Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:30][CH2:29]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CN(C)CCOC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 28.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), N,N-dimethyl-2-(piperidin-4-yloxy)ethanamine (85) (0.116 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.087 g, 28.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.62-1.51 (1H, m), 1.84-1.66 (3H, m), 1.95-1.89 (1H, m), 2.28 (6H, s), 2.52 (2H, t), 3.15-3.01 (1H, m), 3.48-3.40 (1H, m), 3.62-3.51 (3H, m), 4.07-3.98 (1H, m), 4.27 (2H, s), 7.01 (1H, t), 7.32-7.25 (2H, m), 7.77-7.70 (3H, m), 8.47-8.45 (1H, m), 10.62 (1H, s); m/z (LC-MS, ESI+), RT=1.67 (M+H 452).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].C([O-])(O)=O.[Na+].C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]([NH:15][CH2:14][CH2:12][OH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Benzylchloroformate (44.95 kg, 263.5 mol, 1.0 eq.) was added over a 2 hour period at room temperature to a solution of ethanolamine (16.1 kg, 263.5 mol, 1.0 eq.) in water (34 gal). After stirring for 30 minutes, this was added to a cold (5-10° C.) solution of NaHCO3 (33.2 kg, 395.25 mol, 1.5 eq) in H2O (330 L) over a 30 min period and then allowed to stir at room temperature overnight. Ethyl acetate (22 gal) was added, the layers separated, and the aqueous layer extracted again with 22 gal. ethyl acetate. The combined organic extracts were concentrated under vacuum to a volume of 10 gal, and the remainder displaced with isopropyl ether. The resulting slurry was stirred and cooled to +10° C. for 2 hours, then filtered. The solids were washed with isopropyl ether and vacuum dried to give the title compound(39.1 kg, 71.1%). mp 61-63° C. NMR (300 MHz, d6 -DMSO): δ=7.50-7.37 (m, 5H), 7.37-7.16 (m, 1H), 5.05 (s, 2H), 4.70-4.63 (m, 1H), 3.46-3.37 (m, 2H), 3.13-3.03 (m, 2H).
Reaction SMILES: C[Si](C)(C)[I:3].[OH:6][CH2:7][C@@H:8]1[CH:23]=[C:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[N:10]([CH3:11])[CH2:9]1.O.N>CS(C)=O>[I:3][C:15]1[NH:16][C:17]2[C:24]3[C:14]=1[CH2:13][C@@H:12]1[C:22]([C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:23][C@@H:8]([CH2:7][OH:6])[CH2:9][N:10]1[CH3:11]
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: C[Si](C)(C)I
Agent: N
Solvent: CS(C)=O
Solvent: O
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(I)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2.3 g of trimethyliodosilane are portionwise added to 20 ml of dimethylsulfoxide and the mixture is stirred at room temperature for 5 minutes. Then, a solution of 1 g of lysergol in 15 ml of dimethylsulfoxide is added, the reaction mixture is stirred for 15 minutes, then poured into water and made alkaline by adding aqueous ammonia up to a pH value of 8 to 9. The precipitate is filtered off, wash 3 times with 20 ml of water each and dried to give the title compound in a yield of 1.1 g (0.002913, mole, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]=[CH:6][CH:7]([N:21]([C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:22])[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH:7]([N:21]([C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:36])([F:37])[F:35])[CH:25]=1)[CH3:22])[CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 15.0 g (27.3 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methylamino]-5,5-diphenyl-pent-2-enoic acid ethyl ester in 400 ml of tetrahydrofuran is hydrogenated with 1.5 g of 10% palladium on activated carbon under 1 atm. of hydrogen. After 4 hours the suspension is filtered over Hyflo and washed with tetrahydrofuran, and the filtrate is concentrated by evaporation. The title compound is obtained in the form of a yellow oil. TLC: ethyl acetate/hexane (1:2) Rf =0.50; Rt (HPLC)=22.4 min; 1H-NMR (400 MHz, d6 -DMSO, 120° C.) d 7.96 (br, 1H), 7.48-7.18 (m, 12H), 5.44 (br, 1H), 4.31 (d, 1H), 4.05 (q, 2H), 2.56 (br s, 3H), 2.44-2.27 (m, 2H), 1.93 (m, 1H), 1.76 (m, 1H), 1.17 (t, 3H); FAB-MS (M+H)+ =552.
Reaction SMILES: C([Li])CCC.CN(C)CCNC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>O1CCCC1.O>[Cl:23][C:16]1[C:15]([O:14][CH3:13])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc(C=O)c1
Agent: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C=O)c1Cl
Temperature: -70 °C
Reaction time: 2 h

