Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]3[N:12]=[CH:13][S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[O:17]COCCOC.Cl>>[S:14]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[C:3]([OH:17])[C:2]([Cl:1])=[N:7][CH:6]=3)[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13]1
Reactant: COCCOCOc1cc(-c2ccc3ncsc3c2)cnc1Cl
Agent: Cl
Product: Oc1cc(-c2ccc3ncsc3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A 5 mL conical microwave vessel was charged with 6-(6-chloro-5-((2-methoxyethoxy)methoxy)pyridin-3-yl)benzo[d]thiazole (0.0231 g, 0.0658 mmol), 2 mL TFE, 2M HCl (0.0329 ml, 0.0658 mmol), and a stirbar. The vessel was flushed with nitrogen, and then sealed. The reaction was irradiated using a Biotage microwave synthesizer to 100° C. for 15 minutes, and cooled. The solution was concentrated to half volume under a stream of nitrogen, and diluted with 1 mL 10% aqueous EtOH. The slurry was stirred at room temperature overnight, and cooled to −5° C. in a refrigerator. The precipitate was collected using a glass frit with a 0.22 μm PTFE syringe filter attached and positive pressure nitrogen. The solids were washed with 1 mL 10% aqueous EtOH, and then dried under a stream of nitrogen for 2 h. The solids were dissolved in DMF (2×2 mL), and filtered through the PTFE membrane. The solvent was removed in vacuo to afford 5-(benzo[d]thiazol-6-yl)-2-chloropyridin-3-ol (0.0159 g, 91.9% yield). 1H NMR (400 MHz, DMF) δ ppm 7.77 (d, J=2.13 Hz, 1H) 7.90 (dd, J=8.53, 1.76 Hz, 1H) 8.22 (d, J=8.41 Hz, 1H) 8.35 (d, J=2.13 Hz, 1H) 8.60 (d, J=1.00 Hz, 1H) 9.52 (s, 1H) 11.20 (s, 1H). 13C NMR (101 MHz, DMF) δ ppm 121.32 (s, 1 C) 122.52 (s, 1 C) 123.86 (s, 1 C) 125.82 (s, 1 C) 134.31 (s, 1 C) 135.34 (s, 1 C) 136.79 (s, 1 C) 138.14 (s, 1 C) 138.21 (s, 1 C) 150.44 (s, 1 C) 153.79 (s, 1 C) 157.01 (s, 1 C). HPLC-MS: 1.63 min (98.5%@215 nm; 97.9% @254 nm; m/z=262.9, calculated for C12H7ClN2OS+H+=263.0).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:52](=[O:53])[N:34]2[C:35]([C:49]([OH:51])=[O:50])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH2:46][CH:47]=[CH2:48])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([NH:31][CH:32]2[C:52](=[O:53])[N:34]3[C:35]([C:49]([OH:51])=[O:50])=[C:36]([CH2:39][S:40][C:41]4[N:45]([CH2:46][CH:47]=[CH2:48])[N:44]=[N:43][N:42]=4)[CH2:37][S:38][C@H:33]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 3.6 g.) was added to Vilsmeier reagent prepared from N,N-dimethylformamide (1.1 g.) and phosphoryl chloride (2.3 g.) in dry ethyl acetate (48.4 ml.) at 0° to 5° C. and stirred for 30 minutes to give an activated acid solution. The solution was added to a solution of 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.4 g.) and trimethylsilylacetamide (11.4 g.) in ethyl acetate (88 ml.) at -10° C. and stirred at -10° to -5° C. for 1.5 hours. After adding water (100 ml.) to the resultant solution, the solution was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated washed with ethyl acetate and diethyl ether in turn and acidified to pH 2.5 with conc. hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 5.22 g.)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8]C(O)=O)[N:5]=[C:4]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:3]=1>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])[N:3]=1
Reactant: CCN(CC)c1nc(O)cc(CC(=O)O)n1
Solvent: CCO
Product: CCN(CC)c1nc(C)cc(O)n1

Procedure:
4-Hydroxy-2-diethylaminopyrimidin-6-yl acetic acid (4.0 g) was suspended in ethanol (50 ml) and the mixture refluxed for 16 hours. The volatile portion of the mixture was then evaporated under reduced pressure to yield 4-hydroxy-2-diethylamino-6-methyl pyrimidine as a white powder, melting at 135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25]O)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C([N:33](CC)CC)C.CS(Cl)(=O)=O.O.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25][NH2:33])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: OCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: O
Solvent: CC#N
Product: NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
