Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:23])[C:14]([O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:15].[P:24](Cl)(Cl)(=[O:36])[O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(Cl)[Cl:40]>>[Cl:40][C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]=1[O:25][P:24](=[N:12][C@@H:13]([CH3:23])[C:14]([O:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)=[O:15])=[O:36]
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: C[C@H](N)C(=O)OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OC1CCOCC1
Yield: 70 %

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates the tosylate salt of (S)-tetrahydro-2H-pyran-4-yl 2-aminopropanoate (1.00 g, 2.90 mmol), naphthalen-1-yl phosphorodichloridate (0.76 g, 2.90 mmol) and TEA (0.80 mL, 5.79 mmol) in 30 mL of dry DCM, were combined to give (2S)-tetrahydro-2H-pyran-4-yl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate in 70% yield (0.84 g), as a clear, yellow, thick oil.
Reaction SMILES: BrBr.[F:3][C:4]([F:18])([F:17])[O:5][C:6]1[CH:15]=[C:14]2[C:9]([NH:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[S-:19][C:20]#[N:21].[K+]>C(O)(=O)C>[NH:21]=[C:20]1[N:10]2[CH2:11][C:12](=[O:16])[NH:13][C:14]3[CH:15]=[C:6]([O:5][C:4]([F:3])([F:17])[F:18])[CH:7]=[C:8]([C:9]=32)[S:19]1
Reactant: N#C[S-]
Reactant: O=C1CNc2ccc(OC(F)(F)F)cc2N1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N=c1sc2cc(OC(F)(F)F)cc3c2n1CC(=O)N3
Yield: 15.1 %

Procedure:
The procedure is carried out as in Example 23, but starting with 1.1 g of bromine in 3.5 ml of acetic acid, 1.6 g of 7-trifluoromethoxy-3,4-dihydro -1H-quinoxalin-2-one and 1.54 g of potassium thiocyanate in 20 ml of acetic acid. The product obtained (1.8 g) is purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and methanol (99-1 by volume). 0.3 g of 2-imino-8-trifluoromethoxy -2H,4H-thiazolo[3,4,5-de]quinoxalin-5(6H)-one is thus obtained in the form of a yellow solid melting at 255° C. [Analysis C10H6F3N3O2S, % calculated C: 41.53, H: 2.09, F: 19.71, N: 14.53, O: 11.06, S: 11.09, % found C: 41.00, H: 1.7, F: 19.2, N: 14.50, S: 11.6].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.[F:26][C:27]1[CH:28]=[C:29](C=C[C:35]=1[F:36])[C:30](Cl)=O.C(N(C(C)C)CC)(C)C.[CH2:46]([OH:48])[CH3:47]>O.C(Cl)Cl>[F:36][C:35]1[C:27]([F:26])=[CH:28][CH:29]=[CH:30][C:47]=1[C:46]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[CH:6][CH:5]=1)=[O:48]
Reactant: O=[N+]([O-])c1ccc(-c2c(C(F)(F)F)nc3ccccn23)cc1
Reactant: CCO
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2c(C(F)(F)F)nc3ccccn23)cc1)c1cccc(F)c1F
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 690 mg (2.3 mmol) of 3-(4-Nitro-phenyl)-2-trifluoromethyl-imidazo[1,2-a]pyridine (175) in 30 mL of a 1:1 mixture of CH2Cl2 and ethanol (EtOH) was added 4.3 g (23 mmol) of SnCl2 and 4 drops of H2O. The reaction was allowed to stir overnight at which time it was concentrated in vacuo, and the resulting oil dissolved in 40 mL of EtOAc and washed 3 times with 50 mL of 2N NaOH. The organic layer was then dried over MgSO4 filtered and concentrated in vacuo. 73 mg (0.26 mmol) of the resulting solid was dissolved in 4 mL of CH2Cl2 to which 0.035 mL (0.27 mmol) of 3,4 difluorobenzoylchloride and 0.09 mL (0.52 mmol) diisopropyl ethyl amine (DIPEA) were added. The reaction was allowed to stir for 4 hrs at which time it was diluted with 20 mL CH2Cl2, quenched with 15 mL saturated aqueous NaHCO3 and washed with 15 mL brine. The organic layer was then dried over MgSO4 filtered and concentrated in vacuo. The crude oil was purified by silica gel chromatography 1:3 (EtOAc:Hexanes) to yield 91 mg (84%) of 2,3-Difluoro-N-[4-(2-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-benzamide (Compound 70) as a white solid.
