Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6](N2C(=O)C=CC2=O)=[CH:5][C:4]2[C:14]([O:16][C:17]3([C:27]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=4[O:25][C:19]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]3=4)[C:3]=2[CH:2]=1)=[O:15]>CN(C)C=O>[CH:1]1[CH:6]=[CH:5][C:4]([C:14]([OH:16])=[O:15])=[C:3]([C:17]2[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[O:25][C:26]3[C:27]=2[CH:28]=[CH:29][C:30]([CH:31]=3)=[O:32])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N3C(=O)C=CC3=O)cc21
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 8 h

Procedure:
Fluorescein-5-Maleimide, Thermo Scientific (F5M) was dissolved in dimethylformamide, to give a final concentration of 25 mg/mL. This was then further diluted into 18 mls of PBS, pH adjusted to approximately pH 6.5. To this solution either 1 ml of 200 mg/mL rHA or 1 mL of 200 mg/mL K573P variant was added. This gave an approximate 20 fold final molar excess of F5M. These samples were incubated and allowed to conjugate overnight at 4° C., in the dark, to allow the maleimide groups on the F5M to react with predominantly the free sulfhydryl, present in both albumin species.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[C:10]=2[F:37])[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:11]([F:36])[C:10]=2[F:37])[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 82.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (130 mg, 0.20 mmol) prepared in Example 105a, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (80 mg, 81%) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=O.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].[S].O>CN(C=O)C>[NH:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:22]=[C:1]1[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Reactant: Nc1ccccc1N
Agent: [S]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Yield: 89.7 %

Procedure:
To 3-formyl-1H-indazole-6-carboxylic acid (2.35 g, 12.42 mmol) in DMF (60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) and sulfur powder (1.1 eq, 13.66 mmol). This mixture was then heated to reflux for 6 hours. The reaction was followed by TLC and LC-MS. After cooling, water (50 mL) was added to the reaction and the brown precipitate which formed was filtered and collected to provide 3.1 g (90%) of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) δ 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, J=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:21](=[O:23])[NH2:22])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:9][CH:8]=1.[CH:24]([O-])([O-])OCC.CN(C)C=O>C(OCC)(=O)C>[OH:23][C:21]1[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][C:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=4)=[CH:9][CH:8]=3)=[C:2]2[N:1]=[CH:24][N:22]=1
Reactant: CCOC([O-])[O-]
Reactant: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Cc2ccc(-c3cnn4c(O)ncnc34)cc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-carbamoyl-4-{4-(3-methylphenylmethyl) phenyl}pyrazole (3.0 g), ethyl orthoformate (2 ml) and N,N-dimethylformamide (4 ml) was heated and stirred at 100° C. to 110° C. After 1 hour, to the mixture was added ethyl acetate (50 ml). The precipitate was separated by filtration, washed with ethyl acetate, dried to give the title compound (2.0 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:1]2[C:9]3=[CH:8][N:7]=[CH:6][CH:5]=[C:4]3[CH:3]=[CH:2]2)=[CH:13][CH:12]=1
Reactant: c1cc2cc[nH]c2cn1
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccc3ccncc32)cc1
Temperature: 150 °C
Yield: 88.7 %

Procedure:
6-Azaindole (5.00 g, 42.3 mmol) was dissolved in DMF (150 mL) under nitrogen and 1-chloro-4-iodo-benzene (12.2 g, 50.8 mmol), N,N′-dimethylethylenediamine (911 uL, 8.46 mmol), K3PO4 (18.9 g, 88.9 mmol) and CuI (806 mg, 4.23 mmol) were added. The reaction mixture was heated at 150° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was suspended in 1M aq Na2CO3 (250 mL) and extracted into DCM (2×250 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a yellow solid (8.58 g, 88.6%). LCMS (ES+): 229.1 [MH]+. HPLC: Rt 4.48 min, 98.6% purity.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:23]>O1CCOCC1>[NH2:23][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1
Reactant: N
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
4,6-Dichloro-N-(4-(N-methylsulfamoyl)phenyl)pyrimidine-5-carboxamide (238 m g, 0.66 mmol) was dissolved in dioxane (3 ml) and cooled in an ice bath. Ammonia (0.47 ml, 7N in MeOH, 3.3 mmol) was dropwise added and the mixture was stirred at 0° C. for 6 h and at room temperature overnight. The solvent was removed and ethyl acetate added. The solid precipitate was filtered and washed with ethyl acetate to give 181 mg (80% yield) of the title compound. Purity 100%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:29][CH:28]=1)([OH:20])=[O:18]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2nccc(C)c2[nH]1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
7-Methyl-2-propylimidazo[4,5-b]pyridine (described in Example 9) was alkylated with 2-t-butoxycarbonyl-4'-bromomethylbiphenyl and the resulting protected derivatives was deprotected according to the procedure described in Step 2 of Example 3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1.C(N(CC)CC)C.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]1([CH:12]2[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:8][CH:7]2[O:6][CH2:5][C:4]2[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=2[CH2:2][NH:1][C:37]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:44])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(OCc2ccccc2CN)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(OCc2ccccc2CNC(=O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.5 %