{6-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)pyridin-3-yl}methanol (Reference document: WO2010/043315) (1.8 g) and triethylamine (0.5 g) were dissolved in acetonitrile (30 mL), and an acetonitrile (10 mL) solution of methanesulfonyl chloride (0.5 g) was added dropwise thereto under ice cooling. Upon the completion of the dropwise addition, the reaction solution was stirred at room temperature for 1 hour, and then the resulting solution was added dropwise to a mixture solution containing 28% ammonia water (50 mL) and acetonitrile (200 mL), which had been prepared separately, under ice cooling. After stirring at room temperature for 12 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off and the purification was carried out by silica gel chromatography to obtain the title compound (1.25 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Yield: 90.8 %

Procedure:
A mixture of 1-naphthalenesulfonic acid 3-benzyloxy-5-methylphenyl ester (1.0 g, 2.47 mmol), as prepared in the preceding step, and 10% palladium on carbon (200 mg) in ethanol (20 mL) was hydrogenated (balloon) overnight. The catalyst was removed by filtration through diatomaceous earth (methanol washes) and the filtrate was evaporated in vacuo to give the title compound as a colorless syrup (705 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 2.11 (s, 3H), 4.20 (bs, 1H), 6.16 (t, 1H), 6.47 (t, 1H), 7.51 (t, 1H), 7.69 (t, 1H), 7.79 (t, 1H), 7.81 (d, 1H), 8.11 (dt, 2H), 8.77 (dd, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)[CH:16]=[O:17]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(C(F)(F)F)nc1
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 6-(trifluoromethyl)-3-pyridinol and 3,4-difluorobenzaldehyde.
Reaction SMILES: ClN1C(=O)CCC1=O.[F:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:21][OH:22])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]2([C:32]([F:35])([F:33])[F:34])[O:22][N:21]=[C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]([F:9])=[CH:11][CH:12]=3)[CH2:31]2)[CH:27]=[C:26]([Cl:36])[CH:25]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(F)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-chlorosuccinimid (4.7 g) is added to a solution of 4-fluoro-naphthalene-1-carbaldehyde oxime (6.6 g, example 5 step A) in DMF (50 ml). After 45 minutes at 40° C., the reaction is cooled down to 0° C. and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene, (8.4 g, example 1 step A) and triethylamine (5.4 ml) are added. The reaction is then further reacted at room temperature for 3 hours. Water is added (50 ml) and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is dissolved in dichloromethane and filtered over a pad of silica gel to yield 5-(3,5-dichloro-phenyl)-3-(4-fluoro-naphthalen-1-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N1CCOCC1)C.Cl.[CH2:45]([O:47][C:48](=[O:52])[C@H:49]([CH3:51])[NH2:50])[CH3:46]>O1CCCC1>[CH2:45]([O:47][C:48](=[O:52])[C@H:49]([CH3:51])[NH:50][C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H](C)N
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
13.3 g of Nα -tert.butoxycarbonyl-Nε -benzyloxycarbonyl-L-lysine were dissolved in 100 ml of tetrahydrofuran and the solution was cooled to -20° C. 4.58 ml of isobutyl chloroformate and 4.48 ml of N-ethylmorpholine were then added. After stirring at -20° C. for 2 minutes 5.37 g of L-alanine ethyl ester hydrochloride and 4.48 ml of N-ethylmorpholine were added and the mixture was allowed to come to room temperature, whereafter it was stirred for 4 hours. The solvent was removed by evaporation and the residue was partitioned between 200 ml of ethyl acetate and 100 ml of water. The organic phase was washed in sequence twice with 25 ml of 10% citric acid solution each time, twice with 25 ml of saturated sodium hydrogen carbonate solution each time, once with 25 ml of water and once with 25 ml of saturated sodium chloride solution, dried and evaporated. The resulting gum crystallized from ethyl acetate/n-hexane. There were obtained 13 g (77%) of Nα -tert.butoxycarbonyl-Nε -benzyloxycarbonyl-L-lysyl-L-alanine ethyl ester. Rf (chloroform/methanol 9:1) 0.73.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][CH2:8][N:9]1[C@@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[C@@H:17]([C:27](O)=[O:28])[C:16]2[C:11](=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[CH:14][CH:15]=2)[C:10]1=[O:33].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Br:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:19]3[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][C:24]=3[C:27](=[O:28])[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[CH:14][CH:15]=2)[C:10]1=[O:33]
