Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:16](O)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CS(O)(=O)=O>>[C:16]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: OCCOc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCOc1ccccc1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 925.05 g (2.08 moles) of the Alkoxylate from example 27 and 674.95 g (1.98 moles) of Behenic Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:42])[CH2:4][C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([C:15]3[S:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:43]([O-])=[O:44].[Na+].[Cl-].[Na+]>C(O)(=O)C.O>[Br:1][CH2:2][C:3](=[O:42])[C:4](=[N:43][OH:44])[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])=[C:12]([C:15]3[S:16][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)CC(=O)CBr)[C@H]3SC2)s1
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]3SC2)s1
Yield: 89.4 %

Procedure:
In 4 ml of acetic acid there was dissolved 0.37 g of benzhydryl 7-(4-bromo-3-oxobutyrylamino)-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate and, under ice-cooling and stirring, a solution of 0.048 g of sodium nitrite in 0.4 ml of water was added dropwise. After this dropwise addition, the mixture was stirred at room temperature for one hour. Then, 20 ml of a saturated aqueous solution of sodium chloride were added and extraction was carried out with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure and the residue was loosened up with a solvent mixture of petroleum ether and ether (2:1 volume/volume). The resultant powder was recovered by filtration and dried. By the above procedure there was obtained 0.345 g of benzhydryl 7-(4-bromo-3-oxo-2-hydroxyiminobutyrylamino)-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate-(syn-isomer).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=2)=[O:8])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)cc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3,5-difluorophenyl)boronic acid. HPLC (Condition 4) tR=5.71 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=480.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.76 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=11.73 Hz, 1H) 3.16-3.28 (m, 2H) 3.42 (m, J=7.00 Hz, 1H) 4.20 (m, J=2.00 Hz, 1H) 4.85 (d, J=3.52 Hz, 1H) 7.15 (dd, J=8.21, 1.95 Hz, 2H) 7.21-7.29 (m, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78-7.90 (m, 2H) 8.02 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [C:1]([OH:14])(=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH:38]1([N:44]2[CH2:52][C:51]3[C:46](=[CH:47][C:48]([N:53]4[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)=[CH:49][CH:50]=3)[C:45]2=[O:59])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C>[CH:38]1([N:44]2[CH2:52][C:51]3[C:46](=[CH:47][C:48]([N:53]4[CH2:54][CH2:55][N:56]([C:1](=[O:14])[C:2]5[CH:3]=[C:4]([O:5][CH3:6])[C:7]([OH:8])=[C:9]([O:10][CH3:11])[CH:12]=5)[CH2:57][CH2:58]4)=[CH:49][CH:50]=3)[C:45]2=[O:59])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C(=O)N2CCN(c3ccc4c(c3)C(=O)N(C3CCCCC3)C4)CC2)cc(OC)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of syringic acid (20 mg) in dry DMF (2 ml) was cooled to 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (WSCI) and 1-hydroxybenztriazole hydrate (HOBt) were added thereto in that order. The mixture was stirred at 0° C. for one hr. The compound (30 mg) obtained in step (e) of Example 1 and triethylamine were added thereto in that order. The mixture was stirred at 0° C. for one hr, and then stirred at room temperature overnight. A saturated aqueous ammonium chloride solution (5 ml) was added thereto, followed by separation with ethyl acetate and water. The ethyl acetate layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under the reduced pressure. The residue was purified by chromatography on silica gel (chloroform:methanol=20:1) to give 42 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:14]#[C:15][Si](C)(C)C.[NH2:20][C@@H:21]([CH3:26])[C:22]([CH3:25])([OH:24])[CH3:23].CCN(C(C)C)C(C)C.NC1C=CC=CC=1.N1C2C(=CC=CC=2)C=C1.CC([O-])(C)C.[K+]>CN1C(=O)CCC1>[OH:24][C:22]([CH3:25])([CH3:23])[C@@H:21]([N:20]1[C:2]2[C:3](=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=2)[CH:14]=[CH:15]1)[CH3:26]
Reactant: C[C@H](N)C(C)(C)O
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: Nc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](n1ccc2c(C(F)(F)F)c(C#N)ccc21)C(C)(C)O
