Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4](CC#N)[CH2:3]1.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>>[O:24]=[C:22]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([CH2:3][C:2]([OH:1])=[O:20])[CH2:23]1
Reactant: N#CCC1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CC1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Yield: 77 %

Procedure:
To a stirred solution of [5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-acetonitrile (0.25 g, 0.93 mmol) in ethanol (6 mL) was added sodium hydroxide solution (0.074 g, 1.86 mmol, in 3 ml water). The reaction mixture was refluxed for 3 hrs and the solvents were removed under reduced pressure, diluted with water (3 ml), washed with hexane (3×10 mL) and acidified with 2N HCl. The aqueous layer was extracted with DCM (3×15 mL) and the combined extract was washed with brine, dried with Na2SO4, evaporated under reduced pressure to obtain [5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-acetic acid (0.2 g, 77%) as an off white semi solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:18]C(=O)OCC4C=CC=CC=4)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC1Cc2cccc(-c3cccc(F)c3)c2O1)OCc1ccccc1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3cccc(F)c3)c2O1
Yield: 92.8 %

Procedure:
Treatment of (+)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.326 g, 0.864 mmol) with palladium on carbon (0.033 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.195 g (81%) of (+)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=+18.32 (c 10.0 in methanol); mp 186-188° C.; Anal. calcd. for C15H14FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.32; H, 5.1; N, 4.86.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([O:18][CH3:19])[CH:11]=1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[O:30])[CH:25]=[CH:26][CH:27]=1.C[Si](Cl)(C)C>CN(C)C=O.C(#N)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([C:2]2[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]=2[OH:8])[NH:31][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=2)=[O:30])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C(NC(=O)Nc1cccc(C(F)(F)F)c1)C1=C(O)CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of cyclohexane-1,3-dione (700 mg, 6.24 mmol), 4-bromo-2-methoxybenz-aldehyde (1.35 g, 6.28 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (1.27 g, 6.24 mmol) in N,N-dimethylformamide (2.0 mL) and acetonitrile (3.0 mL) is stirred at room temperature for 20 min Trimethylsilyl chloride (1 M in dichloromethane, 9.0 mL, 9.0 mmol) is added, and the mixture is stirred at room temperature for 30 min and poured into ice water. The mixture is stirred for 3 h and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 900 mg; ESI mass spectrum [(79Br)-M+H]+=513, [(81Br)-M+H]+=515; Retention time HPLC: 0.68 min (Z011_S03).
Reaction SMILES: [C:1]1([C:6]([NH:8][CH2:9][C:10]([O-:12])=O)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH2:14](O)C.O.Cl>N1C=CC=C(C)C=1.C(OC(=O)C)(=O)C>[C:1]1([C:6]([NH:8][CH2:9][C:10](=[O:12])[CH3:14])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])CNC(=O)c1cccs1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1cccnc1
Product: CC(=O)CNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 44.0 ml of a suspension of 16.70 g of sodium 2-(2-thenoylamino)acetate in β-picoline, 42.7 ml of acetic anhydride was added, and stirred for 3 hours at room temperature. After ice-cooling, 26.3 ml of ethanol, 129.7 ml of water and 45.2 ml of conc. hydrochloric acid were slowly added dropwise in sequence, and the mixture was stirred for 15 minutes as it is. After removal of ice-bath, the mixture was stirred for another 15 minutes at room temperature. Water (250 ml) was added and the precipitated crystals were collected, and washed with water. To the crystals was added 37.0 ml of water, and the mixture was heated to reflux for 1 hour. After 14.0 g of sodium chloride was added, the mixture was heated to reflux for another 1 hour. The reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After addition of activated carbon (Kyoryoku-sirasagi® MOIWY433), the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure. The residue was crystallized by addition of t-butyl methyl ether to provide 7.15 g of the objective compound as pale brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].Cl[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[C:23]([NH2:31])[N:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:7]=[CH:6][C:4]([NH:5][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:24]=[C:23]([NH2:31])[N:22]=3)=[CH:3][C:2]=2[F:1])[NH:16][CH:17]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
67 mg (0.24 mmol) of 3-fluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 47 mg (0.24 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 4 ml of water/ethanol 1:1. 25 μl (0.29 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: [N+](C1C=CC(O[C:9]([CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:28](=[O:29])[N:17]3[CH:18]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[C:19]([CH3:22])([CH3:21])[S:20][C@H:16]23)=[O:13])=[O:10])=CC=1)([O-])=O.C([N:40](CC)CC)C.C(Cl)(Cl)Cl.N>CO>[C:9]([CH:11]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:12]([NH:14][CH:15]1[C:28](=[O:29])[N:17]2[CH:18]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)[C:19]([CH3:22])([CH3:21])[S:20][C@H:16]12)=[O:13])(=[O:10])[NH2:40]
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: CCN(CC)CC
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(N)=O)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 4 h

Procedure:
To a stirred solution of 523 mg. (0.001 mole) of 6-(2-[p-nitrophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 101 mg of triethylamine in 50 ml. of chloroform is added 1 ml of a 1M solution of ammonia in methanol, at -30° C. Stirring is continued for 4 hours without external cooling and then evaporation in vacuo leaves the crude product as its triethylamine salt.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(CN2CC=C(c3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 56.4 %

