Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][N:19]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
1,1-Dimethylethyl 4-hydroxy-1-piperidinecarboxylate (5.50 g, 27.4 mmol) was dissolved in 100.0 mL of THF and cooled to 0° C. Next, sodium hydride (1.19 g, 29.7 mmol, 60% dispersed in mineral oil) was added portion wise and the mixture stirred at rt for 1 h. The mixture was cooled to 0° C. again and 2-chloro-4-fluoropyridine (3.00 g, 22.8 mmol) was added dropwise as a THF solution. The reaction was allowed to stir at rt, and after 6 h TLC indicated that all of the 2-chloro-4-fluoropyridine had reacted. The mixture was again cooled to 0° C. and quenched with water. EtOAc was added and the organics separated. The organics were washed with brine and dried over anhydrous MgSO4, The crude was purified via silica gel chromatography to give 6.14 g (86% yield) of a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=5.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 6.99 (d, J=5.9 Hz, 1H), 4.62-4.87 (m, 1H), 3.51-3.69 (m, 2H), 2.96-3.22 (m, 2H), 1.78-1.93 (m, 2H), 1.41-1.57 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].Br[CH:11]([CH3:15])[C:12](Br)=[O:13].C(N(CC)CC)C>CC(C)=O>[CH3:15][CH:11]1[O:4][C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[O:1][C:12]1=[O:13]
Reactant: CCCCC(O)C(=O)O
Reactant: CC(Br)C(=O)Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCC1OC(=O)C(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
2.5 g 2-hydroxyhexanoic acid (18.9 mmol) and 2.1 mL 2-bromopropionyl bromide (19.7 mmol) were stirred at 75° C. under nitrogen for 12 h. 150 mL acetone and 5.3 mL anhydrous triethylamine (38 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 300 mL ethyl acetate:hexane mixture (1:2). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.05 (q, 1H), 4.90 (dd, 1H), 1.9-2.15 (br m, 2H), 1.68 (d), 1.65 (d), (3H, of 2 diastereoisomers), 1.3-1.6 (br m, 4H), 0.93 (t, 3H). 13C NMR (500 MHz, CDCl3): δ 167.54, 166.93, 166.25, 165.85, 75.79, 72.50, 72.24, 31.61, 29.70, 26.69, 26.42, 22.19, 21.97, 17.52, 15.81, 13.72, 13.66. ELEM. ANAL. Calcd. for C9H14O4: C, 58.06; H, 7.53. Found: C, 57.62; H, 7.60. Yield: 40%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[N:20]=[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:18]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:24]([O:23][C:21]1[CH:22]=[C:17]([O:16][CH2:14][CH3:15])[N:18]=[C:19]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:28][CH2:27]2)[N:20]=1)[CH3:25]
Reactant: CCOc1cc(OCC)nc(N2CCNCC2)n1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(OCC)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Yield: 115.5 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.2 g), 1-(4,6-diethoxypyrimidin-2-yl)piperazine (1.7 g) and potassium carbonate (1.3 g) in dimethylformamide (20 ml) was stirred at 80° C. for 4.5 hr. The reaction mixture was poured into water(150 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (2.9 g). The obtained brown oil was purified by silica gel column chromatography to give a pale-yellow oil (2.4 g). The obtained pale-yellow oil was crystallized from ethyl acetate/hexane (2:1, 30 ml) to give the title compound (1.7 g) as white crystals, m.p.=119-120° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]([F:28])([F:27])[C:16]([F:26])([F:25])[C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>>[F:23][C:17]([F:24])([C:16]([F:25])([F:26])[C:15]([F:14])([F:27])[F:28])[C:18](=[O:19])[CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1ccc2ccccc2c1

