Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[C:12](=[CH2:15])[CH2:13][CH2:14][C:3]=12.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C(O)(C)C>O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[CH:12]([CH2:15][N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])[CH2:13][CH2:14][C:3]=12
Reactant: C=C1CCc2c(C)c3ccccc3n2C1=O
Reactant: Cc1ncc[nH]1
Solvent: CC(C)O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cn1ccnc1C)CC2
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-methylenepyrido[1,2-a]indol-6(7H)-one (142 mg), 2-methylimidazole (180 mg), isopropyl alcohol (1 ml) and water (0.4 ml) was heated at 100° C. for 3 hours. The reaction mixture was purified by a procedure analogous to that of Example 74 to give 8,9-dihydro-10-methyl-7-[(2-methyl-1H-imidazol-1-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (60 mg).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:43])[C:41]=1[F:42]>>[CH3:9][CH:7]([CH3:8])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:38]2[CH:37]=[C:36]([F:35])[C:41]([F:42])=[C:40]([F:43])[CH:39]=2)[CH:15]=1)[C:4]([OH:3])=[O:34]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(F)c(F)c(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3,4,5-trifluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.92 (d, J=6.60 Hz, 6H), 1.50-1.58 (m, 1H), 1.70-1.78 (m, 1H), 2.01-2.15 (m, 1H), 3.75-3.81 (m, 1H), 7.18-7.25 (m, 2H), 7.46 (s, 1H), 7.52-7.58 (m, 2H), 7.63-7.73 (m, 4H); Calcd for C25H20F6O2 (M+Na) 489.42, Found 488.4.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[CH:9][CH:8]=1)[NH2:5].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27]([NH:5][C@H:4]([C:3]([OH:2])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[CH:9][CH:8]=1)=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COc1ccc(Br)c(C(=O)N[C@@H](Cc2ccc(-c3cn(C)c(=O)n(C)c3=O)cc2)C(=O)O)c1

Procedure:
N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-[1,3-dimethyl-2,4-dioxo-5-pyrimidinyl]-L-phenylalanine was prepared from 4-[1,3-dimethyl-2,4-dioxo-5-pyrimidinyl]-L-phenylalanine methyl ester and 2-bromo-5-methoxybenzoic acid using the general procedures described in example 2. EI-HRMS m/e calcd for C23H22N3O6Br (M+H) 516.0770, found 516.0780.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reaction time: 1.5 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (100 mg, 0.15 mmol) is dissolved and K2CO3 (230 mg) is suspended in DMF (30 mL). To the vigorously stirred reaction mixture a solution of 1-bromodecane (0.016 mL, 0.11 mmol) in DMF (10 mL) is added dropwise at 70° C. during 30 mins and the mixture is stirred for 1.5 h. After evaporation of solvent, the residue is dissolved in toluene:ethanol (1:1 by vol., ca. 3 mL) and purified by chromatography on a column (150 g) of silica gel (Merck 60) using toluene as eluent. After elution of the first 3 fractions, the column is eluted with toluene:ethyl acetate (2:1 by vol.) and the 5th fraction eluted is collected, the solvent removed and the residue dried under high vacuum to give the product as violet crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][C:24](=O)[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO.C(O)(=O)C>[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][CH:24]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[O:8])[CH2:3][CH2:2]3)[CH2:23]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(C1CCNCC1)N1CCOCC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCOCC1
Temperature: 120 °C
Yield: 83.2 %

Procedure:
4-(Piperidin-4-ylcarbonyl)morpholine (0.30 g, 1.26 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.30 g, 1.5 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.1 mL). (Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.38 g) was added and the reaction mixture was heated for 10 min at 120° C. using microwave single node heating. The mixture was filtered through a phase separator and the resin washed with methanol. The solvent was removed by evaporation and the residue was dissolved in methylene chloride. The solution washed twice with a saturated solution of NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol). There was obtained 0.44 g (83%) of 4-({1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 4H), 2.2 (m, 1H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 4H), 3.3-3.5 (m, 3H), 3.5-3.7 (m, 6H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 420 (M+1)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCBr)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A solution of 33 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 330 ml of dichloromethane is mixed at −5° C. with 28.9 g of triphenylphosphine and 36.7 g of carbon tetrabromide and stirred for 0.5 hour. Then, dichloromethane is added, and it is washed with water, saturated sodium bicarbonate and common salt solution. The organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. Then, the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. 28.5 g of 7α-(5-bromopentyl)-11β-fluor-estr-4-ene-3,17-dione with a melting point of 75-76° C. is obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]([C:5]1[NH:6][C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4].Cl.N[C:16]1NC=C(CCCC(NCCCCCCCCCCCC)=O)N=1>>[Cl:13][C:2]([Cl:1])([Cl:12])[C:3]([C:5]1[N:6]([CH3:16])[C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: CCCCCCCCCCCCNC(=O)CCCc1c[nH]c(N)n1
Reactant: O=C(c1cc(Br)c(Br)[nH]1)C(Cl)(Cl)Cl
Agent: Cl
Product: Cn1c(C(=O)C(Cl)(Cl)Cl)cc(Br)c1Br
Yield: 96 %

