Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]N1C(C)(C)CCCC1(C)C.CC1CCCN(C)C1(C)C.CN(CCN(C)C)C.[Li]CCCC.[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[CH:48][C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:61][C:62]([F:68])([F:67])[C:63](OC)=[O:64]>C1COCC1>[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[C:48]([C:63](=[O:64])[C:62]([F:68])([F:67])[F:61])[C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)C(F)(F)F
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Agent: CC1CCCN(C)C1(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (154 mg, 1.10 mmol), TMEDA (127.8 mg, 1.10 mmol) and n-BuLi (0.688 mL, 1.10 mmol)] in THF (5 mL) was added to a cooled (−40° C.) stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.273 mmol) in THF(10 mL). The reaction was stirred for 1 h and then cooled to −78° C. Methyl trifluoroacetate (350 mg, 2.74 mmol) was added and stirring was continued for 2 h. The reaction was quenched carefully with water (50 mL), warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc gave 2-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-one (71 mg, 56%) as a light yellow solid: LCMS RT: 3.43 min, MH+: 462.3. The anion generated from LTMP deprotonation can be quenched with other electrophiles including carbon dioxide and 4-nitrophenyl acetate.
Reaction SMILES: [OH:1][C@H:2]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH2:17])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16].[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C@H:2]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH:17][C:27]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:34])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16]
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OC[C@H](O)CN2CCCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CCCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a slurry of N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.250 g, 0.70 mmol) and nicotinic acid (0.107 g, 0.87 mmol, 1.3 equiv.) in DMF (10 mL) was added PyBOP (0.452 g, 0.87 mmol, 1.3 equiv.) followed by diisopropylethylamine (0.48 mL, 2.78 mmol, 4.0 equiv.). The resulting mixture was stirred at room temperature. After a few hours the mixture turned to a clear solution. The resulting solution was stirred at room temperature for 24 h, then was concentrated under reduced pressure. The residue was separated between water (25 mL) and a 4:1 CH2Cl2/isopropanol solution (50 mL). The resulting organic phase was washed with a saturated sodium bicarbonate solution, dried (anh. sodium sulfate) and concentrated under reduced pressure. The resulting material (0.588 g) purified using MPLC to afford N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide (0.16 g, 50%): HPLC ret. time 1.00 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.83-1.93 (m, 2H), 1.93-2.05 (m, 2H), 3.04-3.15 (m, 2H), 3.29-3.34 (m, 2H), 3.53-3.62 (m, 2H), 4.03 (s, 3H), 4.20-4.32 (m, 5H), 4.53-4.60 (m, 2H), 7.48 (d, J=9.1 Hz), 7.88 (dd, J=5.6, 8.1 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.84, (br d, J=8.1 Hz, 1H), 8.94 (dd, J=1.5, 5.3 Hz, 1H), 9.47 (d, J=1.5 Hz, 1H); mass spectrum m/z 465 ((M+1)+, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:32]=1[CH2:33][NH2:34]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:34][CH2:33][C:32]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:31]=2[O:30][CH3:29])=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: COc1cccc(OC)c1CN
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CNC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
4-Bromo-2-nitrobenzoic acid (30.0 g, 118.3 mmol) was placed in 300 mL dichloromethane and 16.5 mL triethylamine was added. Then the reaction solution heated up and a change in color from yellow to greenish brown was observed. The mixture was then cooled to 5° C. and isobutyl chloroformate (16 mL, 118.3 mmol) was added by drops without dilution. The reaction mixture was allowed to come to room temperature while stirring and stirring was continued for 1.5 hours. The mixture was cooled again to 5° C. and 2,6-dimethoxybenzylamine (19.8 g, 118.3 mmol) was added by portions. Again 300 mL dichloromethane was added for dilution and stirring was continued for 15 minutes at 5° C. and then for 12 hours at room temperature. The clear reaction mixture ultimately changed color from red to brown and the reaction was monitored by thin-layer chromatography. The batch was extracted with water, the separated organic phase was extracted with 5% citric acid (2×), washed with sodium bicarbonate solution until neutral (1×) and extracted with saturated sodium chloride solution. The organic phase was dried over sodium sulfate, the solvent was removed in vacuo. The residue was dissolved in diethyl ether/pentane solvent and the precipitate which gradually formed therefore was ultimately filtered out. Crystalline 4-bromo-N-(2,6-dimethoxybenzyl)-2-nitrobenzamide was isolated. Yield: 35.4 g (89.6 mmol, 76%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.[CH3:28][C:29]([CH3:31])=[O:30]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:29]([OH:30])([CH3:31])[CH3:28])[NH:8]2)=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-(2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (2.76 gm) was cooled in THF to −78° C. A 2.5 M solution of n-BuLi in THF (1.5 eq) was added dropwise over 20 minutes. The reaction was stirred at −78° C. for 30 mins, after which acetone (1.56 mL) was added and the reaction was stirred over 2 hours, slowly warming to 0° C. The reaction mixture was then quenched with water and extracted with ethyl acetate. The crude product 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)propan-2-ol was concentrated and brought up in MeOH. The THP group was then removed via General Procedure D. The reaction mixture was concentrated and the crude solid was brought up in water, filtered and collected and dried overnight to give 2.23 gm of 2-(2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Br[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1>CC(N(C)C)=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: Nc1cc(O)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(Oc2ccc(C(F)(F)F)nc2)ccc1F
Temperature: 75 °C
Yield: 26.8 %

