Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:2]([C:18]([NH:20][C@H:21]([C:34]([NH:36][C@H:37]([C:53]([O:55][CH3:56])=[O:54])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42]C(OCC1C=CC=CC=1)=O)=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O>CO.C(Cl)Cl.[Pd]>[NH:1]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:2]([C:18]([NH:20][C@H:21]([C:34]([NH:36][C@H:37]([C:53]([O:55][CH3:56])=[O:54])[CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of 12 (0.88 g, 0.99 mmol) in MeOH (25 mL) and DCM (25 mL), was added Pd/C (0.20 g). This solution was flushed with H2 for 30 min. and then fitted with an H2 balloon. The reaction was allowed to proceed for 8 h at which time the mixture was filtered through celite, and conc. in vacuo to yield pure clear product 13 (0.622 g, quantitative): 1H NMR (500 MHz, d6 DMSO) δ 8.42 (br s, 1H), 8.16 (br s, 4H), 7.92 (br s, 1H), 6.92 (br s, 1H), 6.74 (br s, 1H), 4.27 (br s, 1H), 4.20 (br s, 1H), 3.89 (br s, 1H), 3.62 (s, 3H), 3.46 (br s, 3H), 2.87-2.73 (m, 5H), 2.52 (s, 1H), 1.80-1.45 (br s, 10H), 1.45-1.15 (m, 22H); 13C NMR (125 MHz, d6 DMSO) δ 173.2, 172.8, 156.4, 156.2, 78.94, 78.19, 54.91, 53.1, 52.7, 52.6, 39.3, 39.2, 32.8, 32.0, 30.9, 29.1, 29.1, 27.3, 27.2, 23.2, 23.1. HRMS (FAB) m/z calcd for C29H56N6O8 (M+H)+ 617.4238, found 617.4236.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)([O-:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N+:14]([O-:16])=[O:15])[CH:5]=[O:6]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: CCOc1cc(C=O)cc(Br)c1OCc1ccccc1[N+](=O)[O-]

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (5 g) with 2-nitrobenzylbromide (4.85 g) was performed according to the method described in example 1a. Yield: 7.88 g. MS-ESI: [M+H]+=380/382
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]#[N:35])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]#[N:35])=[CH:28][CH:27]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC1(C)OB(c2ccc(CCC#N)cc2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCC#N)cc1
Yield: 68.3 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (400 mg, 1.3 mmol) was reacted with 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanenitrile (600 mg, 1.9 mmol) to afford the desired product (320 mg, 69%) as a brown solid: ESI MS m/z 361 [C21H16N2O2S+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH2:21]2)[C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[O:31][C:32]=3[CH3:33])[CH2:21]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)OCc4ccccc4)C3)c(C)o2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1
Yield: 42 %

Procedure:
from benzyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexyloxymethyl]benzoate: 15 g (27.8 mmol) of benzyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoate are dissolved in 300 ml of THF. 700 mg of palladium on carbon (5%) are added. Subsequently, hydrogenation is effected at standard pressure and RT until no more hydrogen is taken up. The reaction mixture is filtered and the organic phase is subsequently concentrated fully under reduced pressure. The residue is taken up in 150 ml of tert-butyl methyl ether, 150 ml of water and 150 ml of saturated sodium hydrogencarbonate solution. After phase separation, the aqueous phase is washed with 150 ml of tert-butyl methyl ether. Subsequently, 150 ml of diisopropyl ether are added and the mixture is acidified with concentrated hydrochloric acid. After phase separation, the organic phase is washed four times with 100 ml each time of water and then concentrated fully under reduced pressure. The residue is stirred with a little diisopropyl ether. The solid is filtered and dried under reduced pressure. 2-methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-oxymethyl]benzoic acid is obtained in 42% yield as a crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>O1CCOCC1.O>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3ccco3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 74 mg, 0.2 mmol) in dioxane/water (10:1, 4.4 mL) was degassed for 20 min and then added to a reaction vial containing potassium carbonate (82 mg, 0.6 mmol) and furan-2-boronic acid (0.6 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was degassed for a further 2 min and then bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 14 mg, 0.02 mmol) was added. The mixture was degassed for 30 seconds and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), dimethylacetamide (1 mL), and 20% methanol in dichloromethane (1 mL). The filtrate was placed in a vial and 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl was added until a solid formed (approxiamtely 2 mL). The vial was centrifuged and the solvent was removed. The product was dried overnight in the oven. Mass spectrum MH+=295.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].C([BH3-])#N.[Na+].Cl>CCO.CCOCC>[ClH:1].[CH3:31][CH:30]([NH:33][CH:26]1[CH2:27][CH2:28][N:23]([C:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[CH:12][N:11]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:24][CH2:25]1)[CH3:32]