Procedure:
A solution of 150 mg (0.38 mmol) of tert-butyl (3RS,4RS)-3-(2-aminomethyl-benzyloxy)-4-phenyl-piperidine-1-carboxylate in 2 ml of methylene chloride was treated with 229 mg (2.26 mmol) of triethylamine, 139 mg (1.05 mmol) of nicotinic acid, 216 mg (1.13 mmol) of EDC and 10 mg (0.08 mmol) of 4-dimethylaminopyridine and the mixture was stirred at room temperature for 24 hours. Thereafter, the reaction solution was diluted with methylene chloride and washed with a saturated sodium hydrogen carbonate solution. The organic phase was separated, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate as the eluent. There were obtained 100 mg (53% of theory) of tert-butyl (3RS,4RS)-4-phenyl-3-(2-{[(pyridine-3-carbonyl)-amino]-methyl}-benzyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 502 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:18]3[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:10]([C:37]([OH:39])=[O:38])[CH2:9]1)=O)(C)(C)C.O1CCO[CH2:42][CH2:41]1>Cl>[ClH:29].[CH2:41]([O:39][C:37]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[N:18]2[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[O:38])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C(C(=O)O)C1
Reactant: C1COCCO1
Agent: Cl
Product: CCOC(=O)C1CNCCN1c1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
4-[9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-piperazine-1,3-dicarboxylic acid tert-butyl ester I-(8A-1)a was dissolved in 4 M HCl in dioxane (0.5 ml). After 30 minutes, the now heterogeneous reaction was concentrated under reduced pressure and then triturated from ether to afford title compound 8A-1 (38 mg, quantitative): +ESI MS (M+1) 497.2; 1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.51–7.30 (m, 7H), 4.35–4.15 (m, 2H), 4.06 (d, J=13.3 Hz, 1H), 3.73–3.47 (m, 5H), 3.40–3.30 (m, 1H), 1.23 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[N:14]=2)=[CH:9][CH:8]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:24]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:15]3[N:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:11]=4)[CH:18]=[CH:17][N:16]=3)=[CH:28][CH:27]=2)=[O:25])[CH2:40][CH2:41]1)=[O:35]
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Nc2nccc(-c3ccc(SCCCCO)cc3)n2)cc1)N1CCN(C(=O)c2ccco2)CC1
Reaction time: 12 h
Yield: 8.8 %

Procedure:
4-{4-[4-(4-Hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}benzoic acid (0.34 g, 0.86 mmol) was dissolved in THF (5 mL). To this solution was added 1-furoylpiperazine (0.170 g), EDCI (0.180 g), and HOBt (0.127 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparatory HPLC (30–80 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(Furan-2-carbonyl)-piperazin-1-yl]-(4-{4-[4-(4-hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.042 g, 9%): HPLC Retention Time; 10.07 min. (Method B) M+H=558.3.
Reaction SMILES: N(CN[C:5](N)=[O:6])=O.[OH-].[K+].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:20])=[C:14]2[CH2:21][C:22](O)=[O:23].N#N>ClCCl.C(OCC)C>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:20])=[C:14]2[CH2:21][C:22]([O:6][CH3:5])=[O:23]
Reactant: NC(=O)NCN=O
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CC1=C(C)Cc2ccc(F)cc21
Yield: 93 %