Procedure:
Using the same general procedure as used for the synthesis of 2,2,2-trichloro-1-(4,5-dibromo-1H-pyrrol-2-yl)-ethanone 8, 5.00 g of 2-trichloroacetyl-1-methylpyrrole 12 gave 8.14 g (96%) of the title compound 14 as white needles. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (s, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.86, 123.81, 122.68, 120.58, 99.58, 94.89, 37.60; HRMS (FAB) calcd for C7H4Br2Cl3NO (M+) 380.7725, found 380.7744.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[Cl:9].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:4]1[S:5][C:6]([Cl:8])=[CH:7][C:3]=1[CH2:2][S:17][C:15]1[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=1
Reactant: Clc1cc(CBr)c(Cl)s1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cc(Cl)sc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of 3-(bromomethyl)-2,5-dichlorothiophene (125 mg, 0.51 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (60 mg, 0.42 mmol), and triethylamine (180 μL, 1.3 mmol) in absolute ethanol (5 mL) was stirred at room temperature overnight. The mixture was recovered and evaporated. The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (1×15 mL), diethyl ether (2×15 mL), and hexanes (2×15 mL), and then dried in vacuo, affording 2-{[(2,5-dichlorothiophen-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (91 mg, 71% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.27 (s, 2H), 6.02 (s (br), 1H), 7.17 (s 1H); M+ 308.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@@H:8]2[OH:17])[CH2:4][O:3]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[O:6][CH:5]([CH:7]2[O:11][CH:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][CH:9]3[CH:8]2[O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1,2:5,6-Di-O-isopropylidene-α-D-allofuranose (30A) (obtained from Pfanstiehl Laboratories Inc.) (40 g) in dimethylformamide at 0° C. was added sodium hydride in smaller portions. The reaction mixture was stirred for 1 h, benzyl bromide was added drop wise over a period of 1 h. The reaction mixture was stirred at room temperature for 16 h. Methanol was added to quench the reaction and dimethylformamide was removed under pressure. The syrup was extracted with ethyl acetate and washed with brine. Evaporation of the ethyl acetate layer yielded a semisolid (93%). Homogeneous by TLC.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[CH2:13]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1)[CH3:14].[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:19][C:18]1[CH:22]=[CH:23][C:15]([CH2:13][CH3:14])=[CH:16][CH:17]=1)[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CCc1ccc(C[Mg]Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1ccc(CC)cc1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution (42) of (4-ethylbenzyl)magnesium chloride prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (10 mL), and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═9/1) to give 1,1-diethoxy-3-(4-ethylphenyl)propan-2-one (43) as a colorless oily substance (1.29 g, 5.04 mmol, 50.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])([O-])=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1(C)C=CC=CC=1.[Pd]>[C:15]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccccc1NC(C)=O
Yield: 83.8 %

Procedure:
Methyl (2-nitrophenyl)acetate (26.6 g, 0.14 mol) and acetic anhydride (51.5 ml, 0.55 mol) were subjected to catalytic hydrogenation for 15 hours in toluene (150 ml) in the presence of 10% Pd/C (53.2% wet, 4.5 g). The reaction mixture was filtered to remove therefrom the catalyst, followed by washing with toluene. The filtrate was distilled under reduced pressure to remove the solvent. The residue was crystallized by the addition thereto of n-hexane and diisopropyl ether. The crystals thus precipitated were collected by filtration, washed with n-hexane, and dried under reduced pressure to give methyl (2-acetamidophenyl)acetate (24.3 g, 84%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](=[N:5][OH:6])[Cl:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C=NO)c(F)c1I
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(Cl)=NO)c(F)c1I
Temperature: 55 °C

