Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[CH2:18][C:17]1=[O:25]>>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[C:18]2[C:19]3[C:24](=[N:23][CH:22]=[CH:21][CH:20]=3)[NH:16][C:17]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Reactant: O=C1Cc2cccnc2N1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(3-cyclopentyl-4-methoxybenzylidene,)-1,3-dihydropyrrolo[2,3-bipyridin-2-one as a yellow-orange solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][C:10]1[CH2:31][O:30][CH2:29][C@:12]2([C:25]3[CH:24]=[C:23](Br)[CH:22]=[C:21]([F:27])[C:20]=3[O:19][C:18]3[C:13]2=[CH:14][C:15]([OH:28])=[CH:16][CH:17]=3)[N:11]=1.[O:32]1[CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:9][C:10]1[CH2:31][O:30][CH2:29][C@:12]2([C:25]3[CH:24]=[C:23]([C:35]4[CH2:36][CH2:37][O:32][CH2:33][CH:34]=4)[CH:22]=[C:21]([F:27])[C:20]=3[O:19][C:18]3[C:13]2=[CH:14][C:15]([OH:28])=[CH:16][CH:17]=3)[N:11]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 120 °C

Procedure:
In a microwave vial, potassium phosphate (0.307 g, 1.448 mmol), PdCl2(AmPhos)2 (0.026 g, 0.036 mmol), (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (0.183 g, 0.483 mmol), and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.147 g, 0.700 mmol) were suspended in dioxane (4 mL) and water (1.6 mL). Argon was blown through the vessel, which was sealed and heated by microwave at 120° C. for 30 min. The reaction was concentrated, and the residue was neutralized with ⅓ saturated aqueous NH4Cl (15 mL) and the aqueous phase was extracted with 5% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL), and concentrated to afford (S)-5-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18]Cl)=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[I-].[K+].[CH2:29]([CH:32]=[CH:33][CH2:34][NH2:35])[CH2:30][CH3:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18][NH:35][CH2:34][CH2:33][CH2:32][CH2:29][CH:30]=[CH2:31])=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Reactant: CCCC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCCNCc1nnc2n1-c1cccc(SCC)c1C(c1cccc(Cl)c1)=NC2

Procedure:
In the manner given in Example 32, 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide and propylallylamine in tetrahydrofuran are reacted to give 7-(ethylthio)-1-[(allylpropylamino)methyl]-6-(m-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].I[CH3:16]>CN(C)C=O>[CH3:16][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of sodium hydride (0.27 g; 6.8 mM) in dimethylformamide (4 ml) at 0° C. under nitrogen, was added 6-nitroindole (1 g; 6.2 mM) in dimethylformamide (12 ml). After stirring at room temperature for 0.5 h, iodomethane (0.42 ml; 6.8 mM) in dimethylformamide (1 ml) was added and stirring continued for 1 h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (1.03 g; 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([SH:11])=[CH:4][CH:3]=1.Br[CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=[O:15].Cl>[OH-].[Na+]>[C:7]([C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[S:11][CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=[O:15])([OH:9])=[O:8]
Reactant: CCCCC(Br)C(=O)O
Reactant: O=C(O)c1cc(Cl)ccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Sc1ccc(Cl)cc1C(=O)O)C(=O)O

Procedure:
A mixture of 5-chlorothiosalicylic acid [prepared by the process set forth in L. Katz et al., J. Org. Chem., 18 (1953) 1380] (2.0 g, 9.8 mmol) and 1N aqueous sodium hydroxide (100 ml) was heated at reflux temperature for 1 hour under a nitrogen atmosphere. 2-Bromohexanoic acid (1.9 g, 9.8 mmol) was then added, and refluxing was continued for an additional hour. The mixture was cooled in an ice bath and acidified with concentrated hydrochloric acid. The acidic mixture was extracted with diethyl ether, and the combined organic layers were washed with water, saturated aqueous sodium chloride solution, dried (sodium sulfate), and evaporated. The product was obtained as a light yellow solid (2.4 g) that was used without further purification in the subsequent step below.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH:15]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[CH:23][CH:22]=3)[C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=2[CH:33]=1)(=[NH:5])[NH2:4]>Cl>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH:15]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[CH:25][CH:26]=3)[C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:33]=1)(=[NH:4])[NH2:5]
Reactant: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2o1)c1ccc(O[C@H]2CCNC2)cc1
Agent: Cl
Product: N=C(N)c1ccc2oc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)cc2c1
Yield: 82.8 %