Procedure:
In DMA (8 mL) was placed 3-amino-4-fluorophenol (281 mg, 2.21 mmol), potassium t-butoxide (248 mg, 2.21 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (500 mg, 2.21 mmol). The mixture was warmed to 75° C. overnight, then cooled to RT and diluted with water (75 mL). The mixture was extracted with ethyl acetate (2×40 mL) and the combined organic phases washed with brine (40 mL), dried (Na2SO4), concentrated in vacuo and purified by column chromatography to yield 2-fluoro-5-(6-(trifluoromethyl)pyridin-3-yloxy)benzenamine (161 mg, 26% yield) as an oil which was used without further purification. MS (ESI) m/z: 273.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]2[CH2:44][CH2:43][CH2:42][C@H:38]2[C:39](O)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:39](=[O:40])[C@@H:38]3[CH2:42][CH2:43][CH2:44][N:37]3[S:34]([C:31]3[CH:32]=[CH:33][C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 15.8 %

Procedure:
Using the general method of Example 181 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (400 mg, 1.28 mmol) was reacted with N-(4-tert-butylphenylsulfonyl)-L-proline (477 mg, 1.53 mmol) to provide 123 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-1-[(4-tert-butylphenyl)sulfonyl]-L-prolinamide as a brown oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:16]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCCOCCO)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)OCCOCCOC(=O)c1ccccc1

Procedure:
2-Benzoyloxyethoxyethyl erucate was prepared by the procedure of Example 1 from 21 gms (0.1 mole) of diethylene glycol monobenzoate and 35.5 gms (0.1 mole) of erucoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: C([O:4][CH:5]1[CH:10]=[CH:9][CH2:8][N:7]([C:11](=[O:24])[C@@H:12]([CH:21]([CH3:23])[CH3:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6]1)(=O)C.[OH-].[Na+].C(O)(=O)C.C(Cl)(Cl)Cl>CCO>[C:14]([NH:13][C@@H:12]([C:11]([N:7]1[CH2:8][CH:9]=[CH:10][CH:5]([OH:4])[CH2:6]1)=[O:24])[CH:21]([CH3:23])[CH3:22])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(=O)OC1C=CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CC(O)C1

Procedure:
0.254 g of 3-acetoxy-N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridine, dissolved in 5 ml of EtOH are treated with 2N ethanolic NaOH under ice-cooling. To the mixture obtained acetic acid is added in order to neutralize the reaction mixture and solvent is evaporated. The evaporation residue obtained is mixed with CHCl3, the mixture obtained is washed with NaCl-solution, the organic phase is dried and solvent is evaporated. N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridin-3-ol is obtained. 1H-NMR: 5.9(m,2H,HIV, HV), 4.51, 4.45(2xdd,1H, NHCHCO,J=5.2 Hz,J=9.0 Hz), 1.4 (b,9H,(CH3)3), 0.9(m,6H,CH(CH3)2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Br)[CH:23]=1.C([O-])([O-])=O.[K+].[K+].N#N>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:22]4[CH:23]=[C:18]([NH2:17])[CH:19]=[N:20][CH:21]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: Fc1ccc(-c2ccn3ccnc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1cncc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Temperature: 120 °C