Procedure:
The compound was synthesized according to example 1 using 2-acetylnaphthalene and ethyl heptafluorobutyrate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.76 (s, 1 H); 7.57-7.66 (m, 2H); 7.90 (bd, 1 H); 7.93-7.94 (m, 2H); 7.98 (bd, 1 H); 8.53 (s, 1H). IR (film): 1602 (C═O); 1232 (C—F).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([O:13][C:14]([F:27])([F:26])[C:15]([F:25])([F:24])[O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([F:12])[F:11])(=O)=O.[CH2:28]([O:36][C:37]1[CH:38]=[N:39][C:40]([C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=2)=[N:41][CH:42]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:28]([O:36][C:37]1[CH:42]=[N:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([O:13][C:14]([F:27])([F:26])[C:15]([F:25])([F:24])[O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([F:12])[F:11])=[CH:45][CH:44]=2)=[N:39][CH:38]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CS(=O)(=O)OCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 2-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)ethyl methane sulfonate (4.54 g, 10 mmol, prepared from 2-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)ethanol and methanesulfonyl chloride) with 5-octyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 10 mmol). The resulting crude product was purified by recrystallization from ethanol followed by Kugelrohr distillation (230° C. at 0.3 torr) to provide a yield of 6.5 g.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1>C(O)(=O)C.O=[Pt]=O>[NH2:11][C@@H:7]([CH:4]1[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1)[C:8]([OH:10])=[O:9]
Reactant: N[C@H](C(=O)O)c1ccccc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: N[C@H](C(=O)O)C1CCCCC1
Yield: 93.6 %

Procedure:
L-Phenylglycine (8.04 g, 53 mmol) was reduced by catalytic hydrogenation using PtO2 in 80% acetic acid (HOAc) (200 mL). The catalyst was removed by filtration and the HOAc removed under reduced pressure to afford the title compound as a white solid (7.8 g, 94%). The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH2:4][S:5](=[O:29])[C@@H:6]2[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:28])[N:7]2[C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10]>FC(F)(F)C(O)=O>[Br:1][CH2:2][C:3]1[CH2:4][S:5](=[O:29])[C@@H:6]2[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:28])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(CBr)CS(=O)[C@H]12
Yield: 102.2 %

Procedure:
A solution of 37.3 g of t-butyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 130 ml of trifluoroacetic acid was stirred for 15 minutes at room temperature and then the solvent was removed by evaporation under vacuo. After addition of 100 ml of 1,2-dichloroethane, evaporation to dryness was repeated. Ether was added to the residue and the crystals were vacuum filtered, washed with ether and dried under vacuo to obtain 33.7 g of 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide as an almost colorless solid having the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C:8]2[C:9]([CH3:20])=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.Cl[C:24]([O:26][C:27]([CH3:29])=[CH2:28])=[O:25]>N1C=CC=CC=1>[F:22][C:3]1[CH:4]=[C:5]([F:21])[C:6]([C:8]2[C:9]([CH3:20])=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]=1[NH:1][C:24](=[O:25])[O:26][C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)OC(=O)Cl
Reactant: CNc1cc2nc(C)c(-c3cc(N)c(F)cc3F)cc2cn1
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3nc2C)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Treat a 0° C. solution of 3-(5-amino-2,4-difluorophenyl)-N,2-dimethyl-1,6-naphthyridin-7-amine (1.45 g, 4.83 mmol) in pyridine (30 mL) drop-wise with isopropenyl chloroformate (0.528 mL, 4.83 mmol), warm to RT and stir overnight. Add EtOAc, wash with satd. NaHCO3 (2×), dry, concentrate and purify by silica gel chromatography (EtOAc/TEA pre-wash, EtOAc/Hex) to afford the title compound (1.449 g, 78%). 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.85 (s, 1H), 8.03 (s, 1H), 7.67-7.63 (m, 1H), 7.49 (t, 1H), 6.87-6.84 (m, 1H), 6.52 (s, 1H), 4.73 (s, 1H), 4.70 (s, 1H), 2.82 (d, 3H), 2.38 (s, 3H), 1.91 (s, 3H); MS (ESI) m/z: 385.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH:17]([CH3:19])[CH3:18].O.O.Cl[Sn]Cl>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)Oc1ccc(N)cc1-c1c(Br)cnn1C
Yield: 50 %

