Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)CCCCCCC1(C2C=CC(O)=CC=2)C=CC(C([O-])=O)=CC1.[CH:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37]([Cl:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1C(Cl)=O>C(N(CC)CC)C>[CH:32]1[C:31]2[C:36](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:35]=[CH:34][C:33]=1[C:37]([Cl:39])=[O:38]
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Agent: O=C([O-])C1=CCC(CCCCCCC(F)(F)F)(c2ccc(O)cc2)C=C1
Solvent: CCN(CC)CC
Product: O=C(Cl)c1ccc2ccccc2c1

Procedure:
The compound (III) is reacted with 2,6-naphthalene-dicarboxylic acid dichloride in the presence of triethyl amine to obtain 6-[3-trifluoromethylheptyloxycarbonyl)-biphenyl-4-oxycarbonyl]-naphthalene-2-carboxylic acid chloride (IV).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[CH3:27]>C1COCC1.CO.[Pt](=O)=O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH3:27]
Reactant: Cc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)ccc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-fluoro-3-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (256 mg) in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN/IPE to give the title compound (169.3 mg) as colorless crystals.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]([F:25])([F:24])[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)=[O:14].N>>[F:11][C:12]([F:25])([F:24])[C:13]([OH:1])=[O:14].[F:24][C:12]([F:11])([F:25])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:19]2[O:21][N:10]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:2]=2)=[CH:22][CH:23]=1)=[O:14]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)cc1
Agent: N
Product: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2nc(-c3cccnc3)no2)cc1)C(F)(F)F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-(2,2,2-trifluoroacetyl)benzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.81 (ddd, J=7.9, 5.2, 0.8 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 8.28 (d, J=8.7 Hz, 2H), 8.76 (dt, J=8.2, 1.8 Hz, 1H), 8.82 (dd, J=5.2, 1.6 Hz, 1H), 9.38 (d, J=1.6 Hz, 1H) ppm; MS (DCl/NH3) m/z 320 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:16]O>>[OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH:6]([CH3:11])[CH2:7][C:8]([O:10][CH3:16])=[O:9])=[O:5]
Reactant: CO
Reactant: CC(CC(=O)O)C(=O)c1ccccc1O
Product: COC(=O)CC(C)C(=O)c1ccccc1O
Yield: 94 %

Procedure:
3-(2-Hydroxybenzoyl)butyric acid (4.0 g, 0.02 mole) was esterified in methanol in a similar manner to that described in Example 4(i) to give methyl 3-(2-hydroxybenzoyl)butyrate (4.0 g, 94%) as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].C(N(CC)C(C)C)(C)C.[CH2:24]([O:31][C:32](ON1C(=O)CCC1=O)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:24]([O:31][C:32]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(CN)cc1O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Methyl 4-aminomethylsalicylate hydrochloride (5.04 g 23.2 mmoles) was suspended in chloroform (80 mL) and N,N-diisopropylethylamine (4.10 mL, 23.5 mmoles) and N-(benzyloxycarbonyloxy)succinimide (6.48 g, 26.0 mmoles) were added. The reaction mixture was stirred at room temperature for 4 hours, during which time all solids dissolved. The reaction mixture was then extracted with 1N aqueous hydrochloric acid (100 mL), water (75 mL), and saturated aqueous sodium chloride (50 mL). The chloroform solution was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give a white solid. The product was crystallized from ethyl acetate:hexanes to afford 6.17 g (84% yield) of methyl N-(benzyloxycarbonyl)-4-aminomethylsalicylate (m.p. 91°-92° C., open capillary, uncorrected).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].[Cl-].[NH4+].CN(C)[CH2:21][CH2:22]N(C)C>N1C=CC=CC=1>[CH3:13][CH:12]([CH2:11][CH2:10][CH2:9][CH:21]([CH3:22])[CH2:7][CH2:6][CH2:5][C:2]([CH3:1])([OH:16])[C:3]#[C:4][C:4]#[C:3][C:2]([CH3:1])([OH:16])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH3:14]
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)(O)C#CC#CC(C)(O)CCCC(C)CCCC(C)C
Yield: 81.8 %