Procedure:
3.2 g of ethyl 3-(5-amidino-2-benzofuranyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride was dissolved in 80 ml of 2N hydrochloric acid, and the solution was refluxed under heating for 30 minutes. After cooling and distilling off the solvent, the resulting residue was purified by subjecting it to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using 5-10% acetonitrile as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, adjusted to pH 2-3 with dilute hydrochloric acid, and then concentrated to dryness. In this way, 1.25 g of the title compound was obtained in a solid form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([C:19]#[CH:20])([OH:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:28]1([N:38]=[C:39]=[O:40])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C([O-])(=O)C.[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([O:18][C:39](=[O:40])[N:38]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[C:19]3=[CH2:20])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: C#CC1(O)CCN(CCC=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Product: C=C1N(c2cccc3ccccc23)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 5 h
Yield: 76.5 %

Procedure:
A mixture containing 11.0 g of 1-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-ethynyl-4-hydroxypiperidine, 6.0 g of 1-naphthyl isocyanate, 0.2 g of anhydrous potassium acetate and 36 ml of C-picoline is refluxed under nitrogen while stirring for 5 hours. After evaporating the solvent under reduced pressure, the residue is taken up in benzene, filtered through an aluminum oxide column and then evaporated under reduced pressure. The residue is recrystallized from methanol under clarifying by activated carbon to give the title product in 76.5% yield, m.p.: 99°-101° C.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:21]>>[CH:1]1([CH2:7][CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCCC1)CC1CCCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(CC1CCCCC1)CC1CCCCC1
Yield: 92.4 %

Procedure:
A solution of 2.97 g (11.8 mmol) of bis-(cyclohexylmethyl)acetic acid in 20 mL SOCl2 was stirred at room temperature overnight. The SOCl2 was removed under reduced pressure, the residue taken up in Et2O, and the solvent removed under reduced pressure. The residue was taken up in hexane and the solvent removed under reduced pressure leaving 2.94 g (92.4% yield) of the product as an oil. The structure was confirmed by mass spectroscopy.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[Br:28][C:29]1[CH:30]=[C:31]([C:35]2([NH2:38])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:28][C:29]1[CH:30]=[C:31]([C:35]2([NH:38][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]4[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=4)[N:3]=3)[CH2:36][CH2:37]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC1(c2cccc(Br)c2)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4cccc(Br)c4)CC3)nc(OCC(F)(F)F)n2)cc1
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To a solution of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1156 mg, 2 mmol) in THF (10 mL) was added 1-(3-bromophenyl)cyclopropanamine (424 mg, 2.000 mmol) and Hunig's Base (1.747 mL, 10.00 mmol). The resulting mixture was stirred for 16 h. After concentration, the residue was purified by Biotage eluting with 20% ethyl acetate in hexane to give 400 mg (35%) of the desired product as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N+:17]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O-:19])=[O:18]
Reactant: C1CNCCN1
Reactant: O=C1CC(CO)C(c2ccc(Cl)c([N+](=O)[O-])c2)=NN1
Product: O=C1CC(CO)C(c2ccc(N3CCNCC3)c([N+](=O)[O-])c2)=NN1

Procedure:
19.86 g (0.07 mol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-hydroxymethyl-3(2H)-pyridazinone are reacted with 18.1 g (0.21 mol) of piperazine in a manner analogous to Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[OH:16])(=[O:4])[CH2:2][CH3:3].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])=[CH:12][CH:11]=[CH:10][C:9]=2[OH:16])(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1N
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Cl
Solvent: C1COCCO1
Product: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reaction time: 8 h