Procedure:
To 7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (0.1093 g, 0.52 mmol) and 3-amino-5-bromopyridine (0.181 g, 1.05 mmol) in DMF (2 mL) was added 0.5 M K2CO3 (2.06 mL, 1.03 mmol). The reaction vessel was purged with N2 and Pd(PPh3)4 (63 mg, 0.055 mmol) added. The vessel was further purged with N2 and then heated in the microwave at 120° C. for 30 mins. Further 3-amino-5-bromopyridine (0.13 g, 0.75 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were added and the reaction heated in the microwave at 140° C. for 1 hour. The solids were filtered and the filtrate was concentrated in vacuo. The residue was partitioned between H2O (20 ml) and EtOAc (2×20 mL). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo and the product used crude in the subsequent reaction.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:17]2[C:16](=[N:22]O)[CH2:15][C@@:14]2([CH3:24])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1>C(O)CC>[NH2:22][C@@H:16]1[CH2:15][C@@:14]2([CH3:24])[C@@H:8]([CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[C@H:7]2[C@H:17]1[C@:18]1([CH3:21])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([OH:1])[CH2:20][CH2:19]1
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=NO)C[C@]12C
Solvent: CCCO
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Yield: 39 %

Procedure:
A solution of (Z)-3α-hydroxy-5α-pregn-17(20)-en-11-one oxime (9.638 g) in propan-1-ol (200 ml) was refluxed under N2 whilst Na (9.6 g) was added portionwise. When all of the Na had reacted, about 90 ml propan-1-ol was distilled and then the residue was poured into water, ice was added and the crystalline solid (9.19 g) was collected by filtration. A portion (6.17 g) was crystallised from ethanol-water to afford title compound (3.6 g), m.p. 118°-125°, [α]D +5.4°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[C:10]([OH:12])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][O:38][C:39]([C@@H:41]1[CH2:52][C@:44]2([C:49]([CH3:51])([CH3:50])[C:45]32[CH2:48][CH2:47][CH2:46]3)[CH2:43][N:42]1[C:53](=[O:70])[C@@H:54]([NH:59][C:60](=[O:69])[C@@H:61]([NH2:68])[CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:37][O:38][C:39]([C@@H:41]1[CH2:52][C@:44]2([C:49]([CH3:50])([CH3:51])[C:45]32[CH2:48][CH2:47][CH2:46]3)[CH2:43][N:42]1[C:53](=[O:70])[C@@H:54]([NH:59][C:60](=[O:69])[C@H:61]([CH:62]1[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1)[NH:68][C:10]([C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][N:4]1[CH:1]([CH3:2])[CH3:3])=[O:12])[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:40]
Reactant: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](N)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Reactant: CC(C)N1CCCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CCCCN1C(C)C)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-1-isopropyl-piperidine-2-carboxylic acid (0.497 g; 2.90 mmol) and HATU (1.65 g; 4.35 mmol) in DCM (100 mL) was cooled to 0° C. and (5R,8S)-7-[(S)-2-((S)-2-Amino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid methyl ester (1.65 g; 2.90 mmol) and DIPEA (2.98 mL; 17.4 mmol) were added. The reaction mixture was stirred for 3 h at room temperature quenched with saturated aqueous bicarbonate. The aq. phase was extracted twice with DCM, the combined organic phases dried with Na2SO4, filtered and the solvent was removed in vacuo. The product was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=1.62 min; M/z=629 [M+]; HPLC (method A3): Rt=5.01 min
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C(N(CC)CC)C.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[C:23]=1[CH2:32][O:33][CH3:34])(=[O:21])=[O:20]>C(Cl)Cl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:23]([CH2:32][O:33][CH3:34])[C:24]=2[CH3:31])=[CH:3]1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)OC2=CC(=O)C3CCC2C3)c1C
Temperature: 0 °C
Yield: 101.6 %

