Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[ClH:32]>O>[ClH:32].[ClH:32].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:30][OH:31])[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Agent: Cl
Solvent: O
Product: Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
7β-[2-(2-Aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (283 mg) was suspended in water (100 ml) and 1.25 ml of 1N hydrochloric acid was added thereto. The mixture was stirred at 40° C. for 10 minutes and then lyophilized to afford 7β-[2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid dihydrochloride (281.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:66][O:67][CH2:68][CH2:69][CH2:70][NH2:71]>CC(N(C)C)=O.C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:71][CH2:70][CH2:69][CH2:68][O:67][CH3:66])=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCCCN
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)O)cc2)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNC(=O)c1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic acid (100 mg; 0.21 mmol; 1 eq.), EDC-HCl (51.87 mg; 0.27 mmol; 1.3 eq.) and HOBT (36.56 mg; 0.27 mmol; 1.3 eq.) were taken up in DMA (5 ml) then DIEA (106.88 μl; 0.62 mmol; 3 eq.) and 3-methoxypropylamine (21.23 μl; 0.21 mmol; 1 eq.) were added. The solution was stirred at rt for 3 h. The DMA was evaporated and the residue was taken up in DCM. The organic phase was washed with a saturated solution of NaHCO3 then a saturated solution of NH4Cl and brine. It was dried over MgSO4 and concentrated to near dryness. The residue obtained was taken up in ACN and refluxed. After cooling at 4° C., the precipitate was filtered off then washed with ACN to afford 76 mg (66%) of the title compound as a parent. Treatment of the parent (74 mg; 0.13 mmol; 1 eq.) with an aqueous solution of potassium hydroxide (268.30 μl; 0.5 M; 0.13 mmol; 1 eq.) affords 76 mg (96%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 8.77 (s, 1H), 8.49-8.45 (m, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H), 7.41-7.38 (m, 1H), 7.31 (d, J=2.3 Hz, 2H), 7.27-7.24 (m, 1H), 7.17-7.08 (m, 2H), 6.13-6.12 (m, 1H), 3.77 (s, 6H), 3.35-3.31 (m, 2H), 3.28-3.22 (m, 2H), 3.20 (s, 3H), 1.75-1.66 (m, 2H). HPLC (max plot) 97%; Rt 4.17 min. LC/MS: (ES+): 552.4, (ES−): 550.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:23][CH2:22][C:10]2([N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:24]>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:23][CH2:22][C:10]2([NH:14][CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCN(c1ccccc1Cl)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1N(c2ccccc2Cl)CCC12CCCN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 7-(2-chlorophenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate was dissolved in a 4.0 M solution of HCl in 1,4-dioxane, and the resulting mixture was stirred for 2 h at RT. The volatiles were removed in vacuo to afford the desired product, which was used in the next step without further purification. LC-MS: 251.0 (M+1H)+.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>C(OCC)C.O>[Cl:14][C:15]1[N:20]=[C:19]([N:6]([CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: O=C1OCCC1CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C1OCCC1CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 1.67 g (0.009 mole) of 3-cyclopentylaminomethyl-dihydro-furan-2-one in 25 mL of ethyl ether was added 15 mL of ice-water followed by 1.68 g (0.0087 mole) of 2,4-dichloro-5-nitro-pyrimidine. A solution of 1.36 g (0.014 mole) of potassium bicarbonate in 5 mL of water was added over 20 minutes. The mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure to remove the ethyl ether and the mixture then filtered, washing with water and then water-acetonitrile. The solid was purified by recrystallization from hexanes-ethyl acetate (1:1) to give 2.2 g of (rac)-3-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-dihydro-furan-2-one (IV-49).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10]O)[N:8]=1)([CH3:3])[CH3:2].CS(Cl)(=O)=O.