Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([OH:25])[CH:18]=2)[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]1)=[O:4].[O:27]1[CH2:30][CH:29]([C:31]2[CH:32]=[C:33]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:34]=[CH:35][CH:36]=2)[CH2:28]1.C([O-])([O-])=O.[K+].[K+].[Na+].[Cl-]>CC(=O)OCC.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([CH:29]4[CH2:28][O:27][CH2:30]4)[CH:32]=3)[CH:18]=2)[CH2:6][CH2:7][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc(C3COC3)c2)cc1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCC(C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C4COC4)c3)c2)CCC(C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
60 mg of 1-(3-Hydroxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester, 53 mg of toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester, and 66 mg of K2CO3 were added to 3 ml of DMF and the mixture was stirred for 8 h at 40° C. Then, 27 mg of toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester were added and stirring was continued for 8 h at 40° C. Then, 10 ml of EA and 15 ml of a half-saturated aqueous NaCl-solution were added. The layers were separated and the aqueous layer was extracted twice using 10 ml of EA each. The combined organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:1 yielded 77 mg of the title compound, amorphous solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:42]([OH:44])=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][CH:29]3[C:41]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:35]4[C:30]3=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O[N:46]1[C:50](=[O:51])[CH2:49][CH2:48][C:47]1=[O:52].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>C(OC(=O)C)C.CN(C)C=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:42]([O:44][CH:48]3[CH2:49][C:50](=[O:51])[NH:46][C:47]3=[O:52])=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][CH:29]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]4[C:41]3=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:26])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC(OC(=O)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1

Procedure:
To a stirred solution of N,N'-bis-(9-fluorenylmethyloxycarbonyl)-D-lysine (12.0 g) in 360 ml of an ethylacetate:dimethylformamide (35:1) mixture are added N-hydroxysuccinimide (3.1 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.2 g) and diisopropylethylamine (2.0 ml). After 15 hours the solution is washed successively with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, and concentrated in vacuo to about 20 ml. The solution is added to hexane (1 l.) and the precipitate is collected and dried to afford the title compound.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:28])[CH:6]([S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16]O)=[CH:10][CH:9]=1.[CH3:31][S:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:37]=1)(=[O:34])=[O:33]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][S:18][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][O:44][C:43](=[O:45])[CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:41][CH:40]=3)=[CH:12][CH:13]=2)[C:5]([OH:28])=[O:4])=[CH:22][CH:23]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCCO)cc1)SCCc1ccc(F)cc1
Reactant: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)Oc1ccc(CC(=O)OCCCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-[4-(3-hydroxy-propyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (45 mg, 0.091 mmol) and (4-methanesulfonyloxy-phenyl)-acetic acid (19 mg, 0.083 mmol) in the same manner as described for example 1. The crude product was purified by HPLC (yield: 3.0 mg, 4.2%). 1H NMR (400 MHz, CDCl3): δ 7.30-7.32 (d, 2H), 7.21-7.23 (d, 2H), 7.05-7.08 (m, 4H), 6.98-7.00 (d, 2H), 6.90-6.94 (t, 2H), 4.04-4.07 (t, 2H), 3.63 (m, 2H), 3.46 (m, 2H), 3.08 (s, 3H), 2.79-2.90 (m, 5H), 2.54-2.58 (t, 2H), 1.87-1.90 (t, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][C:10]2([F:36])[F:35])(=O)=O.[Cl-].[Li+].[CH2:41]([Sn](CCCC)(CCCC)C=C)[CH2:42]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:10]1([F:36])[C:9]2[C:32](=[CH:33][CH:34]=[C:7]([CH:41]=[CH2:42])[CH:8]=2)[C:13]2=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:23])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)=[C:12]2[CH2:11]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 100 °C
