2
Reactant: COCC(=O)Cl
Reactant: Nc1cnc2c(Cl)ccnc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cnc2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A round bottom flask under nitrogen was charged with 8-chloro-1,5-naphthyridin-3-amine (41 mg, 0.23 mmol), triethylamine (64 μl, 0.46 mmol), and dichloromethane (1 mL). To this was added 2-methoxyacetyl chloride (42 μl, 0.46 mmol) dropwise via syringe and reaction allowed to stir overnight at room temperature. Next day reaction mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Layers separated and organic layer dried over sodium sulfate to afford yellow oil. This was purified by ISCO silica gel chromatography (2-5% MeOH/DCM) to afford N-(8-chloro-1,5-naphthyridin-3-yl)-2-methoxyacetamide (43 mg, 75% yield) as light yellow solid. MS[M+H]=251.9. Calc'd for C11H10ClN3O2=251.7.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:17][C:18]1[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[S:21][C:22]=1[CH3:23].C(OC)(C)(C)C>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24](=[O:26])[CH2:25][C:11]([C:6]2[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=2)([OH:16])[C:12]([F:13])([F:14])[F:15])[S:21][C:22]=1[CH3:23]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1cc(Br)c(C)s1
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1sc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 5 h
Yield: 127.2 %

Procedure:
LiH (3.2 g) is added to a solution of 1-(3,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (56 g) and 1-(4-bromo-5-methyl-thiophen-2-yl)-ethanone (41 g) in dry THF (500 ml). After 5 h at 60° C. under nitrogen atmosphere, tert-butylmethylether (500 ml) is added to the reaction mixture. The reaction is slowly quenched with water (500 ml) at 5° C. and further extracted twice with tert-butylmethylether (500 ml). The organic phases are combined, washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo to yield 1-(4-bromo-5-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butan-1-one (110 g, 77% purity) as a brown oil. The crude product is used without further purification.