Procedure:
In a 1-l. three-necked and round-bottomed flask were placed 10.5 g of 3,7,11-trimethyldodeca-l-yne-3ol, 5.0 g of ammonium chloride, 12.0 g of tetramethylethylenediamine and 675 ml of pyridine. The mixture was reacted at temperatures of 50° - 55°C for 6 hours under an oxygen atmosphere. After completion of the reaction, the alcohol as a starting material was not detected. After distillation of pyridine from the reaction mixture, 300 ml of benzene and 200 ml of water were added to the residue and after decantation, the organic layer was washed with 3N--H2SO4 and then water and dried. The benzene solution was distilled off to give 8.55 g of 2,6,10,15,19,23-hexamethyltetracosa-11,13-diyne-10,15-diol as viscous liquid. This compound was treated with active carbon and purified in the same manner as in reference 1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12](OC(OCC)OCC)C.O1CCOCC1.C([O-])(O)=O.[Na+]>CN1CCCC1=O.O>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc(Cl)cc1N
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]cnc2cc(Cl)ccc12
Temperature: 110 °C

Procedure:
To a solution of 2-amino-4-chlorobenzamide (58 g, 0.34 mol) in hot (60° C.) N-methylpyrrolidone (170 mL), triethylorthoformate (151 g, 1.02 mol, 3 equiv) and a 1,4-dioxane 5N HCl solution (ca. 15 mL) were added. The resulting solution was heated at 110° C. for 18 h. Then, the mixture was cooled to room temperature, was poured over cold water and was brought to pH 7 with saturated NaHCO3 solution. The formed precipitate was filtered, washed with water and dried to give the desired product as a slightly beige solid (58 g, 94%).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[NH2:21][C@@H:22]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=1)[C@H:23]([OH:35])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH3:34])[CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:43][C:41]1[CH:42]=[C:37]([CH:38]=[C:39]([F:44])[CH:40]=1)[CH2:36][C@H:22]([NH:21][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:1][CH2:2][CH3:3])[CH2:18][CH2:19][CH3:20])=[CH:10][CH:11]=1)=[O:17])[C@H:23]([OH:35])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH3:34])[CH:28]=1
Reactant: CCCN(CCC)c1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)c1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a stirred solution of 1-(dipropylamino)isoquinoline-7-carboxylic acid (103 mg, 0.38 mmol), (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (154 mg, 0.38 mmol), HOBt (77 mg, 0.57 mmol), and DIPEA (0.2 mL, 1.1 mmol) in methylene chloride (4 mL) was added HATU (216 mg, 0.57 mmol). The reaction mixture was stirred overnight and then partitioned between methylene chloride and 1 N hydrochloric acid. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9:1 chloroform/methanol) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1-(dipropylamino)isoquinoline-7-carboxamide (70 mg): mp: 142–151° C.; APCI MS m/z 589 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][CH:10]=[C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cc(Cn3cc(N)cn3)cs2)OCCO1
Product: CC(=O)c1cc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)cs1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=393.24.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:6]1[CH2:7][CH2:8][C@H:9]2[O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)(=O)[CH3:2].[N-:42]=[N+:43]=[N-:44].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:13]([N:12]1[C@@H:6]2[C@H:5]([N:4]3[C:1]([CH3:2])=[N:44][N:43]=[N:42]3)[CH2:11][C@@:10]1([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:31]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:33]=1)[CH2:8][CH2:7]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnnn1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
(1R*,2R*,5S*,6R*)-6-Acetamido-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 109; 384 mg, 0.67 mmol) and sodium azide in dichloromethane (10 ml) were cooled to 0° C. and trifluoromethanesulphonic anhydride (0.11 ml, 0.67 mmol) added. The reaction was warmed to room temperature and stirred for 3 hours then quenched with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (×3). The organics were dried (MgSO4) and concentrated in vacuo to give a brown solid. This was purified by flash column chromatography [2.5% methanol in dichloromethane] to give the title compound as a cream-coloured solid (134 mg, 34%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][N:20]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(Oc3ccc(C(N)=O)cn3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2cccc3c2CNCC3)nc1
Reaction time: 12 h
Yield: 57.4 %