Procedure:
A solution of 1.0 g (0.0051 mol) of 4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride in 40 ml of dimethylformamide was treated with 2.13 ml (0.0153 mol) of triethylamine and 0.62 g (0.00170 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica with methanol as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. The organic phase was then completely freed from the solvents and the residue was digested in diethyl ether and subsequently filtered off under suction. A total of 0.27 g (56%) of 5-(4-phenyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 239°-241°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29]>C1COCC1.C(Cl)Cl>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccco1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To a solution of furan-2-carboxylic acid (2.0 g, 17.8 mmols) and N-methylmorpholine (1.95 ml, 17.8 mmols) in anhydrous THF (10 ml), cooled at −15° C. was added dropwise under stirring an equivalent quantity of isobutylchloroformate (2.33 ml, 17.8 mmols). After 30 minutes a solution of L-leucine methylester hydrochloride (3.23 g, 17.8 mmol) and N-metylmorpholine (1.95 ml, 17.7 mmols in anhydrous THF (15 ml) was slowly added, maintaining the mixture under stirring at −15° C. for two hours. The reaction mixture was diluted with CH2Cl2 (100 ml) and washed with HCl 1N (30 ml×2), NaHCO3 saturated solution (30 ml×2), and NaCl saturated solution (30 ml). After drying the organic phase on Na2SO4 and removal of the solvent at a reduced pressure, the raw product was obtained as an oily residue which spontaneously solidified. By grinding the solid substance in petroleum ether, white crystals of either N-[(furan-2-yl) carbonyl]- L-leucine methylester were obtained: 3.32 g (80%); m.p. 88-90° C., [a] D22=−23° C. (1, methanol); IR (CHCl3): 3424, 2956, 1741, 1663, 1595, 1517, 1351, 1177 cm−1; 1H-NMR (CLCl3): d 0.95 and 1.02 [two s, 6, CH2CH(CH3)2], 1.45-2.00 [m, 3, CH2CH(CH3)2], 3.85 (s, 3, OCH3), 4.73-5.13 (m, 1, aCH), 6.39-7.45 [m, 3, furan aromatics and 6.89 (d, 1, NH, J=8 Hz)]. Calculated for C12H17NO4: C, 60.24; H 7.16; N 5.85. Found C 60.15; H 7.22; N 5.88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].Cl.CN(C)CCCN=[C:27]=[N:28][CH2:29]C>ClCCl>[CH2:13]([N:15]1[CH2:18][CH2:19][CH:29]([N:28]([CH3:27])[C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:17][CH2:16]1)[C:14]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CC(=O)N(C)C2CCN(Cc3ccccc3)CC2)cc1

Procedure:
4-Methoxyphenylacetic acid (895 mg, 5.39 mmol), triethylamine (2.40 ml, 17.1 mmol) and 1-(3-dimethylaminopropy)-3-ethyl-carbodiimide hydrochloride (1.12 g, 5.88 mmol) were added to a solution of the title compound of preparation 7 (1.00 g, 4.90 mmol) in dichloromethane (20 ml). The mixture was stirred for 12 hours at room temperature, then partitioned between dichloromethane and water. The aqueous layer was separated and extracted with dichloromethane (2×). The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using ethyl acetate:methanol (90:10) as eluant to afford the title compound as a clear oil, 1.26 g.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]([OH:18])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1
Reactant: Cc1ccc(Br)nc1
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 2-bromo-5-methylpyridine (510 mg, 3 mmol) under ice cooling and the mixture was stirred at room temperature for 60 minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution. The temperature of the reaction mixture was raised gradually to room temperature. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. After drying the solvent, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (130 mg, 18%) was obtained as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)cc1
Yield: 76.2 %

Procedure:
A solution of 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 4-(methyloxy)benzenesulfonyl chloride, (0.025 g, 0.13 mmol) and DIPEA (0.05 mL, 0.25 mmol) in CH2Cl2 (2 mL) was stirred overnight. The solvent was concentrated and purification was accomplished by RP-HPLC (water/acetonitrile/0.1% TFA). The desired fractions were lyophilized and EtOAc (25 mL) and sat. NaHCO3 (10 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to afford N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-4-(methyloxy)benzenesulfonamide (0.030 g, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.03 (t, 1H), 7.80 (d, 1H), 7.66 (d, 2H), 7.51 (d, 1H), 7.38 (dd, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 6.99-7.10 (m, 3H), 3.96 (d, 2H), 3.78 (s, 3H). MS: m/z 485 (M+23).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[CH:21]([NH2:23])=O.CN(C=O)C.C(O)=O>C(O)(C)C>[OH:9][C:7]1[C:6]2[CH:5]=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[NH:3][C:2]=2[N:1]=[CH:21][N:23]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)[nH]c1N
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=[N+]([O-])c1ccc(-c2cc3c(O)ncnc3[nH]2)cc1