Procedure:
Impure 3-propanoyl-4-chloro-8-hydroxyquinoline (86 g) and 2-methylaniline (10.7 ml) in dioxan (200 ml) were warmed over a steam bath for 30 minutes, then left to stand overnight. After evaporation of the dioxan, dichloromethane and aqueous sodium bicarbonate were added, the organic layer washed with water and brine, dried and evaporated to a yellow solid. Recrystallization from methanol gave 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (11.6 g), m.p. 125°-128°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]1)(=O)=O>C(O)(C)(C)C.CC(=O)CC>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[CH:8]=2)[CH:3]=1
Reactant: CC(C)(C)[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
6-bromonaphthalen-2-ol (CAS no. 15231-91-1) (3.0 g, 14.8 mmol, 1.0 eq.) was dissolved in a mixture of t-butanol/2-butanone (4 mL/2 mL). Then cesium carbonate (12 g, 37.2 mmol, 2.5 eq.) was added to the mixture and the mixture was stirred at 110° C. for 10 min. Then trans-4-tert-butylcyclohexyl methanesulfonate (3.48 g, 16.2 mmol, 1.1 eq.) was added to the mixture. The suspension was stirred at 110° C. under a nitrogen atmosphere for 15 h. The reaction mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using petroleum ether as eluent to give 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene as a slight yellow solid (1.7 g, yield: 32%). ESI-MS: 361.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.47 (d, 1H), 7.15-7.11 (m, 2H), 4.26-4.24 (m, 1H), 2.27-2.25 (m, 2H), 1.89-1.87 (m, 2H), 1.45-1.09 (m, 5H), 0.89 (s, 9H).
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH:26]=2)[C:20](N(OC)C)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]C(C)C)(C)C.O.C(OCC)(=O)C>C1COCC1>[C:1]1([C:7](=[N:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH:26]=2)[CH:20]=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cncc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a stirred solution of 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 23, 7.50 g, 0.021 mol) in THF (150 mL) at −70° C. was added diisopropylaluminium hydride (42 mL, 0.042 mol, 1.0 M in THF) and the resulting mixture stirred at −70° C. for 2 hours. Water (20 mL) and ethyl acetate (100 mL) were added. The organic phase was separated, concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc: petroleum ether 1:10 to afford the title compound as a brown solid in 65% yield, 4 g.
Reaction SMILES: Cl.[CH:2]([N:5]([C:7]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)=[O:8])[NH2:6])([CH3:4])[CH3:3].[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH:2]([N:5]([C:7]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)=[O:8])[NH:6][C:27](=[O:28])[CH2:26][O:25][CH3:24])([CH3:4])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CC(C)N(N)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Solvent: ClCCl
Product: COCC(=O)NN(C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2)C(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid N-isopropyl-hydrazide hydrochloride (3.5 g, 8.4 mmol) and TEA (4.07 mL, 29.3 mmol) in DCM (35 mL) at 0° C. was added methoxy-acetyl chloride (1.53 mL, 16.7 mmol) dropwise and the reaction mixture was stirred at 0° C. for 0.75 h then 18 h at RT. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and the phases separated. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed with 10% citric acid solution, followed by brine then dried (Na2SO4) and concentrated in vacuo to give a yellow brown solid. The solid was triturated with diethyl ether to give the title compound as an off white solid (2.66 g, 5.86 mmol, 70%). LCMS RT=4.64 min, [M+H]+=454/456.
Reaction SMILES: [C:1]1([CH:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:70][CH2:71][CH2:72][CH:73]([O:77][CH2:78][CH3:79])[O:74][CH2:75][CH3:76]>CN(C=O)C.C(OCC)(=O)C>[N:31]12[CH2:32][CH2:33][CH:34]([CH2:35][CH2:36]1)[C@@H:29]([O:28][C:26](=[O:27])[NH:25][CH:7]([C:8]1[CH:24]=[CH:23][CH:22]=[C:10]([O:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:70][CH2:71][CH2:72][CH:73]([O:77][CH2:78][CH3:79])[O:74][CH2:75][CH3:76])=[CH:15][CH:14]=3)[CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:30]2
Reactant: CCOC(CCN)OCC
Reactant: O=C(NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(CCNC(=O)c1ccc(COc2cccc(C(NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a stirred solution of 4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoic acid (0.300 g, 0.57 mmol) in DMF (2.5 mL), was added HATU (0.262 g, 0.69 mmol) and diisopropylethylamine (0.250 mL, 1.43 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. 1-Amino-3,3-diethoxypropane (0.139 mL, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated sodium hydrogen carbonate and brine (×2). The organic phase was dried wih anhydrous sodium sulfate, and filtered, and the solvent was evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 100% ethyl acetate in iso-hexane to afford the title compound (0.347 g, 99%), which was used directly in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)CN>ClCCCl.C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCC(F)F
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1
Reaction time: 18 h
Yield: 129.1 %