Temperature: 90 °C

Procedure:
4-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (0.063 g, 0.221 mmol), (S)-3-amino-2-methylbutan-2-ol (0.060 g, 0.582 mmol) and DIEA (0.077 mL, 0.442 mmol) were combined in NMP (0.5 mL) and heated to 90° C. LCMS after heating for 9 h showed good conversion to the aniline intermediate and some desired indole formation. The mixture was cooled to rt and then treated with KOtBu (1.98 mL, 1 M in THF). The base did not afford conversion to the desired indole despite heating. The mixture was quenched with sat. aqueous NH4Cl, and then extracted with EtOAc. The combined organic fractions were concentrated to a yellow oil and then diluted with NMP (1 mL). Addition of more KOtBu (1.98 mL, 1 M in THF) afforded a dark brown solution that was heated to 50° C. LCMS after 0.5 h showed conversion to the desired indole. The reaction was again quenched with sat. aqueous NH4Cl and then extracted with EtOAc. The combined organic portions were concentrated to a yellow oil and then chromatographed (ISCO, std grad, hex/EtOAc, 24 g silica) to afford the desired product. The mixture was next subjected to reverse phase semiprep (Agilent, 230 nm detection) to afford the desired product as a colorless gum: MS (ESI): m/z 297 (MH+).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[C:27]([CH3:34])=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[C:27]([CH3:34])=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: Cc1c(F)cccc1NN
Product: Cc1c(F)cccc1-n1nccc1-c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-fluoro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=425.2 (M+H)+
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].C(N(C(C)C)CC)(C)C>C(#N)C>[CH:3]([C@@H:2]1[CH2:6][CH2:7][CH2:8][N:1]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: 50 °C
Reaction time: 10 h
Yield: 124.2 %

Procedure:
A mixture of 3 (11.80 g, 38.8 mmol), N-Boc-L-Pro-OH (10.02 g, 46.6 mmol), and diisopropylethylamine (7.02 g, 54.3 mmol) in acetonitrile (200 mL) was stirred at 50° C. for 10 h. The solvent was evaporated and the residue was partitioned between methylene chloride and H2O. The organic layer was separated and concentrated to dryness. The crude product was purified by silica gel column chromatography (hexanes/ethyl acetate=1/7 to 1/4 (v/v)) to provide 4 (11.53 g, 68% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 1H), 7.48 (m, 2H), 5.58 (m, 1H), 4.40 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 3.04 (m, 1H), 2.37 (m, 2H), 2.04 (m, 1H), 1.96 (m, 1H), 1.46 (ds, 9H) ppm.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[I-:14].[Na+].[OH-].[Na+].Cl[O-].[Na+].S([O-])([O-])=S.[Na+].[Na+].Cl>CO>[I:14][C:5]1[CH:6]=[C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]=1[OH:7]
Reactant: [I-]
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: Oc1ccc(-c2ccccc2)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Biphenyl-4-ol((5.26 g, 30.9 mmol), sodium iodide (4.635 g, 30.9 mmol), sodium hydroxide (1.276 g, 31.9 mmol) was dissolved in methanol (85 mL) and cooled to 0° C. To the solution was added 12% (w/v) sodium hypochlorite (20 mL) dropwise maintaining the temperature below 4° C. The solution was stirred at this temperature for 1 hour and then 2M sodium thiosulfite (50 mL) wad added and the pH of the solution was adjusted to >pH 7 with 1M HCl. The mixture was filtered and the filtrate was washed with water. The solid was dried in a vacuum oven and then the title product was obtained as crystals after recrystallisation from heptane. Yield 7.08 g, 77%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[B:26]1(B2OC(C)(C)C(C)(C)O2)[O:30]C(C)(C)C(C)(C)[O:27]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)=[CH:3][C:2]([B:26]([OH:30])[OH:27])=[CH:7]1
Reactant: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(B(O)O)cn(C)c2=O)nc1
Temperature: 70 °C
Yield: 93.1 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 136b (600 mg, 1.5 mmol), bis(pinacolato)diboron (1.2 g, 4.5 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), X-phos (71 mg, 0.15 mmol), potassium acetate (294 mg, 3.0 mmol), and 1,4-dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 70° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was washed with petroleum ether to afford 136c (520 mg, 93%) as a white solid, which was used directed without further purification. MS-ESI: [M+H]+ 373.1