[CH2:17]([N:19](CC)CC)C.C(N)C>O1CCCC1.C(OCC)(=O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][NH:19][CH3:17])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(CCO)cs1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCCc1csc(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.0 g (12 mmol) of 2-isopropyl-4-(hydroxyethyl)thiazole in 50 ml of tetrahydrofuran was treated with 1.34 g (12 mmol) of methanesulfonyl chloride. The resulting solution was treated dropwise with 3.4 ml (24 mmol) of triethylamine and stirred at ambient temperature for 1 h. A portion (25 ml) of the resulting solution was added to 50 ml of aqueous ethylamine (70% in H2O) with rapid stirring. After addition, the mixture was heated to reflux for 2 h, allowed to cool, diluted with ethyl acetate, washed with aqueous NaHCO3 and saturated brine, dried over Na2SO4, and concentrated in vacuo to provide the crude desired compound. Purification of the residue by silica gel chromatography using 5% methanol in chloroform, 0.52 g (48%) of the desired compound. 1H NMR (CDCl3) δ1.38 (d, J=7 Hz, 3H), 2.46 (s, 3H), 2.93 (s, 4H), 3.30 (heptet, J=7 Hz, 1H), 6.79 (s, 1H). Mass spectrum: (M+H)+ =185.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13]([O-])=[CH:12][C:11]([N+:18]([O-:20])=[O:19])=[C:10]2[C:21]([F:24])([F:23])[F:22]>ClC(Cl)C>[Br:3][C:12]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]([C:21]([F:24])([F:23])[F:22])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([Cl:6])[CH:8]=2)[N:13]=1
Reactant: O=[N+]([O-])c1c[n+]([O-])c2ccc(Cl)cc2c1C(F)(F)F
Reactant: O=P(Br)(Br)Br
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1c(Br)nc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 25 °C

Procedure:
Alternatively, the above reaction can be run using the following procedure: POBr3 (39.2 g, 137 mmol, 2 equiv) was added to a stirred solution of 3 (20 g, 68 mmol) in dichloroethane (150 mL). The reaction was heated to reflux for 8 h. After cooling to rt, the reaction was quenched by the slow addition of ice. (Here I let it stir over the weekend—but not necessary). The organic layer was separated and the aqueous layer was extracted with CHCl3 (2×100 mL). The combined organic layer was washed with NaHCO3 (1×150 mL), H2O (1×150 mL), NaHSO3 (1×150 mL), H2O (1×150 mL), brine (1×150 mL) and dried over MgSO4. The residue was recrystallized from EtOH to afford the desired product, 16.12 g (67%). An additional 1.87 g was obtained by column chromatography of the concentrated filtrate (SiO2, 5% ethyl acetate-hexane). Total yield 17.99 g (74%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:16]=[C:15]4[CH:34]=O)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:3][CH2:2]1.[OH:39][CH2:40][C@H:41]1[CH2:46][NH:45][CH2:44][CH2:43][N:42]1C(OC(C)(C)C)=O>>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=3)[CH:16]=[C:15]4[CH2:34][N:45]3[CH2:44][CH2:43][NH:42][C@@H:41]([CH2:40][OH:39])[CH2:46]3)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(CN3CCN[C@@H](CO)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 112 step i) and (R)-2-(hydroxymethyl)-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][CH:20]([C:22](O)=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C@H:20]([C:22]([NH:10][C:8](=[O:9])[C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[NH2:2])=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-leucinamide hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared. This compound was then purified by column chromatography, eluted first with 1:1 EtOAc/hexane, then with 5% MeOH) in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:17](=[CH:23]OCC)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]>C(O)C>[NH2:16][C:15]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[CH:23][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 24 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (10 g) and ethyl 2-cyano-3-ethoxyacrylate (7.0 g) in absolute ethanol (200 ml) was heated under reflux with stirring for 24 hours. Evaporation of solvent and recrystallisation from diisopropyl ether gave ethyl 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate, m.p. 131°-134°.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[N:36]=[CH:35][C:34]([CH:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)=[CH:39][CH:38]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 47.5 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (300 mg, 1.03 mmol) and 6-amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (313 mg, 1.13 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (212 mg, 48%). MS (ESI) m/z 434.3 (M+H)+
Reaction SMILES: [CH3:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[CH:18]1(CN)[CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:18]1([CH2:1][N:2]=[C:3]2[C:4]3[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=3[CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH2:20][CH2:19]1
Reactant: CN=C1c2ccccc2CCc2ccccc21
Reactant: NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc2c(c1)CCc1ccccc1C2=NCC1CC1
Yield: 65 %

Procedure:
In a Carius tube is placed 4.52 g of N-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-imine, 9.2 g of cyclopropylmethylamine and 0.46 g of p-toluenesulfonic acid hydrate. The tube is sealed under vacuum and heated to 120° for 60 hours. The cooled tube is opened, the excess cyclopropylmethylamine is removed under vacuum, and the resiude is dissolved in ether. The solution is washed with aqueous sodium hydroxide solution and dried. The solvent is removed, and the residue is combined with the recovered cyclopropylmethylamine and 0.43 g of p-toluenesulfonic acid hydrate. The mixture is transferred to a Carius tube which is then sealed under vacuum and heated to 120° for an additional 30 hours to complete the reaction. The mixture is worked up as described above, and the crude product is crystallized from hexane to give 3.47 g (65%) of N-cyclopropylmethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-imine, mp 98°-99°. An analytical sample (hexane) had mp 99°-100°. Nmr spectrum (in CDCl3): multiplets at τ 2.1-3.0 (8H), 6.1-7.5 (6H), 8.3-9.0 (1H) and 9.1-10.0 (4H). Anal. Calcd. for C19H19N: C, 87.31; H, 7.33; N, 5.36; Found: C, 87.52; H, 7.27; N, 5.53.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:15]([C:28]([O:30]CC)=[O:29])[NH:14][C:13]=1[C:33]([O:35]CC)=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+]>C(O)C>[CH2:1]([O:11][C:12]1[C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:15]([C:28]([OH:30])=[O:29])[NH:14][C:13]=1[C:33]([OH:35])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1c(C(=O)OCC)[nH]c(C(=O)OCC)c1OCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCOc1c(C(=O)O)[nH]c(C(=O)O)c1OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Into a 3-L three-necked flask, 68.6 g (131 mmoles) of the diethyl 3,4-didecyloxypyrrole-2,5-dicarboxylate and 680 ml of ethanol were put, and an aqueous sodium hydroxide solution (prepared by dissolving 52.4 g of sodium hydroxide in 655 ml of water) was dropwise added thereto over a period of 15 minutes with stirring at room temperature. Thereafter, the mixture was heated and stirred at about 60° C. for 6.5 hours. After the reaction was completed, the reaction product was cooled to room temperature, and the sodium carboxylate thus deposited was collected by filtration, followed by washing with ethanol. The resultant crystals were dispersed in a solution of a mixture of 3L of ethyl acetate and 350 ml of water, and 91 ml of 3N-hydrochloric acid was added to adjust the pH to about 1. The organic layer formed was washed with water and dried with Glauber's salt. Thereafter, the solvent was evaporated to dryness. The residue formed was recrystallized with an ethyl acetate/hexane mixed solvent to obtain 40.3 g of white crystals of 3,4-didecyloxypyrrole-2,5-dicarboxylic acid (yield: 65.8%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:13]C)[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:15])[CH:3]=1.B(Br)(Br)Br>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: COc1ccc(F)c2c(Cl)cc(C)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c2c(F)ccc(O)c2n1
Temperature: 25 °C

Procedure:
4-Chloro-5-fluoro-8-methoxy-2-methyl-quinoline (0.440 g, 1.95 mmol) was coevaporated in anhydrous toluene (2×15 mL). The residue was dissolved in anhydrous DCM (25 mL) and BBr3 (1 M in DCM, 9.8 mL, 9.8 mmol) was added dropwise at −75° C. The reaction mixture was allowed to warm to room temperature over 3.5 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between DCM (10 mL) and water (7 mL). The pH of the aqueous layer was adjusted to 8 by the addition of saturated aqueous NaHCO3 solution and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS (m/z): 212.3 [M+H+].
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O)([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1)([CH3:9])[CH3:8]
Reactant: Brc1c[nH]cn1
Reactant: CC(C)Oc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)Oc1ccccc1-c1c[nH]cn1
Yield: 72.9 %

Procedure:
Add tetrakis(triphenylphosphine)palladium(0) (500 mg) to a degassed suspension of 4-bromo-1H-imidazole (5.0 g, 34 mmol) and 2-isopropoxyphenyl boronic acid (9.19 g, 51 mmol) in dioxane (250 mL) and 2 M sodium carbonate solution (10.81 g, 102 mmol) at room temperature under nitrogen and heat the mixture at reflux for 21 hours. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate (500 mL) and filter through a plug of Celite. Dry the filtrate over sodium sulfate, treat with silica gel (20 g) and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate, to afford crude 4-(2-isopropoxyphenyl)-1H-imidazole (5.01 g, 73%) which is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH3:12]
Reactant: Nc1cc(F)c(F)cc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(F)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To acetic anhydride (20 mL) was added 2-chloro-4,5-difluoroaniline (4.7 g, 29 mmol), and the resulting solution was stirred at 100° C. for 1 h. After cooling to rt, the mixture was stored in a freezer overnight. A white crystalline precipitate formed, and it was collected by filtration. Residual acetic anhydride was removed in vacuo. The desired N-(2-chloro-4,5-difluorophenyl)acetamide (4.69 g, 22.8 mmol, 79% yield) was isolated as a white crystalline solid. 1H NMR (400 MHz, CDCl3): 8.38 (dd, 1H), 7.53 (br s, 1H), 7.23 (dd, 1H), 2.25 (s, 3H); MS (EI) for C8H6ClF2NO: 206 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[N:20][OH:21])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(CCCOCc2ccccc2)CC1
Agent: Cl
Product: ON=C1CCN(CCCOCc2ccccc2)CC1

Procedure:
1-(3-Benzyloxypropyl)-4-piperidone oxime is prepared from 1-(3-benzyloxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C@@H:7]([C:36](=[O:55])[N:37]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:45][CH:44]=2)[CH2:38][CH2:39][CH3:40])[C@@H:8]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[C@H:9]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:46]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([CH2:42][CH2:41][N:37]([CH2:38][CH2:39][CH3:40])[C:36]([C@@H:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][C@@H:9]([OH:11])[C@H:8]2[NH:29][C:30](=[O:35])[C:31]([F:32])([F:33])[F:34])=[O:55])=[CH:48][CH:47]=1
Reactant: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)OC)=C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H]1NC(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)O)=C[C@@H](O)[C@H]1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a solution of (4R,5R,6R)-6-[(2-biphenyl-4-yl-ethyl)propylcarbamoyl]-4-(tertbutyldiphenylsilanyloxy)-5-(2,2,2-trifluoroacetylamino)-5,6-dihydro-4-H-pyran-2-carboxylic acid methyl ester (1.03 g) in tetrahydrofuran (5.5 ml) was added a solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (1.45 ml of a 1M solution). The orange solution was stirred at room temperature for 4 hours before the solvent was removed in vacuo to give an orange gum. This was dissolved in ethyl acetate (50 ml) and washed with water (2×40ml). The organic phase was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo and the residue was chromatographed over silica (Merck 7734, 65 g) and dichlormethane/methanol (95:5 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white foam (0.64 g). 1H NMR (250 MHz, CDCl3 rotamers) 7.63-7.24 (9H, m), 6.96+6.92 (1H, 2×d, J=8 Hz), 6.13+6.06 (1H, 2×d, J=4 Hz), 5.16+4.86 (1H, 2×d, J=7, 5 Hz), 4.72+4.58 (1H, 2×m), 4.3 (1H, m), 3.82+3.79 (3H, 2×s), 3.78-3.23 (4H, m), 3.02+2.87 (2H, 2×t, J=8 Hz), 2.90+2.78 (2H, 2×broad s), 1.82-1.50(2H, m), 0.96+0.92 (3H, 2×t, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A solution of tert-butyl-4-[4-(methoxycarbonyl)phenyl]-1-piperidinecarboxylate (3.95 g) in a mixture of methanol (80 ml), THF (40 ml) and 4N sodium hydroxide (30 ml) was stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo. To a residue was added water (100 ml) and adjusted to pH 3 with 1N hydrochloric acid. The solution was extracted twice with a mixture of ethyl acetate (100 ml) and THF (50 ml). The extracts was dried over magnesium sulfate and evaporated in vacuo to give 4-[1-(tert-butoxycarbonyl)-4-piperidyl]benzoic acid (3.64 g).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]4[S:25][C:21]([CH3:20])=[CH:22][N:23]=4)[CH:27]=3)[C:5](=[O:7])[CH:4]([CH3:9])[CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 423.87 g/mol.