Reaction SMILES: NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([CH:45]4[CH2:50][CH2:49][CH2:48][CH:47]([C:51]([O:53][CH3:54])=[O:52])[CH2:46]4)[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)([O-])=O>>[NH2:26][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([CH:45]4[CH2:50][CH2:49][CH2:48][CH:47]([C:51]([O:53][CH3:54])=[O:52])[CH2:46]4)[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)C1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)C1
Yield: 72 %

Procedure:
The compound of example 543 was prepared analogous to the compound of example 6 by reduction of the compound of example 542.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24]O>>[F:15][C:16]1[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)c(F)c1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1F

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,3-difluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.32 (3H, s), 5.28 (2H, s), 5.80 (1H, s), 6.98 (1H, d, J=6.8 Hz), 7.11 (1H, d, J=7.2 Hz), 7.40 (1H, d, J=5.2 Hz), 7.58 (1H, s), 8.01 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H12F2N4O, 327. Found, 327.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([O:9][N+:10]([O-:12])=[O:11])[CH2:7][O:8][C@@H:3]2[C@H:2]1[OH:13].[CH2:14]([O:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:20]2[C:59]([C:63]([O:65][C:66]([CH3:81])([O:68][C:69](OC3C=CC([N+]([O-])=O)=CC=3)=[O:70])[CH3:67])=[O:64])=[CH:60][CH:61]=[CH:62][C:19]=2[N:18]=1)[CH3:15]>CN(C)C1C=CN=CC=1.ClCCl.CO.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:14]([O:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:20]2[C:59]([C:63]([O:65][C:66]([O:68][C:69]([O:13][C@H:2]3[CH2:1][O:5][CH:4]4[C@H:6]([O:9][N+:10]([O-:12])=[O:11])[CH2:7][O:8][CH:3]34)=[O:70])([CH3:81])[CH3:67])=[O:64])=[CH:60][CH:61]=[CH:62][C:19]=2[N:18]=1)[CH3:15]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)O[C@H]3COC4C3OC[C@H]4O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Isosorbide-5-mononitrate (0.203 g, 1.06 mmol) was added to a stirred solution of 1-methyl-1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (Intermediate 1, 0.800 g, 0.883 mmol), 4-dimethylaminopyridine (0.162 g, 1.33 mmol) and scandium trifluoromethanesulfonate (0.087 g; 0.177 mmol) in dichloromethane (12 mL). The solution was stirred at room temperature for 24 hours. Then the mixture was diluted with dichloromethane, washed with aqueous sodium dihydrogenphosphate (20 mL) and brine (20 mL); the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 40+M; TLC method: n-hexane/ethyl acetate: 6/4; Rf=0.33) to afford a solid that was dissolved in methanol (8 mL). The mixture was stirred at 40° C. for 5 hours, at 60° C. for 2 hours, and at room temperature for 18 hours. Then the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 25+M; dichloromethane/methanol: 98/2), affording the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, 1H), 7.69-7.58 (m, 2H), 7.48 (d, 1H), 7.31 (d, 1H), 6.88 (t, 1H), 6.80 (d, 2H), 6.76-6.62 (m, 3H), 5.60 (s, 2H), 5.41-5.33 (m, 1H), 5.03 (d, 1H), 4.95 (t, 1H), 4.48 (d, 1H), 4.36-4.15 (m, 2H), 4.10-3.86 (m, 3H), 1.62 (d, 614) 1.43 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]#[N:12])=[CH:6][C:4]=1[OH:5])#[N:2].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.CN(C=O)C>[CH2:13]([O:10][C:8]1[C:7]([C:11]#[N:12])=[CH:6][C:4]([OH:5])=[C:3]([C:1]#[N:2])[CH:9]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N#Cc1cc(O)c(C#N)cc1O
Reactant: CCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(C#N)c(O)cc1C#N
Temperature: 120 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