Reactant: COc1cccc([C@H]2[C@@H](C(=O)O)c3ccc([N+](=O)[O-])cc3C(=O)N2CCCBr)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)-c1c(c3ccc([N+](=O)[O-])cc3c(=O)n1CCCBr)C2=O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
Thionyl chloride (10 mL) was slowly added to a solution of cis-4-carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(4-methoxyphenyl)-7-nitro-1(2H)isoquinolone (48, 1.94 g, 4.18 mmol) in benzene (60 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (80 mL), chilled in an ice bath, and aluminum chloride (3.00 g, 22.5 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1 h. Water (200 mL) was added, and the solution was extracted with CHCl3 (3×70 mL). The combined organic layers were washed with sodium bicarbonate (3×75 mL) and brine (75 mL), and dried over sodium sulfate. The solution was concentrated, hexanes (250 mL) were added, and the liquid was decanted. The solid was washed with hexanes (100 mL) and the liquid was decanted again. The solid was purified by silica gel column chromatography, eluting with chloroform-methanol, 20:1, to provide a red-orange solid (1.02 g, 55%): mp 282-284° C. (dec). IR (Film) 1699, 1667, 1612, 1555, 1499, 1332, 1159, 1078, 840, 785, 688, 662 cm−1; 1H NMR (CDCl3, 300 MHz) δ 8.85 (d, J=2.5 Hz, 1 H), 8.70 (d, J=8.9 Hz, 1 H), 8.55 (d, J=8.9 Hz, 1 H), 7.60 (d, J=8.5 Hz, 1 H), 7.38 (s, 1 H), 7.06 (d, J=8.3 Hz, 1 H), 4.60 (t, J=7.3 Hz, 2H), 3.91 (s, 3 H), 3.75 (t, J=6.4 Hz, 2 H), 2.36 (t, J=7.0 Hz, 2 H); EIMS m/z (rel intensity) 444 (M+, 100), 442 (M+, 100), 363 [(M-Br)+, 69]; HRESIMS calcd for C20H15BrN2O5 442.0164 (MH+), found 442.0158 (MH+); Anal. Calcd for C20H15BrN2O5 0.8H2O: C, 52.49; H, 3.66; N, 6.12; Br, 17.46. Found: C, 52.20; H, 3.54; N, 5.96; Br, 17.46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1.Br.Br[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)Cn1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: BrCc1cccnc1
Agent: Br
Product: CCOC(=O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
216 mg (0.6 mmol) of ethyl {4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetate and 228 mg (0.9 mmol) of 3-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 39 mg (14% of theory)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO>[F:1][C:2]([F:12])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(c1ccc(O)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(C(O)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-phenyl)-ethanone (1) (4.1 g, 21.6 mmol) was dissolved in MeOH (50 mL) at 0° C. NaBH4 (1.6 g, 42.2 mmol) was slowly added to the above solution. After 20 minutes, the reaction mixture was quenched with 300 ml of 1M HCl. The mixture thus formed was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with H2O (3×100 mL), followed by brine (1×200 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation to yield a white solid. Recrystallization of the solid with CHCl3 yields intermediate compound (2) as fluffy white crystals (3.14 g, 76%). 1H-NMR (CD3OD): δ 7.28 (d, 2H, J=8.7 Hz), 6.78 (m, 2H), 4.89 (q, 1H, J=7.2 Hz); 19F NMR (CD3OD): δ −80.4 (d, J=7.2 Hz); 13C-NMR (CD3OD): δ 158.0, 128.9, 126.4, 125.2 (q, JCF=280 Hz), 114.9, 71.7 (q, JCF=31 Hz).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](Cl)=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH3:31])[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.CCCCCCC.O>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][C:23]=1[O:30][CH3:31])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: Clc1nccc2cc(SCc3ccccc3)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1-c1nccc2cc(SCc3ccccc3)ccc12