Reactant: O=C1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
1-[(4-{[4-(4-chlorophenyl)pyrimidin-2yl]amino}phenyl)carbonyl]piperidin-4-one (400 mg, 0.980 mmol) was dissolved in 10 mL EtOH along with isopropylamine (58 mg, 0.980 mmol). Sodium cyanoborohydride (62 mg, 0.986 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water, extracted with ethyl acetate followed by flash chromatography (EtOAc/MeOH; 90:10) to give a residue. This was taken up in ETOH saturated with HCl(g), diluted with ether, filtered to give 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl 4-[(methylethyl)amino]piperidyl ketone hydrochloride (0.150 g, 30% yield): HPLC Retention time; 6.02 min. (Method B) M+1; 450.4.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]2)=[CH:52][N:51]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:51]=[CH:52][C:53]([O:56][CH2:57][C:58]5([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]5)=[CH:54][N:55]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: CC1(COc2cnc(Cl)nc2)COC(C)(C)OC1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCNCC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(OCC6(C)COC(C)(C)OC6)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 120 °C
Reaction time: 26 h
Yield: 92.1 %

Procedure:
To 377 mg (0.559 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 127 mg (0.466 mmol) of 2-chloro-5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine, which was prepared by a method similar to that of Reference Example 17, and 154 mg (1.11 mmol) of potassium carbonate, 1 ml of 1,4-dioxane was added, and the reaction mixture was stirred at 120° C. for 26 hours. After completion of the reaction, water was added to the reaction solution and the reaction solution was extracted with ethyl acetate twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=89/11-68/32 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 391 mg of the title compound as a foam (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Methyl 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10a) (3.7 g, 8.3 mmol) was dissolved in MeOH/THF (1:1.5, 30 mL) and treated with aqueous NaOH (3 N, 15 mL). The mixture was stirred at ambient temperature overnight, then MeOH and THF were removed in vacuo. The resulting aqueous solution was acidified with 6 N aq HCl to a pH of ˜3 and extracted with EtOAc (3×40 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by recrystallization from EtOH to afford pure 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (2.1 g, 58.6%). MS (M−H, 428.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.23 (s, 2H), 4.26 (s, 2H), 6.72 (d, 2H, J=8 Hz), 6.95 (m, 6H), 7.92 (d, 2H J=8 Hz), 8.07(d, 2H, J=8 Hz). The compound had an IC50 on hT2R14 bitter receptor of 1.97 μM.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:33][NH:32][CH2:31][C@@H:30]1[OH:34].CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:32]3[CH2:31][C@H:30]([OH:34])[C@@H:29]([N:28]([CH3:35])[CH3:27])[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@@H]1O
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 63 mg, 0.156 mmol), (3S,4S)-4-(dimethylamino) pyrrolidin-3-ol (50.8 mg, 0.250 mmol) and DIPEA (0.191 mL, 1.094 mmol) and iPrOH (1 mL) in a sealed vial was heated at 110° C. for 4 h The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 4-EP, isocratic 25% in 15 min) followed by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white foam. HPLC (Condition 7) tR=5.71 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=493 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.95-3.03 (m, 1H) 3.16-3.26 (m, 2H) 3.34-3.46 (m, 2H) 4.00-4.13 (m, 1H) 4.97-5.13 (m, 1H) 6.33-6.45 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, J=9.40 Hz, 3H) 8.04 (s, 1H) 8.68-8.81 (m, 1H) 10.20 (s, 1H) 12.88-13.16 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(tetrahydro-furan-3-ylmethoxy)-nicotinic acid (example CK) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane (+) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 483.1038 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[C:21]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at room temperature, solid K2CO3 (30 mmol) was added followed by addition of 4-hydroxybiphenyl (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to room temperature to room temperature, the reaction mixture was poured into EtOAc (100 mL), washed with water (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuo to afford the desired 4-(biphenyl-4-oxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[C:24]1([CH:30]([OH:34])[CH2:31][C:32]#[CH:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:33]#[C:32][CH2:31][CH:30]([OH:34])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Reactant: C#CCC(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3ccccc3)oc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dlhydrofuro[2,3-b]-pyridine-5-carboxamide (Example 79, 0.593 g) was suspended in a mixture of triethylamine (15 mL) and DMF (3 mL). CuI (0.029 g), Pd(PPh3)2Cl2 (0.105 g), and then 1-phenyl-3-butyn-1-ol (0.36 mL) were added. The reaction mixture was stirred at room temperature for 20 min and then was partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with a sat. aq. ammonium chloride solution (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from methanol to yield 0.275 g of the title compound as a yellow solid. Physical characteristics. M.p. 202-203° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.50, 8.58, 7.44-7.25, 7.15, 5.73, 4.85-4.81, 4.55, 3.91, 2.89; MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH2:27][CH2:26]3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1>ClCCl.C(N(CC)CC)C>[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([CH:25]3[CH2:26][CH2:27][CH:28]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:36][CH2:37][N:38]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:39][CH2:40]4)[CH2:29][CH2:30]3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.57 mg, 0.005 mmol) in dichloro-methane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=557.4
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](O)[CH3:22]>>[CH2:21]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([OH:9])[CH2:3][C:1]#[N:2])[CH3:22]
Reactant: CCO
Reactant: N#CC[C@@H](O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CC#N
Yield: 90 %

Procedure:
(R)-4-cyano-3-hydroxybutyric acid (1.0 mol) in ethanol (500 ml) and conc. sulfuric acid (5 g) were refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate ancd filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid ethyl ester (141 g, 90%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:7]=1[Cl:8].O.[NH2:17][NH2:18]>C(O)C(C)C>[Cl:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:5][N:4]=[N:3][C:2]=1[NH:17][NH2:18]
Reactant: Clc1ccc(-c2cnnc(Cl)c2Cl)cc1
Reactant: NN
Solvent: CC(C)CO
Solvent: O
Product: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
3,4-Dichloro-5-(4-chlorophenyl)-pyridazine (6.0 g, 23.1 mmol) was suspended in isobutanol (150 mL) at 0° C. and hydrazine monohydrate (11.1 g) was added dropwise over 10 min. The reaction mixture was slowly warmed up to RT and stirred for 24 h. The mixture was cooled in an ice/water bath for 15 min and filtered. The white solid thus obtained was washed with cold isopropanol and dried to give the title compound, 1-[4-chloro-5-(4-chloro-phenyl)-pyridazin-3-yl]-hydrazine, (5.0 g) as a white solid. HPLC: 1.65 min.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[N:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:9]1[N:10]=[N:11][C:12]([Cl:14])=[CH:13][C:8]=1[N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1
Reactant: C1=CCNCC1
Reactant: Clc1cc(Br)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(N2CC=CCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
1,2,3,6-Tetrahydropyridine, (1.04 ml) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (2.0 g, 8.8 mmol) and potassium carbonate (2.4 g) in dry DMF (10 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 5 hours. The reaction was poured into water (100 ml) and extracted with ethyl acetate (×3). The combined extracts were washed with water (200 ml), brine, dried (MgSO4), filtered and evaporated. The residue was triturated with ether/petroleum ether to afford a white powder (1.96 g, 97%). 1H NMR (250 MHz, CDCl3) 6.82 (1H, s), 5.97 (1H, m), 5.80 (1H, m), 3.77 (2H, m), 3.59 (2H, m), 2.38 (2H, m). MS (ES+) 232 [MH]+.