In a 300 ml-reaction vessel, 350 g (2.19×10-1M) of 2,5-dicyanohydroquinone, 23.8 g (1.44×10-1M) of n-hexylbromide, 20.0 g (1.45×10-1M) of potassium carbonate and 180 ml of DMF were placed, followed by stirring for 3 hours at 120° C. After the reaction, the reaction mixture was cooled and poured into 500 ml of 4N-hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent. The resultant residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to obtain 17.6 g of a crude product. The crude product was dissolved in ethanol and treated with activated carbon, followed by recrystallization from ethanol to obtain 8.2 g of 4-hexyloxy2,5-dicyanophenol (Yield: 22.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH3:14])[CH:5]=1>[Pd].CO.ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(N)c(OC)c1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Palladium on carbon (10%, catalytic amount) was added to a solution of 3-methoxy-4-nitro-benzoic acid methyl ester (1.08 g, 5.11 mmol) in a mixture of methanol (40 mL) and dichloromethane (a few drops). The resulting mixture was stirred under nitrogen atmosphere (balloon pressure) overnight. The catalyst was filtered off on a CELITE™ pad and the solvent was evaporated to give 0.929 g of 4-amino-3-methoxy-benzoic acid methyl ester as a yellow solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([C:31]([O:33]C)=[O:32])=[C:28](/[N:35]=[CH:36]/N(C)C)[CH:27]=2)=[CH:22][CH:21]=1>CO>[C:31]([OH:33])(=[O:32])[CH3:29].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]3[C:31](=[O:32])[N:18]([CH2:17][C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)[CH:12]=4)[CH:36]=[N:35][C:28]=3[CH:27]=2)=[CH:24][CH:25]=1
Reactant: CC(C)N1CCC(Oc2cccc(CN)c2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: CO
Product: CC(=O)O
Product: CC(C)N1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 120 °C

Procedure:
1-{3-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}methanamine (188 mg, 0.757 mmol) and methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (244 mg, 0.757 mmol) were dissolved in MeOH (2 ml). The reaction was heated in a microwave at 120° C. for 15 minutes, during which time a precipitate had been formed in the microwave vial. The precipitate was filtered off and washed with MeOH. The filtrate was purified by reversed phase HPLC yielding the title compound as a white solid. Yield: 37 mg (9%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.59 (m, 2H), 7.43 (s, 1H), 7.39 (m, 2H), 7.24 (t, 1H, J=7.9 Hz), 6.91-6.87 (m, 2H), 6.81 (dd, 1H, J=7.9 Hz, J=2.1 Hz), 5.15 (s, 2H), 4.40 (m, 1H, J=2.8 Hz), 3.06 (m, 1H, J=6.5 Hz), 2.87 (m, 2H), 2.75-2.67 (m, 2H), 2.14 (m, 2H), 1.97 (s, 2H), 1.90 (m, 2H), 1.13 (d, 6H, J=6.6 Hz). 13C NMR (100 MHz, CDCl3) δ 177.0, 157.9, 157.7, 157.1, 151.6, 148.1, 137.5, 135.8, 131.7, 130.5, 129.9, 127.8, 123.3, 121.0, 120.7, 116.3, 115.5, 70.9, 55.3, 49.5, 44.4, 29.3, 23.3, 17.7. MS (ESI+) 494.0 (M+1H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:24][N:25]([CH3:27])[CH3:26])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
16.0 g of 3-benzyloxy-4-nitrotoluene and 23.0 g of tert-butoxybis(dimethylamino)methane are heated for 8 hours to 100° C. After allowing the mixture to stand for 8 hours at room temperature, the pure reaction product is crystallized. This product is filtered off and washed with a mixture of ethyl acetate and cyclohexane 1:4, thus obtaining 18.7 g of 1-(3-benzyloxy-4-nitrophenyl)-2-dimethylaminoethene, mp 111°-114° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[C:19]([F:30])[CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:31])[C:11]=2[CH2:32][OH:33])[CH:3]=1.[F:34][C@H:35]1[CH2:37][C@H:36]1[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:26]([C:21]1[CH:22]=[C:23]2[C:18](=[C:19]([F:30])[CH:20]=1)[C:17](=[O:31])[N:16]([C:12]1[C:11]([CH2:32][OH:33])=[C:10]([C:4]3[CH:3]=[C:2]([NH:1][C:38]([C@@H:36]4[CH2:37][C@@H:35]4[F:34])=[O:39])[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=3)[CH:15]=[CH:14][N:13]=1)[N:25]=[CH:24]2)([CH3:29])([CH3:27])[CH3:28]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(N)c1=O