Yield: 64.3 %

Procedure:
A mixture of 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate (Preparation 66E, 0.024 g, 0.042 mmol) and lithium chloride (2.60 μL, 0.127 mmol) in dioxane (5.0 mL) was degassed with nitrogen for 15 minutes. To the reaction mixture was added tributyl(vinyl)stannane (0.015 g, 0.047 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (4.90 mg, 4.24 μmol) at room temperature. The resulting reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and filtered. The brownish residue was washed with ethyl acetate (3×10 mL), and the combined filtrates were concentrated in vacuo. The residue was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to yield 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.012 g, 0.027 mmol, 63.7% yield) as a tan viscous liquid. The product had an HPLC ret. time=3.77 min. (condition B). LC/MS M+1=444.20. 1H NMR (500 MHz, CD3OD) δ ppm 7.75 (1H, d, J=7.93 Hz), 7.55-7.68 (2H, m), 7.38-7.57 (4H, m), 7.18-7.38 (1H, m), 6.63 (1H, dd, J=17.70, 10.99 Hz), 5.75 (1H, d, J=17.70 Hz), 5.19 (1H, d, J=10.99 Hz), and 2.85-3.02 (2H, m).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][OH:5].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].FC1C=CC=CC=1C=O.Cl>C1CCCCC1.CCCCCC>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH:4]=[O:5]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: CC(C)[O-]
Agent: Cl
Agent: O=Cc1ccccc1F
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
(2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrien-1-ol (1.3 g, 6.0 mmol) was dissolved in cyclohexane (4.5 mL), added with aluminum isopropoxide (123 mg, 0.1 eq, 0.6 mmol) and 2-fluorobenzaldehyde (968 mg, 1.3 eq, 7.8 mmol) and stirred at room temperature for 3 hours. The reaction mixture was added with hexane, then made acidic with addition of 1 N hydrochloric acid and extracted twice with ethyl acetate. Subsequently, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 1.23 g (yield: 92%, E:Z=99:1) of the title compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[CH:21](=O)[CH2:22][CH3:23].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:17]1([CH3:18])[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:9]1[C:4]2[C:5](=[O:8])[NH:6][N:7]=[C:2]([NH:1][CH2:21][CH2:22][CH3:23])[C:3]=2[CH:11]=[CH:10]1
Reactant: Cc1cc(C)c(-n2ccc3c(N)n[nH]c(=O)c32)c(C)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCNc1n[nH]c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of 4-amino-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (50 mg, 0.19 mmol), propionaldehyde (0.034 ml, 0.47 mmol), AcOH (0.013 ml, 0.224 mmol) and dichloromethane (10 ml) was stirred for 30 min before addition of NaBH(OAc)3 (99 mg, 0-47 mmol). The mixture was stirred for 3 hours, then washed with saturated sodium bicarbonate (20 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (1:1-1:2) to give 19.4 mg (34%) of the title compound as crystals.
Reaction SMILES: [CH3:1][C@H:2]([C@@:10]([OH:25])([C:17]1[CH:18]=[CH:19][C:20]([F:24])=[CH:21][C:22]=1[F:23])[CH2:11][N:12]1[N:16]=[CH:15][N:14]=[CH:13]1)[C:3]1[N:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:9].[C@@:26]12([CH2:36][S:37]([OH:40])(=[O:39])=[O:38])[C:33]([CH3:35])([CH3:34])[CH:30]([CH2:31][CH2:32]1)[CH2:29][C:27]2=[O:28]>>[CH3:1][C@H:2]([C@@:10]([OH:25])([C:17]1[CH:18]=[CH:19][C:20]([F:24])=[CH:21][C:22]=1[F:23])[CH2:11][N:12]1[N:16]=[CH:15][N:14]=[CH:13]1)[C:3]1[N:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:9].[CH3:1][C@H:2]([C@@:10]([OH:25])([C:17]1[CH:18]=[CH:19][C:20]([F:24])=[CH:21][C:22]=1[F:23])[CH2:11][N:12]1[N:16]=[CH:15][N:14]=[CH:13]1)[C:3]1[N:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:9].[C@@:26]12([CH2:36][S:37]([O-:40])(=[O:38])=[O:39])[C:33]([CH3:35])([CH3:34])[CH:30]([CH2:31][CH2:32]1)[CH2:29][C:27]2=[O:28]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: C[C@@H](c1ncncc1F)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: CC1(C)C2CC[C@]1(CS(=O)(=O)[O-])C(=O)C2

Procedure:
More specifically, the invention relates to a process which comprises the dehalogenation of a haloderivative of Voriconazole via catalytic transfer hydrogenation of i.e (2R,3S/2S,3R)-3-(4-halo-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol to obtain racemic Voriconazole (i.e (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol). Thereafter, racemic Voriconazole (compound V) is resolved using (1R)-(−)-10-camphorsulfonic acid ((−)-CSA) and isolating Voriconazole (compound I) from the diastereomeric salt Voriconazole (1R)-(−)-10-camphorsulfonate (compound VI).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[C:15](=[O:17])=[O:16]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dichloro-5-methylbenzene (2.0 g, 12.4 mmol) in THF (20 mL) was added n-BuLi (2.0 M in hexane, 9.3 mL, 18.6 mmol) at −78° C. dropwise over a period of 10 min and mixture was stirred at −78° C. for 30 min. A dry-ice was added to the reaction mixture slowly and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was slowly warmed to room temperature, quenched with 6 M HCl (10 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get compound A111-1 (1.1 g, 44%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]3[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[CH:21]=3)[C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[Cl:34][C:17]1[CH:18]=[C:19]([F:33])[C:20]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:24])=[CH:21][C:16]=1[C:7]1[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:1][C:35](=[O:37])[CH3:36])[CH:11]=2
Reactant: CC(=O)Cl
Reactant: CC(C)n1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2Cl)cc2cnc(N)cc21
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3cccc(F)c3)c(F)cc1Cl)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A solution of 1-(5-(7-amino-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (0.07 g, 0.145 mmol) in pyridine (2 mL) was treated with acetyl chloride (0.011 mL, 0.159 mmol) and stirred at RT for 2 h. The mixture was concentrated to dryness, treated with EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with Et2O and the solid collected via filtration to afford N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (65 mg, 84% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.31 (s, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.46 (dt, J=11.9, 2.3 Hz, 1H), 7.29 (m, 1H), 7.06 (m, 1H), 6.79 (td, J=8.5, 2.6 Hz, 1H), 5.36 (m, 1H), 2.14 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 526.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].[H-].[Na+].Cl[CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][CH2:20]3)[CH:14]=[N:15][CH:16]=1.O>CN(C=O)C>[CH3:27][N:23]1[C:22](=[O:28])[CH2:21][CH2:20][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH2:10][NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:16]=[N:15][CH:14]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CCS(N)(=O)=O
Reactant: CN1C(=O)CCc2nc(-c3cncc(CCl)c3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)NCc1cncc(-c2ccc3c(n2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
To a stirred solution of ethanesulfonic acid amide (118 mg, 1.08 mmol) in DMF (5.0 mL) was added 60% NaH (35 mg, 0.81 mmol) at RT and the resulting reaction mixture was stirred for 0.5 hour before 6-(5-chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (156 mg, 0.54 mmol) was added. After continued stirring at RT for additional 2 hours, water (1.0 mL) was added. After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (15 mg, 7.7%) as a light yellow solid. MS: 361.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:8]=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(=[O:17])[CH3:16]>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:8]=[C:23]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)c1ccccn1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C=C2C=CC=NC2C(C)=O)cc(OC)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a well stirred solution of NaOH (12 g, 0.3 mmole) in H2O (125 ml) and methanol (250 ml) at 0° C. was added 3,5-dimethoxy benzaldehyde (19 g, 0.11 mmole) followed by a solution of 2-acetylpyridine (14.4 g, 0.12 mmole) in MeOH. The reaction was stirred at 0° C. for 1 hour and at room temperature for 16 hours. The precipitate was filtered and recrystallized from MeOH (Yield: 18 mg, 57%). The preparation scheme is shown below:
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[C:13]([F:19])=[C:14]([F:18])[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([F:19])=[C:14]([F:18])[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC=C(c2cccc(F)c2F)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2cccc(F)c2F)cc1
Reaction time: 2 h

Procedure:
A solution of 0.225 mol of 3-(4-pentylcyclohexenyl) -1,2-difluorobenzene (analogous to Example 6) and 0.55 mol of DDQ in 1.5 1 of toluene is heated to boiling for 2 hours. The mixture is subsequently worked up as customary, b.p. 0.5 : 125° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([OH:39])=[O:38])[CH3:28].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:27][CH3:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCc1ccccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
PS-DCC (962 mg, 1.37 mmol, loading: 1.33 mmol/g) is suspended in THF (10 mL). HOBT (210 mg, 1.37 mmol), (2-ethyl-phenylamino)-phenyl-acetic acid hydrochloride (I60) (200 mg, 0.68 mmol), and (R)-quinuclidin-3-ol (262 mg, 2.06 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and washed with THF and the filtrate is evaporated under reduced pressure. The resulting residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is separated, dried over Na2SO4, filtered and evaporated. The residue is first purified by flash chromatography (DCM/MeOH=9/1) and then by preparative HPLC. The fractions containing the product are pooled, concentrated under vacuum, basified with sat. NaHCO3 and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and evaporated to afford the title compound as a colorless oil (52 mg, 21% yield, mixture of diastereoisomers).
Reaction SMILES: C(O/[CH:4]=[C:5](\[C:11](=O)[C:12]([F:15])([F:14])[F:13])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(N(C(C)C)CC)(C)C.F.[F:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][NH2:35])=[N:32][CH:33]=1>C(O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:35]2)=[N:32][CH:33]=1
Reactant: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Reactant: NNc1ccc(F)cn1
Agent: F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2ccc(F)cn2)c1C(F)(F)F
Temperature: 80 °C
Yield: 29.7 %

Procedure:
To (E)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.441 g, 1.835 mmol) in ethanol (2 mL) was added diisopropylethylamine (0.427 mL, 2.447 mmol) followed by 5-fluoro-2-hydrazinylpyridine, hydrofluoride (0.3 g, 2.039 mmol) dissolved in 1 mL of ethanol (slightly exothermic). The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (2 mL) and subjected to column chromatography using an ISCO setup (40 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield ethyl 1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.165 g, 27%) as a white solid. LC/MS M+1=304.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reaction time: 18 h
Yield: 42.4 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (263 mg, 1.39 mmol) in THF (3 mL) was added sodium hydride (55% dispersion in mineral oil, 66.7 mg, 1.53 mmol). After stirring for 15 min at room temperature methyl 6-chloronicotinate (286 mg, 1.67 mmol) was added and the reaction mixture was stirred for 18 h. The mixture was then diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic extracts dried over sodium sulfate. Filtration and concentration followed by purification by chromatography (silica, heptane:ethyl acetate 1:0 to 7:3) afforded the title compound (191 mg, 42%) as a colorless oil MS: m/e=325.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]([CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:23]([CH3:22])[CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:29][CH:28]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCC(N(C)c2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 34 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide and N1-methyl-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in 34% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 8.60 (d, 1H, J=8.2 Hz), 8.06 (s, 1H), 8.18 (d, 1H, J=8.0 Hz), 7.47 (t, 1H, J=7.7 Hz), 7.31 (d, 2H, J=8.9 Hz), 7.16 (t, 1H, J=7.5 Hz), 6.77 (d, 2H, J=8.9 Hz), 3.51 (tt, 1H, J=11.3, 3.8 Hz), 3.00 (d, 2H, J=10.6 Hz), 2.76 (s, 3H), 2.72 (s, 3H), 2.34 (s, 3H), 2.11 (t, 2H, J=10.2 Hz), 1.90 (q, 2H, J=11.3 Hz), 1.73 (d, 2H, J=12.0 Hz); MS (ESI): 530.3 [M+H]+.