Procedure:
The crude reaction mixture of 4-bromo-5-(2-isopropoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (as described below) was reduced in the presence of SnCl2.2H2O, in a similar manner as described in Example 1.1, providing 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.043 g, 0.14 mmol, 50% for three steps). LCMS m/z (%)=310 (M+H79Br, 99), 312 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.51 (s, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.76 (dd, J=2.7, 8.6 Hz, 1H), 6.62 (d, J=2.7Hz, 1H), 4.08 (ddd, J=6.1, 6.1, 12.2 Hz, 1H), 3.74 (s, 3H), 1.21 (d, J=6.1 Hz, 3H), 1.01 (d, J=6.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C1COCC1.C1(C)C=CC=CC=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[C:23]([CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:22][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[C:23]([CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[N:22][N:21]=[C:20]2[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: COc1cc2c(Cl)nnc(Cc3ccncc3)c2cc1OC
Reactant: Brc1nccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(Cc3ccncc3)nnc(-c3nccs3)c2cc1OC
Yield: 38.4 %

Procedure:
In anhydrous environment, bromothiazole (831 mg, 5.067 mmoles) and 2:1 THF/toluene (15 ml) were added dropwise to powder zinc (500 mg, 7.6 mmoles), with mild heating. The mixture was brought to reflux for 1.5 hours, then added with 1-chloro-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine (800 mg, 2.53 mmoles), obtained as described in example 15, palladium acetate (28 mg) and triphenylphosphine (66 mg). The mixture was kept under reflux for 3 hours, then added with palladium acetate (56 mg) and triphenylphosphine (133 mg) and kept under reflux overnight. Further palladium acetate (56 mg) and triphenylphosphine (133 mg) were added and after 4 hours the mixture was poured into methylene chloride/30% aqueous ammonia. The phases were separated and the organic one was washed with water, dried and brought to dryness to give a crude which was chromatographed (eluent: methylene chloride/methanol 2.4%) to give 354 mg of the title compound (yield: 38.4%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl.Cl.[C:28]1([CH:34]2[C:39]3[N:40]=[C:41]([NH:43][CH:44]4[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]4)[S:42][C:38]=3[CH2:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)C(C)C)(C)C.Br[C:60]1[S:61][C:62]([CH3:65])=[N:63][N:64]=1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:65][C:62]1[S:61][C:60]([N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:41]3[S:42][C:38]4[CH2:37][CH2:36][CH2:35][CH:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:39]=4[N:40]=3)[CH2:49][CH2:48]2)=[N:64][N:63]=1
Reactant: c1ccc(C2CCCc3sc(NC4CCNCC4)nc32)cc1
Reactant: Cc1nnc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(N2CCC(Nc3nc4c(s3)CCCC4c3ccccc3)CC2)s1
Temperature: 200 °C

Procedure:
Palladium (II) acetate (3.6 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (11.6 mg, 0.032 mmol) were stirred under nitrogen at room temperature in dioxane (1.8 mL) for 10 minutes. Sodium tert-butylat (29 mg, 0.3 mmol), (4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidin-4-yl-amine dihydrochloride (77.3 mg, 0.2 mmol), N,N-diisopropylethylamine (69 L, 0.4 mmol) and 2-bromo-5-methyl-1,3,4-thiadiazole (40.2 mg; 0.22 mmol) were added and the reaction was heated to 200° C. for 30 minutes in a microwave oven. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc as eluent. The title compound was obtained as a yellow solid (23 mg, 28%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(OCC)(=O)C>C1CCCCC1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1
Yield: 43.7 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 1.15 g (3.50 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate, obtained in step 10.1., 1.99 g (10.49 mmol) of 3-(trifluoromethyl)phenyl-boronic acid, 2.97 g (13.99 mmol) of hydrated potassium phosphate and 0.40 g (0.35 mmol) of tetrakis(triphenyl-phosphine)palladium, and after chromatography on silica gel, eluting with a 35/65 and then 45/55 mixture of ethyl acetate and cyclohexane, 0.67 g of pure product is obtained in the form of a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1nc(N)sc1C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)Cc1nc(NS(=O)(=O)c2ccc(Cl)cc2)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 4-chlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (29.2 mg) with purity >90%. LCMS (pos) m/z 361.2.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=2)=[CH:15][CH:16]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccccc3C(F)(F)F)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 446.4. HPLC (Condition A), Rt: 4.23 min (HPLC purity: 96.5%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)C.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([NH:31][C:4](=[O:3])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN
Reactant: CCOC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: CCCCNC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 27 from 100 mg (0.27 mmol) ({2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetic acid ethyl ester and 70 mg (0.94 mmol) n-butylamine yielding 95 mg (89%) N-butyl-2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetamide as a brown foam. MS ISP (m/e): 400.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.45 (s, 1H), 7.93 (t, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.23 (d, 1H), 7.19 (d, 1H), 7.02 (s, 1H), 6.62 (s, 1H), 3.79 (s, 3H), 3.57 (s, 2H), 3.05 (br q, 2H), 2.14 (s, 3H), 1.39-1.26 (m, 6H), 0.85 (t, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:7])[CH3:3].[CH:20]([O-])=[O:21].[Na+]>>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:7][CH:20]=[O:21])[CH3:3]
Reactant: O=C[O-]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC=O

