Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1)=O.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2cc(C)nc(NC(=O)OC(C)(C)C)c2)CC1

Procedure:
2-Chloro-6-methyl-pyridine-4-carbaldehyde (13-2, 0.609 g, 3.91 mmol), tert-butylcarbamate (0.550 g, 4.70 mmol), cesium carbonate (1.91 g, 5.87 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.040 mmol) and Xantphos (0.068 g, 0.030 mmol) were stirred in 10 mL of anhydrous dioxane under N2. The reaction was heated to 80° C. and after 18 hours the reaction was cooled to room temperature. The mixture was diluted with water and extracted 3× with EtOAc. The extracts were dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography afforded impure tert-butyl 4-formyl-6-methylpyridin-2-ylcarbamate. This aldehyde was dissolved in 2 mL of 1,2-dichloroethane. N-Acetylpiperazine (0.074 g, 0.58 mmol) was added followed by addition of 0.05 mL HOAc and NaBH(OAc)3 (0.122 g, 0.58 mmol). After 3 hours the reaction was quenched by the addition of half-saturated NaHCO3 (aq). The mixture was extracted 3× with DCM (dichloromethane) and the extracts were dried over Na2SO4, filtered and concentrated to afford the titled compound, 13-3. 1H NMR (CDCl3) δ 7.67 (s, 1H), 7.47 (s, 1H), 6.84 (s, 1H), 3.64 (t, 2H, J=4.9 Hz), 3.47 (m, 4H), 2.44 (m, 7H), 2.09 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:20][CH2:21][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:23][CH2:24]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:32]=1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 9 h
Yield: 110.2 %

Procedure:
After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (88 mg) under a nitrogen atmosphere, 10% palladium-carbon (45 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 9 hours. The atmosphere in the reaction vessel was then replaced with nitrogen and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (90 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=O)[C:21]([F:24])([F:23])[F:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1.ClCCCl.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH:10]=[C:20]([C:15]2[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=2)[C:21]([F:24])([F:23])[F:22])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Yield: 88.5 %

Procedure:
3.0 g of 4-chloro-3-methylacetophenone, 4.35 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 30 ml of 1,2-dichloroethane, 2.46 g of potassium carbonate and 0.18 g of triethylamine were fed and the mixture was refluxed by heating for 16 hours. The reaction solution was cooled to room temperature, and separated by adding 200 ml of ethyl acetate and iced water. The organic phase was washed with diluted hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent is a mixed liquid of hexane:ethyl acetate=9:1) to obtain 6.2 g of 1-(4-chloro-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one as brown liquid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[ClH:39].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 mg (0.08 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzo-thiophene-2-carboxamide dihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) of triethylamine are added. At 0° C., 16.9 mg (0.12 mmol) of benzoyl chloride are added. After 3 h of stirring at RT, the reaction mixture is separated by preparative HPLC. The product fraction is concentrated under reduced pressure and codistilled with 4M HCl in dioxane. 9 mg (25.4% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][C:25]([CH2:24][N:10]2[C:11]3[C@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@@H]2CC[C@@]3(C)C2(C)C)cc1
Yield: 48.9 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 300 mg, 0.99 mmol), tetrabutylammonium iodide (270 mg, 0.7 mmol) and methyl 4-(bromomethyl)benzoate (1.00 g, 4.37 mmol) in dimethylformamide (10 mL) was heated at 100° C. for 3 h. The reaction mixture was allowed to cool. Dichloromethane (100 mL) was added, and the solution was washed with (5×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL), dried (magnesium sulfate, filtered, and evaporated. The residue was purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions containing the product were concentrated and then dried under high vacuum at 50° C. give 4-[(4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-ylmethyl]-benzoic acid methyl ester (219 mg, 49%) as a pale yellow solid. ES(+)-MS (M+H) 453.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[O:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[N:53]=[CH:52]1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:54]4[N:53]=[CH:52][O:51][CH:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: NCc1cocn1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cocn1
Yield: 51 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with oxazol-4-ylmethanamine hydrochloride, the title compound was obtained as a white solid in 51% yield: mp 183-184° C. (ethyl acetate/hexane): 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.41-7.32 (m, 2H), 7.08-6.97 (m, 2H), 6.31 (t, J=5.3 Hz, 1H), 4.97 (s, 2H), 4.52 (d, J=5.3 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 415.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[CH:8]=[CH:9][C:10](O)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH:26][CH2:10][CH:9]=[CH:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:15]([OH:16])=[C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[CH:13]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NCC=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 35.5 %

Procedure:
First, 20 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 11.2 g of serine methyl ester hydrochloride, 13.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 10 ml of triethylamine were added to 300 ml of dichloromethane, and then the mixture was allowed to react for 2 hours at room temperature. After completion of the reaction, this mixture was washed by addition of water, and the dichloromethane was distilled off under reduced pressure. The residue so obtained was separated and purified by column chromatography on silica gel using chloroform as an eluent, thereby obtaining 9.3 g of N-(3,5-di-t-butyl-4-hydroxycinnamyl)serine methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9]
Reactant: CC1(CC(=O)O)CCCCCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CC1(C)CCCCCC1=O
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-2-oxocycloheptaneacetic acid (3.0 g, 0.0163 mole, obtained as described above), anhydrous potassium carbonate (2.76 g, 0.020 mole) and methyl iodide (8 ml) in acetone (50 ml) is stirred and heated to reflux for 2 hrs. Methyl iodide (3ml) is added and heating to reflux is continued for another 3 hrs. The solvent is evaporated, the residue taken up in water (50 ml), saturated with sodium chloride, and extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to yield 1-methyl-2-oxocycloheptaneacetic acid methyl ester as an oil, νmaxCHCl3 1730, 1700 cm-1, nmr (CDCl3) δ1.2 (s), 3.67 (s).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[CH3:32][NH:33][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4ccccc4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3ccccc3)c2O1

Procedure:
The title compound was prepared (0.031 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-phenyl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.060 g, 0.13 mmol) and methylamine (0.12 g, 3.9 mmol). mp 189-190° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[OH:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (3.65 g, 24 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (5.00 g, 24 mmol), HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF6] (11.0 g, 29 mmol) in anhydrous DMF (30 mL) is added DIPEA (8.30 mL, 50 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (400 g silica gel, gradient elution: 10-80% EtOAc in heptane) to give a pure product (3) as white solid (5.5 g, 67%).
Reaction SMILES: F[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[NH2:23]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
2-fluoroadenosine (4 g, 14 mmol) was dissolved in 100 mL ethanol in a 300 mL three-necked flask. Hydrazine hydrate (4.1 mL, 6 equivalents, 84 mmol) was added and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and stirred overnight (16 hours). The resulting white precipitate was isolated by filtration and dried in oven at 40° C. overnight to afford 2-hydrazinoadenosine (yield: 94%, 3.5 g, 96% purity).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:16][N:17]([CH3:21])[C:18](=[O:19])[O:13][C:8]1[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:7]=1
Reactant: COC(COc1cc(C)cc(O)c1)OC
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(COc1cc(C)cc(OC(=O)N(C)C)c1)OC
Temperature: 80 °C