Procedure:
Combine 8-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (249.6 mg, 1.01 mmol), CH2Cl2 (25 ml), and TFA (10 ml) at room temperature under nitrogen atmosphere. After the reaction stirs for 12 hours then concentrate under reduced pressure. Solubolize the mixture in MeOH and add to a 2 g SCX Column (pre-treated with 5% AcOH-MeOH), wash several times with MeOH, and elute the product with 1N NH3MeOH to afford 156.1 mg, 0.58 mmol (57% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13]([C:15](OCC)=[O:16])[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:16][CH2:15][C:13]1[N:14]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 6 h
Yield: 40.5 %

Procedure:
To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)picolinate 79 (11.0 g, 33 mmol) in THF (120 mL) under nitrogen was added LiAlH4 (3.80 g, 100 mmol) in THF (60 mL) over a period of 30 min at 0° C. The reaction mixture was stirred at 0° C. for 6 h and carefully quenched by the addition of H2O (2.0 mL) and 10% NaOH solution (4.0 mL) at 0° C. The reaction mixture was filtered and the filtrate was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue purified by chromatography (1:1 petroleum ether:ethyl acetate) to afford 80 (3.0 g, 41% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[C:3]1=[O:12].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([Pb+3])=[C:33]([CH2:38][CH3:39])[CH:32]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:6]2[C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[C:3](=[O:12])[C:2]([CH3:13])([CH3:1])[C:7]2=[O:8])=[C:33]([CH2:38][CH3:39])[CH:32]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 80 °C
Yield: 35.5 %

Procedure:
2,2,6,6-Tetramethylcyclohexane-1,3,5-trione (5 g, 0.027 mol) and 4-dimethylamino-pyridine (16.47 g, 0.135 mol) are added to a mixture of chloroform (100 ml) and toluene (25 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (17.16 g, 0.03 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The organic phase is collected, and the aqueous phase is extracted with dichloromethane (2×75 ml). the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethyl-cyclohexane-1,3,5-trione as a white solid (3.5 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: Oc1cccc(I)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Ic1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
The solution of 3-iodophenol (70.31 g), PPTS (750 mg) and 3,4-dihydro-2H-pyran (55.68 g) in CH2Cl2 (400 mL) was refluxed under N2 for 3 h. TLC of the reaction solution indicated the presence of starting material, 3-iodophenol. Consequently, more 3,4-dihydro-2H-pyran (30 mL) and PPTS (350 mg) were added to the reaction solution. The reaction was refluxed for another 3 h. After being cooled to room temperature, the reaction solution was washed by saturated NaHCO3 (100 mL×2), H2O (120 mL×3) and brine (120 mL×1), dried by Na2SO4 and concentrated to give crude product, which was purified to give pure 2-(3-Iodo-phenoxy)-tetrahydro-pyran (89.5 g; 92%). 1H NMR (300 MHz, CDCl3) □ 7.42 (m, 1H), 7.31 (m, 1H), 7.00 (m, 2H), 5.39 (dd, 1H, J=3.0, 3.0 Hz), 3.87 (m, 1H), 3.61 (m, 1H), 1.97 (m, 1H), 1.84 (m, 2H), 1.65 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C.C(Cl)Cl>[CH2:16]([C:7]1([CH2:10][CH2:11][CH:3]=[CH2:4])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCBr
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCC1(CCC=C)Cc2cc(OC)ccc2C1=O
Reaction time: 20 h