Procedure:
0.8 g (5.8 mmols) of bicyclo[3.2.1]octan-2,4-dione (the preparation thereof is described for example in U.S. Pat. No. 5,608,101 and in the references cited therein) are dissolved in 15 ml of methylene chloride at 20° C. The solution is mixed with 0.97 ml of triethylamine and cooled to a temperature of 0° C. Then, a solution of 1.6 g (5.8 mmols) of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid chloride in 10 ml of methylene chloride is added dropwise. The reaction mixture is stirred for half an hour at a temperature of 0° C. and is subsequently diluted with methylene chloride. After washing and drying, the organic phase is concentrated by evaporation. 2.23 g of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl-ester is obtained in amorphous form. This can be used for the next step without purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product of Example 86A and 3-methyl-3-phenylbutanoic acid were treated as in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.39 (s, 1H), 8.39-8.44 (m, 1H), 7.88-8.02 (m, 2H), 7.70-7.77 (m, 1H), 7.63-7.67 (m, 2H), 7.60-7.63 (m, 2H), 7.42-7.46 (m, 2H), 7.28-7.34 (m, 2H), 7.15-7.21 (m, 1H), 2.62 (s, 2H), 1.47 (s, 6H); MS (APCI+) M/Z 432 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26](O)[CH3:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[Na+].[I-]>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=[CH2:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)oc4c(C(C)O)cccc34)c(C)nc12
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cccc2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
1-{3-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-benzofuran-7-yl}-ethanol (0.64 g, 1.63 mmol) is dissolved in CH2Cl2 (20 mL), treated with Et3N (0.27 mL, 1.95 mmol) and MsCl (0.14 mL, 1.79 mmol). The reaction is stirred at rt overnight. It is diluted with CH2Cl2 (40 mL), washed with H2O (2×40 mL); dried with Na2SO4; filtered and concentrated. The resulting crude material is dissolved in acetone (20 mL), refluxed with NaI (0.31 g, 2.04 mmol) overnight. The organic solvent is removed in vacuo, the residue is taken up with H2O (30 mL) and extracted with EtOAc (2×30 mL); the combined organic layers are dried with Na2SO4; filtered and concentrated. Purification of the crude material by chromatography gives the title compound (0.28 g, 0.75 mmol, 46%). 1H NMR (CDCl3): δ. 0.90 (t, J=7.0 Hz, 3H), 0.91 (t, J=7.0 Hz, 3H), 1.76-1.95 (m, 4H), 2.45 (s, 3H), 2.46 (s, 3H), 2.47 (s, 3H), 3.32-3.44 (m, 1H), 5.52 (dd, J=11.5, 1.3 Hz, 1H), 6.23 (dd, J=19.0, 1.3 Hz, 1H), 6.68 (s, 1H), 7.04 (dd, J=19.0, 11.5 Hz, 1H), 7.15 (d, J=1.3 Hz, 1H), 7.16 (s, 1H), 7.29 (t, J=4.8 Hz, 1H) ppm. ES-MS (m/z): calcd for C24H27N3O (M+H)+: 374.5. found: 374.2.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[CH2:23][CH:13]1[CH2:14][O:15][C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1>ClCCl>[O:12]1[CH2:23][CH:13]1[CH2:14][O:15][C:16]1[CH:17]=[N+:18]([O-:9])[C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: Cc1ccc(OCC2CO2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(OCC2CO2)c[n+]1[O-]
Reaction time: 0.5 h

Procedure:
A solution of 12.2 g of m-chloroperbenzoic acid in 100 ml of dichloromethane is added dropwise over the course of approx. 10 minutes, whilst stirring, to a solution of 10 g of crude 3-(2,3-epoxy-propoxy)-6-methyl-pyridine in 100 ml of dichloromethane, the temperature of the solution rising to 32° C. The reaction mixture is stirred for a further 30 minutes and is then extracted with 40 ml of saturated potassium bicarbonate solution, dried and evaporated in vacuo. 3-(2,3-Epoxy-propoxy)-6-methylpyridine-1-oxide, thus obtained, is used further in the crude state.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][C:7]1[CH:8]=[C:9]([F:13])[CH:10]=[CH:11][CH:12]=1>[Pd].C(O)C>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([F:13])[CH:10]=[CH:11][CH:12]=1
Reactant: FCCCC=Cc1cccc(F)c1
Agent: [Pd]
Solvent: CCO
Product: FCCCCCc1cccc(F)c1
Yield: 64.4 %

Procedure:
Then, 5% Pd—C 4 g and ethanol 100 ml were added to 3-(5-fluoro-1-pentenyl) fluorobenzene 86 g (472 mmol) to conduct a reaction of catalytic hydrogenation reduction. After the hydrogen absorption was stopped, the catalyst was filtered off, and the filtrate was distilled(62° C./2 mmHg) to obtain 3-(5-fluoropentyl) fluorobenzene 56 g. (Yield: 64.4%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1.BrC1C=CC=CC=1.COC(C)(C)C>CCCCCC>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:10]([C:4]2[C:3](=[O:15])[N:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[OH:9])=[O:12])=[N:18][CH:19]=1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Cc1ccc(N)nc1
Solvent: CCCCCC
Solvent: Brc1ccccc1
Solvent: COC(C)(C)C
Product: Cc1ccc(NC(=O)c2c(O)cc(C)n(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
214 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 101 mg of 2-amino-5-methylpyridine were added to 2.5 ml of bromobenzene and the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, and t-butyl methyl ether and n-hexane were added to the mixture. The resulting solid was collected by filtration, washed with t-butyl methyl ether and n-hexane, and dried to obtain N-(5-methyl-2-pyridyl)-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide