Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[N:16]1[O:20][N:19]=[C:18]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:17]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:6]1([CH2:5][C:4]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:2]([C:22]3[CH:23]=[CH:24][C:17]4[C:18]([CH:21]=3)=[N:19][O:20][N:16]=4)[CH:3]=2)[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: COc1ccc(Cn2ccnc2)cc1Br
Reactant: OB(O)c1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnc2)cc1-c1ccc2nonc2c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
A suspension of 1-(3-bromo-4-methoxy-benzyl)-1H-imidazole (I-167, 267 mg, 1.00 mmol), benzo[1,2,5]oxadiazole-5-boronic acid (I-105, 164 mg, 1.00 mmol), palladium(0)bis(dibenzylideneacetone) (28.7 mg, 0.050 mmol), and triphenylphosphine (26.2 mg, 0.10 mmol) in dimethylformamide (20 mL) and 1 M aqueous cesium carbonate (3.0 mL, 3.0 mmol) was heated to 85° C. with stirring overnight. The solvent was removed under vacuum and the residue suspended in ethyl acetate (25 mL). The organic suspension was washed with water (3×20 mL) and brine, dried over sodium sulfate, decolorized over activated carbon, filtered, and concentrated under. The residue was purified by silica gel preparatory thin layer chromatography (ethyl acetate:dichloromethane 3:1) to give 10.4 mg of P-006 in 9.1% yield. 1H NMR (400 MHz, CDCl3) 3.86 (s, 3H) 5.13 (s, 2H) 6.93 (s, 1H) 7.01 (d, J=8.32 Hz, 1H) 7.10 (s, 1H) 7.17-7.25 (m, 2H) 7.52-7.62 (m, 2H) 7.78-7.85 (m, 2H) ppm. LCMS=100% purity. APCI (+)=307.1 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][C@@H:9]([NH:13]C(OC(C)(C)C)=O)[C:10](O)=[O:11])(C)(C)C.CCN=C=NCCCN(C)C.[ClH:33].[CH2:34]([N:38]1[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=2)=[O:45])[N:40]=[C:39]1[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])[CH2:35][CH2:36][CH3:37]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:33].[NH2:13][C@@H:9]([C:10]([O:63][CH2:62][CH2:61][NH:60][C:58]([C:39]1[N:38]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]([F:55])([F:56])[F:57])=[CH:51][CH:52]=2)=[O:45])[N:40]=1)=[O:59])=[O:11])[CH2:8][CH2:7][C:6]([OH:21])=[O:5]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCOC(=O)[C@H](N)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
91 mg (0.3 mmol) of (2R)-5-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid are dissolved in 1 ml of DMF and, after addition of 58 mg (0.3 mmol) of EDCI×HCl and 37 mg (0.30 mmol) of DMAP, stirred at room temperature for 10 minutes. Then 70 mg (0.15 mmol) of 1-butyl-N-(2-hydroxyethyl)-4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1H-imidazole-2-carboxamide (Example 81) are added, and the mixture is stirred at room temperature overnight. The reaction mixture is purified by preparative HPLC. The product-containing fractions are evaporated in vacuo.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.C([Mg]Cl)(C)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26]C)[CH:24]=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([NH:22][CH:23]([CH3:26])[C@@H:24]([C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: c1cnc2ncoc2c1
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)[C@H](O)c1nc2ncccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in 30 mL THF and the reaction mixture was cooled to 0° C. under N2 atmosphere. Isopropylmagnesium chloride (2M in THF, 2.5 ml, 5 mmol ) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in 20 ml THF was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:36])=[O:17])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCc1ccccc1OCCCCCBr
Product: CCCc1c(OCCCCCOc2ccccc2CCCCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 4, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(5-bromopentyl)oxy]benzenepentanoic acid methyl ester from the preceding example, followed by saponification, in 46.5% overall yield. The product was an off-white solid, mp 75°-76° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CS(C)=O>O>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:20])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1cc(-c2ccccc2)no1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cc(-c2ccccc2)no1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 71.7 %

Procedure:
A solution of 2,2,2-trichloroethyl (3-phenylisoxazol-5-yl)carbamate (336 mg, 1.00 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol) diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration. This was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (310 mg, 71.8%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[Br:12].[Al+3].[Cl-].[Cl-].[Cl-].CCS>ClCCl>[Br:12][C:5]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)c1cc(O)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cold solution (ice water bath) of the methyl-2-bromo-5-methoxybenzoate (2.00 g, 8.16 mmol) in dichloromethane (15 mL) was added AlCl3(5.44 g, 40.8 mmol) under argon, and the reaction temperature was maintained below 10° C. using an ice-water bath. The light brown suspension was stirred for 10 min, then EtSH (3.02 mL, 40.8 mmol) was added dropwise at such a rate that the reaction temperature was maintained below 5° C. After 2.5 h of stirring below 10° C., the reaction mixture was slowly poured into ice water with agitation. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to afford a light yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[N:37]([C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(N=[N+]=[N-])n1
Temperature: 25 °C

Procedure:
A solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and Sodium azide in DMF (0.2 M) was heated at 90° C. for 3 hours. The reaction mixture was then cooled to room temperature and quenched with water then the aqueous layer was separated and extracted with EtOAc (×2). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford N-(3-(2-azido-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide. The compound was utilized in the subsequent reaction without further purification. LCMS (m/z) (M+H)=484.0/485.1, Rt=0.96 min.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.ClC([O:9][CH3:10])Cl.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19]>ClCCl>[CH3:11][C:12]1[C:13]([CH3:19])=[C:14]([CH3:18])[CH:15]=[CH:16][C:17]=1[CH:10]=[O:9]
Reactant: COC(Cl)Cl
Reactant: Cc1cccc(C)c1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C=O)c(C)c1C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of SnCl4 (39 g, 0.15 mol) in 50 mL of dichloromethane was added dropwise at -5° C. a solution of 15 g (0.13 mol) of dichloromethylmethylether. This solution was stirred at -5° C. for one hour before adding dropwise over 10 min a solution of 12 g (0.1 mol) of 1,2,3-trimethylbenzene. The mixture was stirred at 0° C. for 15 min before warming to room temperature where it was stirred an additional 1.5 hrs. After quenching onto 100 g of ice the organic layer was separated, washed with water, saturated aqueous sodium bicarbonate and water before drying over Na2SO4, filtering and evaporating to dryness in vacuo. The product was purified by distillation in vacuo. B.p. 120°-122° C. (11 mm). Lit. b.p. 121.5 (11 mm) Yield: 9.2 g (70%).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][NH2:31])[CH2:26]1>COCCOC>[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][NH:31][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:14]=[C:13]4[C:9]([CH2:10][CH2:11][CH2:12]4)=[CH:8][C:6]=3[N:7]=2)[CH2:26]1
Reactant: COC1CN(CCN)C1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC1CN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Yield: 47 %

Procedure:
A solution of chloride 21 (1.32 g, 6.0 mmol), Et3N (1.65 mL, 11.8 mmol) and 2-(3-methoxy-1-azetidinyl)ethylamine (277) (950 mg, 7.3 mmol) in DME (30 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×50 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 34 (890 mg, 48%) as a yellow solid: mp 139-141° C.; 1H NMR δ 8.06 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.67 (br s, 1H, NH), 4.04 (p, J=5.8 Hz, 1H, CHO), 3.63-3.69 (m, 2H, CH2N), 3.47 (dt, J=5.9, 5.6 Hz, 2H, CH2N), 3.26 (s, 3H, OCH3), 2.93-3.03 (m, 6H, H-6, H-8, CH2N), 2.74 (t, J=5.9 Hz, 2H, NCH2), 2.14 (p, J=7.4 Hz, 2H, H-7); 13C NMR δ 158.7, 154.5, 148.7, 143.3, 129.8, 120.6, 114.6, 70.0, 61.4 (2), 58.0, 56.0, 39.3, 33.1, 32.3, 25.7; MS (APCI) m/z 316 (MH+, 100%). Anal. calcd for C16H21N5O2.¼H2O: C, 60.1; H, 6.8; N, 21.9. Found: C, 60.0; H, 6.6; N, 21.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:14]([C:26]3[N:27]([CH3:31])[N:28]=[CH:29][CH:30]=3)[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:32]N1C(=O)CCC1=O>CO>[Cl:32][C:30]1[CH:29]=[N:28][N:27]([CH3:31])[C:26]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CCCC1
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CCCC1
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution 1-(4-chloro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea in cold methanol was added a solution of N-chloro succinimide (0.044 g, 0.3215 mmol) in methanol. The reaction mixture was stirred for 60 minutes. Then the methanol was evaporated and the residue was purified using silica flash chromatography with 15% methanol in DCM as eluant. The fractions containing the product were evaporated and dried in vacuo to afford 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea (Compound 17) (0.05 g, 38%) as an off-white solid. LCMS m/z (%)=474 (M+H 35Cl 35Cl, 100), 476 (M+H 35Cl, 37Cl, 81.7), 478 (M+H 37Cl 37Cl, 11.2). 1H NMR (400 MHz, DMSO-d6) δ: 8.83 (bs, 1H), 8.73 (bs, 1H), 7.61 (s, 1H), 7.54 (dd, J=2.65, 2.69 Hz, 1H), 7.46 (dd, J=2.06, 2.11 Hz, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.31 (dd, J=2.09, 2.04 Hz, 2H), 7.16 (d, J=9.03 Hz, 1H), 4.2-4.0 (bm, 2H), 3.65 (s, 3H), 2.7-2.5 (bm, 2H), 2.4-2.3 (bm, 4H), 1.7-1.5 (bm, 4H).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si]([C:11]([F:14])([F:13])[F:12])(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>[F:12][C:11]([F:14])([F:13])[C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: OC1(C(F)(F)F)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Cyclopentanone (0.89 mL, 10 mmol) was added to a solution of TMSCF3 (0.5M in THF, 25 mL, 12 mmol) at 0° C. TBAF (1M in THF, 0.076 mL, 0.076 mmol) was added and the resulting yellow solution was allowed to warm to rt over 2 h. 1M HCl (30 mL) was added and the resulting solution stirred 1 h at rt. Extraction with Et2O was followed by washing of the combined organics with brine and drying over anhydrous Na2SO4. Following concentration in vacuo, 1-trifluoromethylcyclopentanol (1.4 g, 88%) was isolated as a colorless liquid that was immediately converted to carbonic acid 4-nitrophenyl ester 1-trifluoromethylcyclopentyl ester analogously to carbonic acid cyclobutyl ester 4-nitrophenyl ester as described in Example 184 by substituting 1-trifluoromethylcyclopentanol (1.3 g, 8.4 mmol) for cyclobutanol with appropriate adjustments for scale and performing the reaction in a sealed tube for 40 h. The reaction volume was doubled with DCM and washed with 1M HCl (2×20 mL) followed by washing with 20 ml each of sat. NaHCO3, water, brine and finally dried over anhydrous MgSO4. Following concentration in vacuo, the residue was purified by column chromatography on SiO2 (12-25% EtOAc/hex) to produce 0.59 g (22% yield) of the desired product. 1H NMR (CDCl3, 400 MHz) δ 8.29 (m, 2H); 7.40 (m, 2H); 2.38 (m, 2H); 2.26 (m, 2H); 2.04 (m, 2H); 1.78 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C@H:15]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH3:16])=[CH:10][C:9]=1[CH3:33])[CH3:6])[CH3:2].C(OC(=O)C(C)(OC1C=CC(O[C@@H](C2SC(C3C=CC(C(F)(F)[F:64])=CC=3)=NC=2C)C)=CC=1C)C)C>>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:6])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[C:26]([F:64])[CH:27]=3)=[N:19][C:18]=2[CH3:32])[CH3:16])=[CH:10][C:9]=1[CH3:33])[CH3:34])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O[C@H](C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O[C@@H](C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C

Procedure:
(S)-2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]ethoxy}-phenoxy)-propionic acid ethyl ester p1 (R)-2-methyl-2-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl]ethoxy}-phenoxy)-propionic acid ethyl ester
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cc(C)c1C1C(=O)C=CC1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(F)cc(C)c1C1C(=O)CCC1=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 2-(4-fluoro-2,6-dimethylphenyl)cyclopent-4-ene-1,3-dione (2.9 g, 13.3 mmol) in acetic acid (116 ml) is added zinc powder (6 g, 91.7 mmol) at 25-30° C. The resulting solution is stirred at 25-30° C. for 16 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product (2.9 g) which is used for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40](Br)[CH:39]=1>>[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:39]=[C:40]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-bromo-5-chloro-phenyl)acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[CH2:12][C@@H:11]2[C:33]([O-:35])=O)=[O:8])=[CH:4][CH:3]=1.[Li+].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:49][NH:50][CH2:51][CH2:52][OH:53]>C1COCC1.CN(C=O)C>[OH:53][CH2:52][CH2:51][N:50]([CH3:49])[C:33]([C@@H:11]1[C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])[CH2:12]1)=[O:35]
Reactant: CNCCO
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](C(=O)[O-])C1)Nc1ccc(-n2ccccc2=O)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
Lithium (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylate (example 41; 0.09 g) is dissolved in THF/DMF (1:1; 3 ml) and CDI (0.083 g) is added. The mixture is stirred for 1 h at 25° C., after that 2-(methylamino)-ethanol (0.03 ml) is added. The reaction mixture is stirred for 18 h at 25° C. and evaporated to dryness followed by flash chromatography over silica gel using DCM/MeOH/NH3 as eluent to yield 0.033 g (33.4%) (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylic acid (2-hydroxy-ethyl)-methyl-amide. White solid. MS 576.5 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=[C:18]([Cl:20])[N:19]=1)(C)(C)C.Cl.CO>O1CCOCC1>[ClH:20].[Cl:20][C:18]1[N:19]=[C:14]([NH:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:7][CH2:8]2)[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(Cl)nc2c1SCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1nc2c(c(NC3CCCNC3)n1)SCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
1.77 g (4.8 mmol) of tert-butyl 3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-carboxylate (V) is placed in 21.5 mL of a 4% hydrochloric acid solution in dioxane, and methanol is added. The solution is stirred for 0.5 hours at ambient temperature, whereupon a precipitate is formed. This is suction filtered, washed with diethyl ether, and dried. 1.33 g of product (VI) (91%) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:27])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)[CH:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:28]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:28][C:24]1[O:23][C:22]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[CH2:15][N:13]2[C:12](=[O:27])[CH:11]=[CH:10][C:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)=[N:14]2)=[N:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncco2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncc(Br)o2)c1

Procedure:
A solution of 184 mg (0.504 mmol) of 6-(3,5-difluorophenyl)-2-(3-oxazol-2-ylbenzyl)-2H-pyridazin-3-one, 108 mg (0.605 mmol) of N-bromosuccinimide and 6.3 mg (0.026 mmol) of benzoyl peroxide in 1 ml of chlorobenzene is stirred at 80° C. for 42 hours. The reaction mixture is evaporated and chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 2-[3-(5-bromooxazol-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one as yellowish crystals; ESI 444, 446.