Procedure:
At 40° C. n-butyl lithium (6.25 mL, 1.6 M in hexane) was added to a solution of N,N,N′-trimethylethylenediamine (1.27 mL) in 10 mL tetrahydrofuran. After 15 min. the reaction mixture was cooled to −70° C. and a solution of 3-methoxybenzaldehyde (1.22 mL) in 5 mL of tetrahydrofuran was added. The reaction mixture was allowed to warm to 0° C. and was cooled again to −70° C. and n-butyl lithium (6.25 mL, 1.6 M in hexane) was added. The reaction mixture was allowed to warm to 10° C. and was cooled again to −30° C. before it was added to a solution of hexachloroethane (7.10 g) in 10 mL tetrahydrofuran. The reaction mixture was stirred for 2 h. at room temperature, poured into 20 mL 10% HCl in water and extracted several times with ethyl acetate. The combined organic phases were washed with saturated brine, dried on MgSO4 and concentrated. The title product was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (75/25, v/v), Rf=0.38), followed by crystallisation from heptane.
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=C)=[CH:7][N:6]=1)([F:4])[CH3:3].N1C(C)=CC=CC=1C.C1C[O:24]CC1>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:24])=[CH:7][N:6]=1)([F:4])[CH3:3]
Reactant: C1CCOC1
Reactant: C=Cc1cnc(C(C)(F)F)nc1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC(F)(F)c1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
2-(1,1-difluoroethyl)-5-vinylpyrimidine (110 mg, 0.646 mmol) was dissolved in THF (5 ml) and water (2 ml). NaIO4 (571 mg, 2.67 mmol), 2,6-lutidine (143 mg, 0,155 ml, 1.3 mmol) and osmium tetraoxide (138 mg, 0.17 ml, 0.013 mmol, 0.078 molar in tBuOH) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. 1H NMR showed a mixture of aldehyde and lutidine, which was used directly in the next reaction, (166 mg, 42% yield, 28% pure). 1H NMR (CDCl3 500 MHz): δ 10.24 (s, 1H), 9.30 (s, 2H), 2.12 (t, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.O>C1COCC1>[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[CH:9][C:7]#[N:8])[CH2:21][CH2:20]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(=CC#N)CC1

Procedure:
9.36 g of K2CO3 and 8.89 ml of diethyl (cyanomethyl)phosphonate are placed in 12 ml of THF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen, and the mixture is left to react for 15 minutes at room temperature and then refluxed for 20 minutes. The resulting mixture is allowed to cool and 6.5 ml of 1-methyl-4-piperidone are added dropwise. This mixture is refluxed for 16 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 6.8 g of oil are obtained.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3].Br[CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(C2CCN(CCO)CC2)c1
Yield: 55.7 %