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.O>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Reactant: NC1CC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
15.6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxy-acrylate are dissolved in 50 ml of ethanol, and 2.75 g of cyclopropylamine are added dropwise, while cooling. The mixture is stirred at room temperature for 1 hour, 50 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, rinsed with ethanol/H2O (1:1) and dried. 14.1 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-cyclopropylamino-acrylate of melting point 106°-107° C. are obtained.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C([Li:23])CCC>C1C=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([Li:23])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: CCCCCc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: [Li]c1ccc(CCCCC)cc1
Temperature: 25 °C

Procedure:
18.35 g (0.081 mol) of 4-pentylbromobenzene was dissolved in 30 ml of benzene and the solution was stirred at room temperature in a stream of nitrogen. To the resulting solution was added drop-wise 50 ml (0.081 mol) of hexane solution including 15% butyllithium for 30 minutes and the solution was stirred for 2 hours. Then the produced precipitate gathered by the filtration in a stream of nitrogen was dried under reduced pressure to yield 9.2 g of 4-pentylphenyllithium.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.I[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1>COCCOC.[Cu]Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccs1
Reactant: OCc1ccccc1
Agent: Cl[Cu]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: COCCOC
Product: c1ccc(COc2cccs2)cc1
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
To a solution of benzyl alcohol (3.45 mL, 33.3 mmol) in 1,2-dimethoxyethane (80 mL) was added n-butyl lithium (2.6M hexane solution, 13.5 mL, 33.3 mmol) dropwise, which was then stirred for 10 minutes. Copper(I) chloride (5210 mg, 49.45 mmol) was added thereto, followed by stirring for 10 minutes on an ice bath, then, it was stirred for 2.5 hours at room temperature. 2-Iodothiophene (4995 mg, 23.78 mmol) and pyridine 320 mL were further added, and the solution was stirred for 13 hours under reflux. Ethyl acetate was added to the reaction mixture, which was sequentially washed with 1N hydrochloric acid, an aqueous solution of sodium hydrogen sulfate and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (420 mg, 2.21 mmol, 9.5%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[C:16]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.BrC1C=CC=C2C=1C=CN2.Br[CH2:43][C:44]1[O:45][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:48]=1.BrCCCCC>>[O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[C:16]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:43][C:44]1[O:45][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(c2)C2(CO3)C(=O)Nc3ccccc32)C1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(c2)C2(CO3)C(=O)N(Cc3ccc(C(F)(F)F)o3)c3ccccc32)C1

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations using tert-butyl 3-(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl)piperidine-1-carboxylate to replace 4-bromoindole, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 1-bromopentane, the title compound was obtained (10%) as a white solid: mp 59-61° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m, 2H), 7.12 (d, 1H), 7.04-6.96 (m, 2H), 6.89 (d, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 6.41 (s, 1H), 5.10-4.86 (m, 3H), 4.66 (d, 1H), 4.16-3.94 (m, 2H), 2.68-2.38 (m, 2H), 1.90-1.60 (m, 3H), 1.40 (s, 10H), 1.27-1.21 (m, 1H); MS (ES+) m/z 591.2 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:17][C:18]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2cc(C(C)(C)C)on2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (5° C.) solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1 g; 4.362 mmol) and 3-amino-5-t-butylisoxazole (589 mg; 4.2 mmol) in anhydrous pyridine (12 mL) is added phosphorus oxychloride (0.393 mL; 4.362 mmol). The reaction mixture is stirred at room temperature for 30 minutes. The mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride provides the title compound, m/z 352 [M+H+].