Procedure:
Nitrosomethylurea (99.5 mmol) is added in portions to a cold (0° C.) mixture of aqueous 50% KOH (50 ml) and diethylether (150 ml) at 0° C. The yellow ether solution of diazomethane (Note: explosive) is separated, is washed with water, and is added in portions to a solution of 5-fluoro-2-methylindene-3-acetic acid (90 mmol) in dichloromethane (200 ml). When the evolution of N2 ceases, the reaction is complete. After evaporation of the solvents, the residue is recrystallized from hexane to give methyl 5-fluoro-2-methyl-3-indenylacetate (yield 93%; m.p. 53° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH2:9][CH2:10][S:11][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+]>O.CO>[CH3:1][C:2]1[C:7]2[S:8][CH2:9][CH2:10][S:11][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1ccc2c(c1C)SCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1SCCS2

Procedure:
9.6 g (0.04 mol) of methyl 8-methyl-2,3-dihydrobenz[1,4]dithiin-7-carboxylate were initially charged in 100 ml of a 1:1 mixture of water/methanol and 2.4 g (0.06 mol) of sodium hydroxide were added. The solution was heated under reflux for two hours, then the organic solvent was distilled off, 200 ml of water were added and the mixture was acidified with cooling using conc. hydrochloric acid. The precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[N:11]1([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCCN3CCCC3)c2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(NCCN2CCCC2)cc(N2CCNCC2)c1
Reaction time: 18 h
Yield: 137.3 %

Procedure:
To a solution of 4-[3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (338 mg, 0.90 mmol) in MeOH (10 mL) was added a solution of HCl in EPA (5M, 1.8 mL). The mixture was stirred for 18 h then concentrated to provide the title compound (339 mg, 99%). m/z (M+1) 275.49 (free base).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[N+:17]([O-])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]nc(C)c2[N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Reaction time: 2 h

Procedure:
4.84 g of 5-(3,4-dimethoxyphenyl)-3-methyl-4-nitro-1H-pyrazole (43) were dissolved in 80 ml of ethanol, and 0.5 g of Pd/C was added to this solution. The solution was shaken under hydrogen for 2 h, then filtered through magnesium sulfate and subjected to rotary evaporation. The residue was chromatographed through silica gel (ethyl acetate/heptane 3/1). The following was obtained: 44 C12H15N3O2 (233.27); MS (ESI) 234 (M+H)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)=[N:8][C:7]=12)[CH3:2].Cl.[NH:27]1[CH2:30][CH:29]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=3)[NH:34][N:35]=2)[CH2:28]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:18]3[CH:25]=[CH:24][C:21]([CH2:22][N:27]4[CH2:28][CH:29]([C:31]5[N:32]=[C:33]([C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=6)[NH:34][N:35]=5)[CH2:30]4)=[CH:20][CH:19]=3)=[N:8][C:7]=12)[CH3:2]
Reactant: Cc1cccc(-c2nc(C3CNC3)n[nH]2)n1
Reactant: CCc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCc1cnn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6cccc(C)n6)n5)C4)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A mixture of 142 mg (0.43 mmol) 4-(3-ethyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde and 314 mg (0.65 mmol, ca 60% pure) 2-(5-azetidin-3-yl-2H-[1,2,4]triazol-3-yl)-6-methyl-pyridine hydrochloride salt in 3.65 mL NMP was treated with 0.146 mL triethylamine and 0.045 mL acetic acid and stirred overnight at rt. The mixture was treated with 101 mg sodium triacetoxyborohydride and stirred overnight at rt. The reaction was partitioned between DCM and saturated sodium hydrogencarbonate solution, the organic phase dried and concentrated in vacuo and the residue purified by preparative reverse phase HPLC to give 49 mg of the title compound contaminated with formic acid.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH2:2][OH:3].[O:8]=[CH:9][C:10]([Cl:13])([Cl:12])[Cl:11]>>[Cl:11][C:10]([Cl:13])([Cl:12])[CH:9]([NH:7][C:5]([NH:4][CH2:1][CH2:2][O:3][CH:9]([OH:8])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:6])[OH:8]
Reactant: NC(=O)NCCO
Reactant: O=CC(Cl)(Cl)Cl
Product: O=C(NCCOC(O)C(Cl)(Cl)Cl)NC(O)C(Cl)(Cl)Cl