Procedure:
To a stirred solution of 1-Boc-4-piperidone (0.300 g, 1 eq) and 2,2-difluoroethylamine (0.244 g, 2 eq) in 1,2-dichloroethane (6 mL) is added NaBH(OAc)3 (0.640 mg, 2 eq). After 18 h, the solution is diluted with CH2Cl2, washed with NaHCO3 (sat.), brine, dried over Na2SO4 and concentrated. The resulting residue is purified by flash chromatography Hex/EtOAc (1:1) to give the corresponding N-Boc piperidine (0.360 g, 90%). The obtained N-Boc piperidine (29 mg, 1.5 eq) is dissolved in a solution HCl in dioxane (4 M, 0.5 mL) and stirred during 30 min at RT. The solution is concentrated, the resulting residue is dissolved in DMSO (0.5 mL), Et3N (40 μL, 4 eq) is added followed by 50d (35 mg, 1 eq). The solution is heated at 50° C. for 1 h and ammonium acetate (500 mg) is added and the heating is pursued at 140° C. during 4 h. The solution is diluted with H2O/AcOH and purified by prep HPLC to give 5004 (10 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:11]=1)=[O:4].Br.C(S[C:28](=[NH:30])[NH2:29])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:28]([N:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[N:11]=[C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[S:8][CH:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)(=[NH:29])[NH2:30]
Reactant: CCSC(=N)N
Reactant: COC(=O)CCc1nc(-c2ccc(C3CCNCC3)cc2)cs1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(-c2ccc(C3CCN(C(=N)N)CC3)cc2)cs1

Procedure:
Prepared from 2-(2-methoxycarbonyl-ethyl)-4-[4-(4-piperidinyl)-phenyl]-thiazole and S-ethylisothiourea-hydrobromide by heating to 100° C. for 4 hours in dimethylformamide in the presence of sodium carbonate.
Reaction SMILES: [OH:1][C:2]([CH3:15])([C:6]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:7])[C:3](O)=[O:4].[NH2:16][C@@H]1C(=O)N(CC(F)(F)F)C2C=C(F)C=CC=2O[C@@H]1C>>[OH:1][C:2]([CH3:15])([C:6]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:7])[C:3]([NH2:16])=[O:4]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Product: CC(O)(C(N)=O)C(=O)NCCC(F)(F)F

Procedure:
N-[(6R,7S)-2-Fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N′-(3,3,3-trifluoro-propyl)-malonamide was obtained as mixture of epimers according to the procedures described for example 2b using racemic 2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid and (6R,7S)-7-amino-2-fluoro-6-methyl-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one. The epimers were separated by chromatography on Chiralpak AD using ethanol/heptane 15:85 to yield (−)-N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N′-(3,3,3-trifluoro-propyl)-malonamide, entity A, MS m/e (%): 504.0 (M+H+, 100), as first eluting fraction, and (−)-N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N′-(3,3,3-trifluoro-propyl)-malonamide, entity B, as second eluting fraction, MS m/e (%): 504.0 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:24][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxy carbonylbutyl)propanamide (152.5 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-methoxycarbonylbutyl)propanamide (32.4 mg) together with a less polar by-product. The by-product was not investigated further.