Procedure:
2.0 g (7.8 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 20 ml of N,N-dimethylformamide, and then 1.3 g (10.2 mmol) of 2-bromoethanol and 3.2 g (23.4 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 60° C. for 5 hours. The reaction mixture was combined with 100 ml of water and extracted with ethylacetate (70 ml×5), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% methanol/CH2Cl2) to obtain 1.14 g (yield 56%) of the title compound.
Reaction SMILES: OO.B(F)(F)F.CC[O:9]CC.OC([C:16]1[C:17]([CH3:41])=[C:18]2[C:23]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[C:22]([C:38]#[N:39])[CH:21]=[N:20][N:19]2[CH:40]=1)(C)C>C(Cl)Cl>[OH:9][C:16]1[C:17]([CH3:41])=[C:18]2[C:23]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:29][CH:30]=3)=[C:22]([C:38]#[N:39])[CH:21]=[N:20][N:19]2[CH:40]=1
Reactant: Cc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Solvent: ClCCl
Product: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a mixture of H2O2 (50% wt in H2O, 0.0115 mL, 0.20 mmol) and CH2Cl2 (2 mL) at −5° C. was added BF3.OEt2. The reaction was stirred at −5° C. for 40 min before a solution of compound 145 (56 mg, 0.14 mmol) in CH2Cl2 (3 mL) was added. The reaction was kept at −5° C. for 10 min and quenched with an aqueous solution of Na2SO3 (2 g, 10 mL). The reaction was diluted with CH2Cl2 and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL). The CH2Cl2 layers were combined and concentrated in vacuo to give a brown oil. This crude oil was purified by silica gel flash chromatography (eluted with 10% EtOAc/CH2Cl2) to give compound 146 as a yellow solid (32 mg, 64%). HPLC: 90% at 1.89 min (retention time) (Phenom-Prime S5 C18 column, 4.6×30 mm, eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at 220 nm). MS (ES): m/z 357 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]1)(=[O:27])=[O:26]
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1Cl)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 73.3 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55 mmol) with 2-chlorobenzene-1-sulfonyl chloride (382.2 mg, 1.555 mmol) was carried out according to a similar to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.35 mL, 7.775 mmol) as base. 1-[(2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 73.3% yield (481.8 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:4]2[C:5]([F:12])=[C:6]([F:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[C:3]=2[F:14])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(c2c(F)c(F)c([N+](=O)[O-])c(F)c2F)CC1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Pentafluoronitrobenzene (10 g, 46.9 mmol) is cooled to 0° C. and treated dropwise with 1-methylpiperazine (5.2 ml, 47 mmol) in triethylamine (14 ml, 94 mmol). After 30 minutes at 0° C., the reaction mixture is allowed to reach room temperature. After one hour, the orange suspension is diluted with water (100 ml) and extracted with ether (3×100 ml). The combined organic layers are washed with saturated aqueous sodium chloride solution (100 ml), dried with magnesium sulfate and evaporated. Recrystallization from n-hexane-ether (1:1) yields 10 g of 1-methyl-4-(2,3,5,6-tetrafluoro-4-nitrophenyl)piperazine as red-brown crystals (73%): mp: 77°-78° C.; NMR(CDCl3):2.35(s,3H),2.54 (m,4H),3.44(m,4H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1.CN([CH:24]=[O:25])C.OS(O)(=O)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:15]=1[CH:24]=[O:25]
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(Br)cccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To anhydrous THF (70 ml), diisopropylamine (8.3 ml, 59.34 mmol) was added and then n-BuLi (1.6 M, 59.34 mmol) was slowly added dropwise at 0° C. using a syringe in a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min, and the temperature thereof was cooled to −78° C. Subsequently, 1,3-dibromobenzene (7 g, 29.67 mmol) in THF (35 ml) was slowly added using a dropping funnel. The reaction mixture was stirred at −78° C. for 30 min, following the slow addition of DMF (4.6 ml, 59.34 mmol), and then continuously stirred for 1 hour. After the termination of the reaction, an aqueous solution of dilute H2SO4 was added, and the resulting solution was extracted two times with ethyl acetate, washed with a saturated NaCl solution, dried over anhydrous MgSO4, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=40:1), thus obtaining the title compound as a white solid (6.64 g, 25.16 mmol, 85%).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[Cl:9][C:10]1[N:15]=[N:14][C:13]2[CH2:16][CH2:17][NH:18][CH2:19][C:12]=2[CH:11]=1.[C:20]1([CH3:29])[C:21]([C:26](Cl)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C(O)C.CCOCC>[Cl:9][C:10]1[N:15]=[N:14][C:13]2[CH2:16][CH2:17][N:18]([C:26]([C:21]3[C:20]([CH3:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[CH2:19][C:12]=2[CH:11]=1
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccccc1C(=O)N1CCc2nnc(Cl)cc2C1

Procedure:
Produced in a manner analogous to that described in Example 8 (g), from 28.5 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 16.9 g of o-toluoyl chloride. Reaction time 24 hours. M.P. 123°-126° (decomp., from 95% ethanol/ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.CN1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)CCC1=O.BrC1C=NC=C(Br)C=1.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH:60]=[C:59](B2OC(C)(C)C(C)(C)O2)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>>[C:49]([O:53][C:54]([N:56]1[CH2:57][CH:58]=[C:59]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]4)[CH:3]=2)[CH2:60][CH2:61]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CN1C(=O)CCc2cc(-c3cncc(Br)c3)ccc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Brc1cncc(Br)c1
Agent: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(C4=CCN(C(=O)OC(C)(C)C)CC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 6-(5-bromo-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (prepared from 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) and 3,5-dibromo pyridine also with a procedure as used for the preparation of example 45) has been coupled to 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester to give the title compound as light yellow amorphous solid. MS: 420.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:24][C:22]1[N:23]=[C:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[S:20][CH:21]=1
Reactant: Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 20 h