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(NC(=O)[C@@H]2C[C@@H]2F)c1=O
Yield: 73 %

Procedure:
A solution of 123d, (1S,2S)-2-fluorocyclopropanecarboxylic acid (15 mg, 0.14 mmol, 1.3 equiv), HATU (65 mg, 0.17 mmol, 1.5 equiv) and N,N-diisopropylethylamine (60 uL, 0.33 mmol, 3.0 equiv) in DMF (1.0 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm) to give 43 mg (73%) of 123 as an off white solid. LC-MS m/z: 536.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.80-7.72 (m, 2H), 7.49 (d, J=5.0 Hz, 1H), 5.03-4.73 (m, 1H), 4.89 (t, J=5.2 Hz, 1H), 4.43-4.36 (m, 2H), 3.60 (s, 3H), 2.50-2.41 (m, 1H), 1.68-1.52 (m, 1H), 1.39 (s, 9H), 1.20-1.08 (m, 1H).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]=[N+:20]=[N-:21])[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.C(OC(=O)C)C.O>[O:25]=[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]=[N+:20]=[N-:21])[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:5][CH2:6]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.7 %

Procedure:
(5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one (2.3 g, 6.5 mmol) (see WO 01/81350) was dissolved in methanol/ethylacetate (1:1, 100 ml) and sodium periodate (1.75 g, 8.2 mmol), dissolved in water (20 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 7 hours at room temperature, filtered to remove most of the salts and the methanol was evaporated under vacuum. The aqueous solution thus obtained was extracted with ethyl acetate, dried over sodium sulfate and it was evaporated to dryness. The residue was subjected to chromatography on silica gel with acetone/hexane (2:1) to give 2.18 g of the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:47][O:48][CH2:49][CH2:50][O:51][CH2:52][O:53][C:54]1[CH:63]=[C:62]2[C:57]([CH:58]=[CH:59][CH:60]=[C:61]2[NH:64][CH3:65])=[CH:56][CH:55]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:10])[C:11]([N:64]([C:61]1[C:62]2[C:57](=[CH:56][CH:55]=[C:54]([O:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH3:47])[CH:63]=2)[CH:58]=[CH:59][CH:60]=1)[CH3:65])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNc1cccc2ccc(OCOCCOC)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc2cccc(N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C)c2c1
Reaction time: 48 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)alanine (1.09 g, 5.78 mmol) in dry CH2Cl2 (4 mL) under argon were added PYBOP (3.01 g, 5.78 mmol), 7-[(2-methoxyethoxy)methoxy]-1-(methylamino)naphthalene, as described above in Step B, (302 mg, 1.16 mmol), and N,N-diisopropylethylamine (1.00 mL, 5.75 mmol). The reaction mixture was stirred for 48 hrs, then partitioned between CH2Cl2 (500 mL) and 10% aqueous citric acid (150 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with a gradient of hexane −10% to 60% EtOAc to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:26])[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCCc1cc(Cl)c(Oc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: [K+]
Solvent: CI
Product: CC(=O)OCCc1cc(Cl)c(Oc2cc(C(C)C)c(=O)n(C)n2)c(Cl)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