Reaction SMILES: [CH3:1][CH:2]([C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15]C(=O)C)=[CH:8][CH:7]=1)=[O:5])[CH3:3].BrBr.[OH-:21].[Na+]>C(O)(=O)C.C(O)C>[OH:21][C:2]([C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)=[O:5])([CH3:3])[CH3:1]
Reactant: [OH-]
Reactant: CC(=O)OCCOc1ccc(C(=O)C(C)C)cc1
Agent: BrBr
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(O)C(=O)c1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
336 g (3.2 mol) of isobutyryl chloride are added dropwise over the course of 40 minutes while stirring to 880 g. (8.8 mol) of anhydrous aluminium chloride in 480 ml of dichloromethane at -5 to 0° C. 540 g. (3.0 mol) of 2-phenoxyethyl acetate are then added dropwise over the course of 2 hours at the same temperature. The reaction mixture is stirred for a further 2 hours at the stated temperature and then poured into a mixture of 1.8 l of concentrated hydrochloric acid and 5 kg of ice. The organic phase is separated off and the aqueous layer is extracted with dichloromethane. The combined organic phases are washed with water, dried and evaporated, and the residue is distilled in vacuo. 740 g. of 4-(2-acetoxyethoxy)phenyl-2-propyl ketone of boiling point 145-152° C./0.3-0.5 torr are obtained. b) 205 g. (1.0 mol) of 4-(2-acetoxyethoxy)phenyl 2-propyl ketone are dissolved in 200 ml of glacial acetic acid, and 192 g. (1.2 mol) of bromine are added over the course of 2 hours with stirring at 25° C. The mixture is then stirred for about a further 10 hours and then poured into 3 L of ice water. The product is extracted with ethyl acetate. The combined extracts are dried, and 365 g. of a viscous oil are obtained by evaporation. This oil is dissolved in 1 L of ethanol, and 380 g. of 32% strength sodium hydroxide solution are added over the course of 20 minutes with stirring at 25° C. The mixture is stirred for a further 10 minutes and the ethanol is then removed. The oily residue is transferred into 3 l of ice water, and this mixture is extracted repeatedly with a total of 1.5 l of ethyl acetate. After drying, filtering and evaporating the solution, 250 g. of an oily crude product are isolated. Through recrystallization from acetone/petroleum ether and/or chromatographic purification, 145 g of 4-(2-hydroxyethoxy)phenyl 2-hydroxy-2-propyl ketone are obtained in the form of a colourless solid of melting point 88°-90° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](O)=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.B.C1COCC1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[NH2:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1C(=O)O
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)nc1CO
Temperature: 20 °C
Reaction time: 48 h

Procedure:
3-amino-6-chloro-pyridine-2-carboxylic acid (95 mg, 0.55 mmol) is taken up in THF (1 mL) and combined with BH3-THF complex (2.2 mL, 2.2 mmol, 1 M in THF). The reaction mixture is stirred for 2 d at 20° C. The reaction is ended with dilute HCl and H2O, then neutralised with NaHCO3, extracted with EtOAc, the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and (3-amino-6-chloro-pyridin-2-yl)-methanol is obtained (HPLC-MS: tRet.=0.79 min, MS(M+H)+=159; method AFEC).
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[C:7]([C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH:6]=[N:5][CH:4]=1>O.CO>[OH:10][CH:9]([C:7]1[CH:6]=[N:5][CH:4]=[N:3][CH:8]=1)[C:11]([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)C(=O)c1cncnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(O)c1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1.27 g (0.034 mole) of sodium borohydride in 10 ml of water are added to 16.4 g (0.1 mole) of tert.-butyl 5-pyrimidinyl ketone in 100 ml of methanol at room temperature. The reaction mixture is stirred at room temperature for 1 hour and concentrated in vacuo, the residue is distilled in methylene chloride and the solution is concentrated again in vacuo. 15.8 g (95% of theory) of 5-(1-hydroxy-2,2-dimethyl-propyl)-pyrimidine of melting point 93°-95° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:19])[N:13](CC)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1.C(O[CH:26](O)[C:27]([F:30])([F:29])[F:28])C>>[F:22][C:2]([F:1])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:19])[N:13]([CH2:26][C:27]([F:28])([F:29])[F:30])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1
Reactant: CCOC(O)C(F)(F)F
Reactant: CCN1c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2CCC1C
Product: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 187 (Structure 33 of Scheme VI, where R1=methyl, n=1) and trifluoroacetaldehyde ethyl hemiacetal. 1H NMR (400 MHz, CDCl3) 11.08 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 3.99 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.10-2.95 (m, 1H), 2.92-2.82 (m, 1H), 2.07-1.97 (m, 1H), 1.93-1.80 (m, 1H), 1.19 (d, 3H, J=6.5).