Procedure:
To a round-bottomed flask containing 2-(1-tert-butoxycarbonyl-piperazin-4-yl)-acetic acid×2HCl (0.100 g, 0.36 mmol) was added 2-amino-4-methylthiazole (0.045 g, 0.39 mmol) and anhydrous dichloromethane (4 ml). The reaction mixture was cooled into an ice-bath under argon, and then diisopropylethylamine (0.139 g, 1.08 mmol) was added followed by PyBOP (0.187 g, 0.36 mmol). The ice-bath was removed and the reaction mixture was allowed to stir for 20 h under argon. The solvent was removed in vacuo, the residue was absorbed on silica gel and the free running powder was placed on a 20 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane and then 60% ethyl acetate in dichloromethane. The title compound was obtained as a gummy material (0.076 g, 62%). 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.25 (s, 3H, CH3), 2.45 (br s, 4H, piperazine N(CH2)2), 3.27 (s, 2H, NCH2CO), 6.76 (s, 1H, thiazole 5-H), 11.78 (s, 1H, CONH);
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[NH:10][CH:9]=[C:8]([C:11]([OH:13])=O)[C:7](=[O:14])[N:6]2[CH:15]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.N1C=CC=CC=1.[NH2:40][C:41]1[C:42]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:43][C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])=[C:45]([OH:47])[CH:46]=1>CC1CCCO1>[C:52]([C:42]1[CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([OH:47])=[CH:46][C:41]=1[NH:40][C:11]([C:8]1[C:7](=[O:14])[N:6]2[CH:15]=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[NH:10][CH:9]=1)=[O:13])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)cc1N
Reactant: CCc1cc2[nH]cc(C(=O)O)c(=O)n2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: CCc1cc2[nH]cc(C(=O)Nc3cc(O)c(C(C)(C)C)cc3C(C)(C)C)c(=O)n2c1
Temperature: 45 °C

Procedure:
To a solution of 7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxylic acid (32.3 mg, 0.1566 mmol) in 2-methyltetrahydrofuran (400 μL) was added 1-Propanephosphonic acid cyclic anhydride (249.1 mg, 233.0 μL, 0.3915 mmol) followed by the addition of pyridine (24.77 mg, 25.33 μL, 0.3132 mmol). The reaction was sealed and heated at 45° C. for 30 minutes upon which 5-amino-2,4-di-tert-butylphenol (41.59 mg, 0.1879 mmol) was added and the reaction was heated at 45° C. for 16 h. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC (40-100% acetonitrile with 0.035% TFA in water with 0.05% TFA) to give N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxamide. LC/MS (10-99% CH3CN/0.05% TFA in H2O/0.05% TFA gradient over 3 min): M+H m/z 410.5, retention time 2.24 minutes. 1H NMR (400.0 MHz, DMSO) δ 13.07 (d, J=6.6 Hz, 1H), 10.72 (s, 1H), 9.20 (s, 1H), 8.55 (d, J=6.8 Hz, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 6.11 (d, J=1.7 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H), 1.36 (s, 18H) and 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:3]=1.C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C.BrC1C=C([F:65])C=CC=1S(NC1C(C(OC)=O)=C2C(C3C(F)=COC=3CO2)=CC=1)(=O)=O>>[CH2:36]([N:32]([CH2:33][CH3:34])[CH2:31]/[CH:30]=[CH:29]\[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]2[C:15]([C:16]3[C:28]([F:65])=[CH:27][O:26][C:17]=3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:9])=[O:10])[CH3:35]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occ(F)c1-2
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCc1occc1-2
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occ(F)c1-2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 53, starting from N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3) and methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1-fluoro-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 97).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)C(Cl)=O)([O-])=O.[CH2:13]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])N)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21](=[O:25])[C@H:22]([C:11]1[CH:10]=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=1)[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Product: C[C@H](C(=O)OCc1ccccc1)c1cccc(N)c1

Procedure:
3-Nitrobenzoyl chloride was reacted with L-alanine benzyl ester, then reduced with aluminium amalgam to produce (S)-2-(3-amino-phenyl)-propionic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 11.96 (1H, br s), 9.46 (1H, br s), 8.57 (1H, br d), 8.16 (1H, s), 7.95 (1H, m), 7.54 (1H, d), 7.40-7.35 (1H, m), 4.40 (1H, m), 2.87 (2H, m), 2.63 (1H, m), 1.94-1.32 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 58.89; H, 8.28; N, 8.97%. C39H59N4O9.3.0 mols H2O requires: C, 58.85; H, 8.23; N, 8.86%.