Temperature: 100 °C
Yield: 74.6 %

Procedure:
A round-bottom flask was charged with 6-(benzylthio)-1-chloroisoquinoline (from STEP 1 of INTERMEDIATE LLL) (688.23 mg, 2.408 mmol), (4-chloro-2-methoxyphenyl)boronic acid (494 mg, 2.65 mmol), Pd(AmPhos)2Cl2 (85 mg, 0.120 mmol), potassium phosphate (1534 mg, 7.22 mmol), dioxane (6020 μl), and water (2007 μl). The vial was flushed with Ar (g), then 1,4-dioxane (6020 μl) and water (2007 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The mixture was cooled to room temperature, then diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (40-g, 10 to 40%, then 40-70% EtOAc/Heptane, 25-g silica gel loading column) to give 6-(benzylthio)-1-(4-chloro-2-methoxyphenyl)isoquinoline (704.36 mg, 1.797 mmol, 74.6% yield) as a light-yellow foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.56 (d, J=5.8 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.55-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.38-7.27 (m, 5H), 7.11 (dd, J=1.9, 8.1 Hz, 1H), 7.04 (d, J=1.9 Hz, 1H), 4.30 (s, 2H), 3.70 (s, 3H); m/z (ESI) 392.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:10]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
In DMF (3 ml) was dissolved methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g), and the solution was added dropwise to a suspension of 60% sodium hydride (0.05 g) in DMF (1 ml) under ice-cooling. The mixture was stirred under nitrogen atmosphere for 10 minutes. Benzyl bromide (0.15 ml) was added thereto, and the mixture was heated at 45° C. for 4 hours. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzyl-7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) as yellow oil.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N([O-])=O.[Na+].[ClH:23]>[Cu]Cl>[Cl:23][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5-amino-1-(4-fluorophenyl)pyrazole-4-carboxylate (5.4 g) was dissolved in 12N hydrochloric acid, and aqueous solution (10 ml) containing sodium nitrite (4.5 g) was added dropwise thereto under ice-cooling, which was followed by stirring for 2 h. An aqueous solution (10 ml) containing copper(I) chloride (10.7 g) was added and the mixture was stirred for 30 min. The mixture was warmed to room temperature and stirred further for 2 h. Solid was filtered off with Celite and ethyl acetate was added to the filtrate to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the obtained residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give ethyl 5-chloro-1-(4-fluorophenyl)pyrazole-4-carboxylate (3.5 g), melting point: 70–72° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CC1C=CC(S(O[CH2:37][CH2:38][CH:39]([OH:41])[CH3:40])(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:37][CH2:38][CH:39]([OH:41])[CH3:40]
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC(C)O)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and 3-hydroxybutyl 4-methylbenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:5][CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].C(C(CCCC)C=O)C.[OH-].[Na+]>C(C(C)=O)C(C)C>[CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:4]=[CH:5][C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCCCC(CC)CCC(O)CC(C)C
Agent: CCCCC(C=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: CCCCC(C=CC(=O)CC(C)C)CC

Procedure:
In particular, the process of the invention is suitable for preparing 7-ethyl-2-methyl-4-undecanol (tetradecanol) by aldol condensation of methyl isobutyl ketone and 2-ethylhexanal at 90-110° C. in the presence of a 40-50% strength aqueous sodium hydroxide solution to form 7-ethyl-2-methylundec-5-en-4-one with subsequent hydrogenation to give the above-mentioned alcohol. The hydrogenation catalyst used here is, preferably, a nickel catalyst supported on kieselguhr.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:41]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)N1CCCC1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N5CCCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available 1-pyrrolidinecarbonyl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=575 by positive ion CI.