Procedure:
To a solution of 5-methoxy-1-indanone (1 g, 6.17 mmol) in DMF (6 mL) at rt was added NaH (740 mg, 61% in oil, 18.5 mmol) and 4-bromo-1-butene (2.5 mL, 24.7 mmol). After 20 h at rt, the solution was diluted with CH2Cl2 and quenched with saturated aqueous NH4Cl. The slurry was dried with MgSO4 and filtered through a plug of silica and rinsed with 10% EtOAc in hexanes. The filtrate was concentrated and provided crude 2,2-di(3-butenyl)-5-methoxy-1-indanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:65])[CH:5]=[C:6]([Cl:64])[C:7]=1[CH2:8][C@@H:9]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH:56]([F:58])[F:57])=[C:51]([O:59][CH2:60][CH:61]2[CH2:63][CH2:62]2)[CH:50]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:48])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12].Cl.[C:67](Cl)(=[O:77])[O:68][C@@H:69]1[CH:74]2[CH2:75][CH2:76][N:71]([CH2:72][CH2:73]2)[CH2:70]1>N1C=CC=CC=1.Cl>[CH:11]([OH:12])=[O:10].[Cl:1][C:2]1[CH:3]=[N+:4]([O-:65])[CH:5]=[C:6]([Cl:64])[C:7]=1[CH2:8][C@@H:9]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH:56]([F:58])[F:57])=[C:51]([O:59][CH2:60][CH:61]2[CH2:62][CH2:63]2)[CH:50]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:48])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:67]([O:68][C@@H:69]4[CH:74]5[CH2:75][CH2:76][N:71]([CH2:72][CH2:73]5)[CH2:70]4)=[O:77])[CH:34]=3)[CH:22]=2)(=[O:19])=[O:20])[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: O=C(NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)c1cccc(CNc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Product: O=CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
3,5-Dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(2-(3-((phenylamino)methyl)benzamido)ethylcarbamoyl)phenylsulfonyl)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (35 mg, 0.036 mmol) was dissolved in pyridine (2 ml). (R)-quinuclidin-3-yl carbonochloridate hydrochloride (described in the co-pending International Patent Application No. PCT/EP2013/075529 (published as WO 2104/086855) (8.15 mg, 0.036 mmol) was added, and the reaction was stirred at room temperature for 6 hrs to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The crude was purified by preparative HPLC to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-((phenyl(((R)-quinuclidin-3 yloxy)carbonyl)amino)methyl)benzamido)ethyl)carbamoyl)-phenyl)sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide formate (12.65 mg, 10.81 μmol, 30% yield).
Reaction SMILES: [CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22](S(C)=O)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CN(C=O)C>[CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22]([NH:28][CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1
Reactant: NCCN1CCOCC1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(S(C)=O)o3)cc12)C1(C)CC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(NCCN4CCOCC4)o3)cc12)C1(C)CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a solution of 4-((R)-1-(1-methylcyclopropyl)ethylamino)-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (16.00 mg, 0.041 mmol) in NMP (0.5 mL, 0.082M) was added 4-(2-aminoethyl)morpholine (26.80 mg, 0.206 mmol) followed with DIPEA (0.029 mL, 0.165 mmol) and stirred at 130° C. for 30 min in a Biotage Initiator microwave. The reaction mixture was dissolved in 1.5 mL of DMF and directly purified on Reverse Phase HPLC to yield desired product (2.23 mg, 12% yield). MS (ES+) m/z: 454.87 (M+H); HPLC: 92% retention time: 1.57 min (analytical HPLC Method B).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].O1CCCC1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].Cl>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]([OH:16])[CH:1]([CH3:3])[CH3:2])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1cccc(Br)c1

Procedure:
With cooling with ice, 150 mL of 1.0 M isopropylmagnesium chloride/tetrahydrofuran solution was added to tetrahydrofuran (200 mL) solution of 21.9 g of 3-bromobenzaldehyde. 4 N hydrochloric acid was added to the reaction liquid, extracted with diethyl ether, and washed with saturated sodium hydrogencarbonate solution and saturated saline water in that order. This was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=19/1 to 4/1) to obtain 4.20 g of the entitled compound as an oily substance.