Procedure:
52 g (0.5 mole) of monoethanolurea was heated to 80° C.; 149.0 g (1.01 mole) of chloral was added dropwise thereto between 80°-90° C. with stirring and heated between 80°-90° C. for an additional hour. On cooling, a clear viscous liquid product was obtained that weighed 200 g.
Reaction SMILES: COC(=O)N.[CH3:6][O:7][C:8](=[O:52])[NH:9][CH:10]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][C:39]([C:42]5[NH:43][C:44]([CH:47]6[CH2:51][CH2:50][CH2:49][NH:48]6)=[N:45][CH:46]=5)=[CH:38][CH:37]=4)[CH:32]=3)[CH:27]=2)=[CH:24][N:25]=1)=[O:15])[CH:11]([CH3:13])[CH3:12].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[O:68][CH3:69])[C:59](O)=[O:60])=[O:56].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:52])[NH:9][CH:10]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][C:39]([C:42]5[NH:43][C:44]([CH:47]6[CH2:51][CH2:50][CH2:49][N:48]6[C:59](=[O:60])[CH:58]([NH:57][C:55]([O:54][CH3:53])=[O:56])[C:62]6[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=6[O:68][CH3:69])=[N:45][CH:46]=5)=[CH:38][CH:37]=4)[CH:32]=3)[CH:27]=2)=[CH:24][N:25]=1)=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)N[C@H](C(=O)O)c1ccccc1OC
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: COC(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1OC
Temperature: 0 °C
Yield: 46.9 %

Procedure:
{1-[2-(5-{6-[4-(2-{1-P-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester. To a solution of {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester (0.04 g, 0.05 mmol) and (S)-Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid (0.02 g, 0.08 mmol, 1.5 equiv.) in CH2Cl2 (0.5 mL) was added K3PO4 (0.03 g, 0.15 mmol, 3 equiv.). The slurry was cooled to 0° C. and COMU (0.03 g, 0.06 mmol, 1.25 equiv.) and the reaction was stirred at 0° C. for 1 hour. The slurry was diluted with CH2Cl2 and filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.02 g, 50%) as a white powder. LCMS-ESI+: calc'd for C48H52N8O7: 852.4 (M+). Found: 853.6 (M+H+). 1H-NMR: 400 MHz, (acetone-d6) δ: (Mixture of rotomers) 10.96-11.01 (m, 2H), 8.29 (s, 1H), 8.07 (s, 1H), 7.73-7.89 (m, 7H), 7.35-7.48 (m, 4H), 7.33 (t, 1H), 7.05 (d, 1H), 6.96 (t, 1H), 6.36 (d, 1H), 5.91 (d, 1H), 5.21-5.26 (m, 3H), 4.29 (t, 1H), 3.90 (s, 3H), 3.78-3.93 (m, 2H), 3.60 (s, 3H), 3.58 (s, 3H), 3.30 (q, 2H), 2.59-2.65 (m, 2H), 2.36 (m, 1H), 1.90-2.21 (m, 6H), 0.85-0.93 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CS(C)=O>[F:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:21][CH:20]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)nc1
Yield: 34.5 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (5.8 g), dimethylsulfoxide (20 ml), potassium carbonate (4.8 g) and 6-fluoro-3-(bromomethyl)pyridine (6.7 g) according to the similar method described in Production Example 4 was obtained 3.3 g of 2-((6-fluoro-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (13)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:28])[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][CH:17]=2)=O)=[CH:7][CH:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:28][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCOc1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)OC)cc3)o2)cc1
Yield: 91.2 %

Procedure:
A solution of 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (765 mg) and p-toluenesulfonic acid monohydrate (8 mg) in toluene (10 ml) was refluxed for 6 hours. The reaction mixture was diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure and the precipitate was triturated with methanol, collected by filtration, washed with methanol and dried under reduced pressure to give methyl 4-[5-(4-n-pentyloxyphenyl)furan-2-yl]benzoate (665 mg).