Procedure:
3-(2,2-Dimethoxyethoxy)-5-methylphenol (0.05 mole), N,N-dimethylcarbamoyl chloride (0.08 mole), triethylamine (0.05 mole) and xylene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is stirred and heated at 80° C. for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then washed with water and dried over anhydrous magnesium sulfate. The dried solution is then filtered and stripped of solvent and unreacted starting materials to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-methylphenyl] N,N-dimethylcarbamate as the residue.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]2[O:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)[CH:7]=[C:6]([CH3:25])[CH:5]=1.[Li+].[OH-]>C1COCC1.O.Cl>[CH3:25][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[O:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)[CH:7]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1cc(C)cc(-c2cc3nccc(-c4ccccc4)c3o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(-c2cc3nccc(-c4ccccc4)c3o2)c1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
3-Methyl-5-(7-phenyl-furo[3,2-b]pyridin-2-yl)-benzoic acid methyl ester (61.321 μmol) is dissolved in THF (300.00 μl) and LiOH 1M (122,600 μmol) is added. The reaction solution is stirred 26 h at RT and diluted with H2O (10 ml) and 1M HCl (122.6 μl) is added. The precipitate is filtered and washed with water and dried in vacuo. The product is obtained as colorless solid in quantitative yield; LCMS (ESI+) (method E): Rt 2.25 min, M+H+ 330.1 m/z.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]([O:13][CH3:14])=[O:12])[CH2:8]2.C([N-]C(C)C)(C)C.[Li+].[CH3:23][O:24][CH2:25][CH2:26]Br>O1CCCC1>[CH3:23][O:24][CH2:25][CH2:26][C:2]1([C:11]([O:13][CH3:14])=[O:12])[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: COCCBr
Reactant: COC(=O)C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 56A (0.314 g) in tetrahydrofuran (5 mL) was added dropwise lithium diisopropylamide (1.401 mL) at −78° C. The reaction mixture was stirred for 60 minutes and 2-bromoethyl methyl ether (0.562 g) was added. The reaction mixture was slowly warmed up to room temperature, stirred at room temperature overnight, quenched with saturated aqueous NH4Cl solution (2 mL), and extracted with ether. The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromotography (silica 40 g, 0%-30% ethyl acetate/hexanes).
Reaction SMILES: [S:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[CH:6][CH:5]=1)C#N.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].Cl>C(O)C>[SH:1][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[CH:6][CH:5]=1
Reactant: N#CSc1ccc(O)c(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Oc1ccc(S)cc1-c1ccccc1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
To a solution of 5-thiocyanato-biphenyl-2-ol (160 mg, 0.97 mmol) in absolute ethanol (8 mL) under nitrogen, sodium sulfide nonahydrate (298 mg, 1.1 6 mmol) was added. The resulting mixture was stirred at 85° C. for 20 min. The mixture was cooled down, made acidic with 10% aqueous HCl and extracted with ethyl acetate (×2). The combined organic layers were dried on MgSO4 and concentrated in vacuo to give the title compound as a yellow solid (105 mg, 95%) which was quickly submitted to the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>C(O)C>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N#CCCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CCO
Product: N#CCCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The above thiourea (12.5 g.) was dissolved in 8M ammonia in ethanol (120 ml.). Mercuric oxide (12.8 g.) was added and the mixture was stirred at 20° for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile as an oil. A sample of the oil was dissolved in acetone and 5 molecular equivalents of maleic acid were added. Ether was added to the resulting clear solution to produce the crystalline maleate, m.p. 123°-125°.
Reaction SMILES: [Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[C:5]2[CH2:14][CH:15]([NH:17][C:18](=[O:20])[CH3:19])[CH2:16][C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>FC(F)(F)C(O)=O>[Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[C:5]2[CH2:14][CH:15]([NH:17][C:18](=[O:20])[CH3:19])[CH2:16][C:4]=2[C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NC1Cc2cc(Br)c3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC1Cc2c([N+](=O)[O-])c(Br)c3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
N-(5-Bromo-2,3-dioxo-2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoxalin-8-yl)-acetamide (0.24 g, 0.7 mmol) was dissolved in trifluoroacetic acid (10 mL), cooled in an ice bath to 0° C., and then treated with fuming nitric acid (0.5 mL) and stirred for 4 h at 0° C. After removing the solvent by rotoevaporation, the syrupy residue was triturated with water and the resulting solid was collected by filtration, washed with water and then ether and dried in vacuo (0.22 g, 81% yield). Anal. calc'd for C13H11BrN4O5.H2O: C, 38.92; H, 3.27; N, 13.94. Found: C, 38.60; H, 3.00; N, 13.66.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1)=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N1CCN(c2ccccc2)CC1
Yield: 136.3 %

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-asparagine (4.3 g) and 1-phenylpiperazine (4.3 g) were condensed to obtain colorless powder 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-phenylpiperazine (9.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:26]1([C:32]2[N:37]=[N:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:38]([C:35]3[N:36]=[N:37][C:32]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:33][CH:34]=3)=[O:39])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(N2CCOCC2)nn1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)c2ccc(N3CCOCC3)nn2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-morpholin-4-yl-pyridazine-3-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 6-morpholin-4-yl-pyridazine-3-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 572.2 [M]+.