A mixture of acetic acid 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (34) (531 mg, 1.38 mmol), potassium carbonate (280 mg, 2.03 mmol) and methyl iodide (2 mL, 32.1 mmol) was warmed to 40° C. for 2 h. Additional methyl iodide was added (1 mL, 16.05 mmol) followed by potassium carbonate (140 mg, 1.01 mmol). The mixture was heated at 40° C. for 2 h and then was stirred at room temperature for 24 h. The reaction mixture was concentrated and the resulting residue was partitioned between ethyl acetate (50 mL) and water (25 mL). The water layer was re-extracted with ethyl acetate (25 mL). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in 25% ethyl acetate in hexanes and was purified by flash chromatography (Biotage 40S) using silica gel eluted with 25-50% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum. The resulting solid was dried under high vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]ethyl ester (35) (395 mg, 72%) as a clear oil; LRMS for C18H20Cl2N2O4 (M+) m/z=399. Molecular Weight=399.2771; Exact Mass=398.0800
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][S:7]([CH2:10][CH:11]([CH2:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[C:12](O)=[O:13])(=[O:9])=[O:8].[NH2:29][CH:30]([CH2:42][O:43][CH3:44])[CH:31]([C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[OH:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[O:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[CH:31]([OH:32])[CH:30]([NH:29][C:12](=[O:13])[CH:11]([CH2:10][S:7]([CH2:6][C:5]1[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=1[O:3][CH:2]([F:28])[F:1])(=[O:8])=[O:9])[CH2:15][C:16]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:17])[CH2:42][O:43][CH3:44]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1OC(F)F
Reactant: COCC(N)C(O)c1nc2ccccc2o1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: COCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1OC(F)F)C(O)c1nc2ccccc2o1
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a stirred mixture of 2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid (210.5 mg, 0.5 mmol), 2-amino-1-benzooxazol-2-yl-3-methoxy-propan-1-ol (112.5 mg), and HOBt (91.8 mg, 0.6 mmol) in MeCl2 (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine (0.35 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 301 mg of N-(2-benzooxazol-2-yl-2-hydroxy-1-methoxymethyl-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; MS: 624.5(M−1), 626.3(M+1).
Reaction SMILES: CN(CCN(C)C)C.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].[Li]CCCC.[O-]S(C(F)(F)[F:44])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>CCCCCC.C1COCC1>[CH2:9]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[C:26]([F:44])[CH:25]=3)=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[CH2:10][CH3:11]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)CCN(C)C
Agent: Cc1cc(C)[n+](F)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(F)(F)F)c(F)c3)cc2)CC1
Temperature: 25 °C

Procedure:
0.01 mol of TMEDA is added to a solution of 0.01 mol of 4-(trans-4-n-propylcyclohexyl)-4'-trifluoromethylbiphenyl in 10 ml of n-hexane. At 0°-5° C., 0.01 mol of n-BuLi is added, and stirring at RT is continued for another half an hour and at 40° C. for half an hour. The mixture is then cooled to 0° C., 20 ml of THF are added, and the fluorinating agent 1-fluoro-2,4,6-trimethylpyridinium triflate (in THF) is added dropwise at this temperature according to scheme 21. Extractive work-up and, as is customary, chromatography and crystallization give 4-(trans-4-n-propylcyclohexyl)-3'-fluoro-4'-trifluoromethylbiphenyl.