Procedure:
2.5 g (97 mmol) of 2-amino-3-ethoxycarbonyl-5-(4-nitrophenyl)pyrrole, 19.4 ml of formamide, 9.7 ml of DMF and 3.1 ml of formic acid are stirred at 150° C. together for 22 h. 1 ml of isopropanol is added to the warm reaction mixture. After cooling the reaction mixture, the precipitated product is filtered off. It is washed successively three times with 10 ml of ethanol each time, twice with 10 ml of isopropanol each time and twice with 10 ml of hexane each time. 4-Hydroxy-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained as rust-brown crystals which are employed for the next stage; MS: (M)+=256.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][CH:30]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:40][CH2:41][C:42](Cl)=[O:43]>O1CCCC1>[ClH:27].[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][CH:30]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:15][CH2:14]1)=[O:12])[C:42](=[O:43])[CH2:41][Cl:40])([CH3:3])[CH3:2]
Reactant: CC(C)OCCNc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OCCN(C(=O)CCl)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Product: Cl
Reaction time: 0.25 h

Procedure:
2.77 g of 1-[3-(2-isopropyloxyethylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine are dissolved in 50 ml of absolute tetrahydrofuran and stirred at RT with 1.07 g of Hunig base and 0.794 g of chloroacetyl chloride in 5 ml of absolute tetrahydrofuran. After approximately 15 minutes, the thin suspension is concentrated by evaporation, dissolved in ethyl acetate and washed with water until neutral. Concentration by evaporation, chromatography of the residue over silica gel (eluant: ethyl acetate) and treatment with ethereal hydrochloric acid yield 1-{3-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 115°-117°.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O.C(O)(=O)C>[C:1]([NH:4][C:5]1([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NC1(Cc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
To a suspension of 1.4 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 35 ml of anhydrous dimethyl sulphoxide, maintained at 20° C. under a nitrogen atmosphere, is added 0.36 g of 80% sodium hydride and the mixture is stirred for 20 minutes. A solution of 0.7 g of benzyl chloride in 1 ml of anhydrous dimethyl sulphoxide is then added dropwise over 5 minutes at the same temperature and, after stirring for 3 hours, the reaction mixture is poured into a mixture of 200 ml of distilled water, 80 g of ice and 6 ml of acetic acid. The insoluble material formed is removed by centrifugation and the supernatant solution is stored for 15 hours at a temperature in the region of 20° C. The insoluble product formed is isolated by filtration, washed twice with 10 ml in total of distilled water and with 5 ml of acetone, and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 80° C. 0.52 g of 10-acetamido-10-benzyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, melting at 325° C. (decomposition) (Analysis, % calculated C: 71.34, H: 4.90, N: 15.13, O: 8.64, % found C: 71.2, H: 4.5, N: 15.0).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][Br:5].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br-:5].[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)CCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 15.7 %

Procedure:
Reaction of 3-methylbutylbromide (6.4 g, 42.0 mmol) with triphenylphosphine (10.0 g, 40.0 mmol) following the procedure of 2c affords the title compound as a white solid (2.6 g). MS (m/e): 335 (M+H).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].Br[CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Na+].O>CS(C)=O>[CH2:20]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: CCCCC=CBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.5 %

Procedure:
Theobromine (11.9 g, 66 mmol, available from Sigma) was added to a mixture of bromohexene (10.7 g, 66 mmol, available from Aldrich) and sodium hydride (1.58 g, 66 mmol) in dimethylsulfoxide (100 ml) and the resulting mixture stirred for 43 hours. The solution was treated with water (200 ml) and then extracted with three 80 ml aliquots of dichloromethane. The combined extracts were washed with three 100 ml aliquots of water and dried over magnesium sulfate. The solvent was evaporated under vacuum, leaving 17 g of a white powder, 1-(5-hexenyl)-3,7-dimethylxanthine (65 mmol, 98% yield).
Reaction SMILES: C([Si](C(C)C)(C(C)C)N1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=C1)(C)C.[O:30]1C=CC=[C:31]1B(O)O>>[O:30]1[CH:31]=[CH:9][CH:8]=[C:7]1[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[CH:15]=1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Reactant: OB(O)c1ccco1
Product: CCOC(=O)c1cn2cc(-c3ccco3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with furan-2-boronic acid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH:13]([N:17]4[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=5)=[O:23])[CH2:18]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CC=C(c2ccc3nc[nH]c3c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4nc[nH]c4c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by hydrogenation of 4-(3H-benzoimidazol-5-yl)-cyclohex-3-enone (as prepared in the previous step) using the procedure described in Step C of Example 5 followed by reductive amination of the ketone with N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:15])=[CH:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH2:16][NH2:17]>CCO>[Cl:15][C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cc(Cl)nnc1NN
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of tert-butyl 3,6-dichloropyridazine-4-carboxylate (66A) (3.9 g, 15.6 mmol) in EtOH (20 mL) was added anhydrous hydrazine (2 mL). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The crude product was triturated with 80% EtOH in H2O to afford 1.58 g (40%) of the title compound as a yellow solid. HPLC/MS (Method B): retention time=1.77 min, [M+H]+=189.3.