Procedure:
reacting 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride with sodium formate to produce N-formyl-3,4-dimethoxy-L-phenylalanine ethyl ester,
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=2)[N:8]=1)#[N:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CC#N>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:5]2[C:4](=[O:20])[C:3]([C:1]#[N:2])=[N:8][N:7]([C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)[C:6]2=[O:19])=[CH:24][CH:23]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(=O)Nc1cccc(-n2nc(C#N)c(=O)[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1cccc(-n2nc(C#N)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
According to Scheme 7 Step 3: A suspension of 11(B) (500 mg, 1.8 mmol), 4-chlorobenzyl bromide (455 mg, 2.2 mmol) and potassium carbonate (510 mg, 3.7 mmol) in CH3CN (10 mL) was stirred 12 h under reflux. The mixture was cooled at room temperature and 100 mL of water were added. The aqueous layer was extracted thrice with DCM (100 mL). The organic layers were mixed, dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (AIT Flashmart prepacked column 50 g SiO2) using CH2Cl2/MeOH (98/2) as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 11(C) (460 mg, 63%) as a beige solid.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].O>CN(C=O)C>[CH3:3][S:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:10]([F:9])([F:19])[F:20]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)Oc1ccccc1S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSc1ccccc1OC(F)(F)F
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of methyl iodide (59.0 g, 0.41 mol) in DMF (150 mL) was added potassium carbonate (23.0 g, 0.16 mol). 2-(Trifluoromethoxy)thiophenol (16.0 g, 0.08 mol) was added in portions during 30 min. The reaction mixture was then stirred vigorously overnight. Water (250 mL) was added. The reaction mixture was extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with a 50% saturated aqueous solution of sodium chloride (4×100 mL), dried (magnesium sulphate), and concentrated in vacuo to give 15.0 g of 1-methylsulfanyl-2-trifluoromethoxybenzene.
Reaction SMILES: C(OC([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](/[C:15]1[CH2:21][C@H:20]2[N:17]([C:18](=[O:25])[C@@H:19]2[C@H:22]([OH:24])[CH3:23])[C:16]=1[C:26]([O:28]CC=C)=[O:27])\[CH3:14])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:24][C@@H:22]([C@H:19]1[C:18](=[O:25])[N:17]2[C@@H:20]1[CH2:21][C:15](/[C:13](/[CH3:14])=[CH:12]/[C@@H:8]1[CH2:9][CH2:10][CH2:11][NH:7]1)=[C:16]2[C:26]([OH:28])=[O:27])[CH3:23]
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.82 g) in a mixture of tetrahydrofuran (28 ml) and ethanol (14 ml) were added successively triphenylphosphine (0.51 g), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (1.79 g), and tetrakis(triphenylphosphine)palladium (0) (220 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration, washed with tetrahydrofuran (40 ml) and dissolved in water (150 ml). The solution was washed with ethyl acetate (50 ml×2), concentrated in vacuo and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3- [(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.52 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:20]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CON
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone (5 g, 30 mmol) in 30 ml pyridine under nitrogen was added methoxylamine hydrochloride (3.8 g, 45 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 17 hours. The pyridine was removed in vacuo with heating. The residual solids were a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification. Rf : 0.48, 0.70 (CH2Cl2).