Procedure:
To a solution of 2-fluoro-3-iodo4-methylbenzaldehyde oxime (0.48 g, 1.7 mmol) in DMF (0.5 mL) was added N-chlorosuccinimide (83 mg, 0.62 mmol) and the mixture was heated at 55° C. for 5 min. The mixture was allowed to cool to <50° C., an additional N-chlorosuccinimide (166 mg, 1.24 mmol) was added, then it was heated at 55° C. for 10 min. The reaction mixture was allowed to cool to RT, treated with water (5 mL), and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine, dried and concentrated to afford the intermediate, 2-fluoro-3-iodo-4-methylbenzoyl chloride oxime as a light yellow amorphous solid, which was used without further purification. MS (ESI, pos. ion) m/z: 314.3 (M+1). Cyclopropylamine (0.60 mL, 8.6 mmol) was added dropwise to an ice-cold solution of the above obtained 2-fluoro-3-iodo-4-methylbenzoyl chloride oxime in anhydrous THF (2 mL). The reaction mixture was stirred at ambient for 3 h. The volatiles were removed under reduced pressure and the residue purified on a 40 g ISCO column (eluted with 25-60% ethyl acetate in Hexanes) to provide the title compound as an amorphous off-white solid. MS (ESI, pos. ion) m/z: 335.0 (M+1).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].S(Cl)(Cl)=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:14][CH:15]=1>>[Cl:9][C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][CH2:3][CH:2]=[CH2:1])=[O:21])=[N:14][CH:15]=1
Reactant: C=CCO
Reactant: O=C(O)CCC(=O)Nc1cnc(Cl)cn1
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)CCC(=O)Nc1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of prop-2-en-1-ol (2 mL) was added dropwise thionyl chloride (3 eq, 1.7 mmol). After 5 min, 4-[(5-chloropyrazin-2-yl)amino]-4-oxo-butanoic acid A6 (prepared as described before, 0.13 g, 0.57 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was washed with a saturated solution of sodium hydrogenocarbonete and dried on magnesium sulfate, then concentrated under vacuum. The residue was first washed with cyclohexane and the solid obtained was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give allyl 4-[(5-chloropyrazin-2-yl)amino]-4-oxo-butanoate A10 (37%). 1H NMR (400 MHz, CDCl3) 9.29 (s, 1H), 8.27 (s, 1H), 8.18 (bs, 1H), 5.92 (m, 1H), 5.29 (m, 2H), 4.62 (m, 2H), 2.80 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu](I)I.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 85 °C
Yield: 57.5 %

Procedure:
To a 3-L 4-neck flask equipped with mechanical stirrer, N2 inlet and thermocouple was added compound 1a (124 g, 0.71 mol), toluene (0.99 L), 4-fluoro-iodobenzene (cpd 3e, 314.27 g, 1.42 mol), racemic trans-N,N′-dimethylcyclohexane-1,2-diamine (cpd 3f, 30.2 g, 0.21 mol), copper iodide (13.48 g, 0.078 mol) and tribasic-N-hydrate potassium phosphate (330.54 g, 1.56 mol). The mixture was heated to 85° C. for 12 h. A second charge of 4-fluoro-iodobenzene (47.14 g, 0.21 mol) was added and the mixture was heated to 85° C. for 4 h. The reaction mixture was filtered through a diatomaceous earth pad and was washed with CH2Cl2 (2 L). The solvent was evaporated and the residue was purified by column chromatography (2.5 Kg Biotage SiO2 column, 15 column volumes, 10% EtOAc/Heptane) to give 110 g (58%) of compound 1c. 1H NMR (Chloroform-d) δ: 8.45 (d, J=1.5 Hz, 1H), 7.92 (dd, J=8.8, 1.5 Hz, 1H), 7.41-7.50 (m, 3H), 7.34 (d, J=3.2 Hz, 1H), 7.17-7.29 (m, 1H), 6.77 (d, J=3.4 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)[CH2:6][N:7](C)[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.Cl[CH2:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH3:51]>>[CH3:6][N:7]([CH2:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH3:51])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc2ccccc2c1CCl
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1c(C)ccc2ccccc12

Procedure:
The parent compound was obtained as a white solid in comparable yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 16, step d) using 1-chloromethyl-2-methylnaphthalene instead of 3,5-bis-trifluoromethyl-benzyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)C1CCNCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-piperidinecarboxylic acid ethyl ester (5.0 g) and 2-methoxyphenylboronic acid (5.0 g) in dichloromethane (100 ml) are added pyridine (12.9 ml), anhydrous copper (II) acetate (5.78 g) and Molecular sieves 4 Å (100 g), and the mixture is stirred at 25° C. for 2 days. The reaction solution is filtered, and the filtrate is poured into 10% aqueous citric acid solution, and the organic layer is washed successively with aqueous sodium hydrogen carbonate solution, and saturated brine. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient, 0% to 100% hexane/ethyl acetate) to give the title compound.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]2[NH:16][C:11]3[CH:10]=[C:9]([C:1]4[CH:2]=[C:3]([NH2:8])[C:4]([NH2:7])=[CH:5][CH:6]=4)[CH:14]=[CH:13][C:12]=3[N:15]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(-c2nc3ccc(-c4ccc(N)c(N)c4)cc3[nH]2)cc1
Temperature: 180 °C

Procedure:
Prepared by Method 2, using a 1:1 ratio of biphenyl-3,3′,4,4′-tetraamine to 4-methoxybenzaldehyde, and heating to 180° C. for 10 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:33]=[CH:32][C:23]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:32][CH:33]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-(4-bromobenzoyl)morpholine (Intermediate 174), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.C(N(CC)CC)C.Cl.Cl.[CH:46]1([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][CH2:47]1>ClCCl>[CH:46]1([N:49]2[CH2:54][CH2:53][N:52]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:51][CH2:50]2)[CH2:48][CH2:47]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C5CC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
100 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 205 mg triethylamine are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere 1-cyclopropylpiperazine dihydrochloride (184 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.