Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:16][C:17]([NH:19][CH2:20][CH2:21]O)=[S:18])[C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC>[S:18]1[CH2:21][CH2:20][N:19]=[C:17]1[NH:16][CH:10]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[CH2:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(CC(NC(=S)NCCO)c2ccco2)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(C)cc(CC(NC2=NCCS2)c2ccco2)c1
Temperature: 90 °C
Yield: 69.1 %

Procedure:
Following the procedure as described in example a solution of 1-[2-(3,5-dimethylphenyl)-1-furan-2-yl-ethyl]-3-(2-hydroxy-ethyl)-thiourea (0.46 g) and diisopropyethylamine (0.26 g) in propionitrile (20 ml) was treated with cyanomethyl trimethylphosphonium iodide (0.44 g) and heated for 16 h at a temperature of 90° C. Work-up yielded the title compound (0.30 g, 69%) as an amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:27]=[C:26]2B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O.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>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:27]=[C:26]2[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2cc(Br)ccc21
Reactant: COc1ccc(COc2cc(Cl)nc(S(C)(=O)=O)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2cc(-c3cn(C(=O)OC(C)(C)C)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 41.4 %

Procedure:
A glass microwave reaction vessel was charged with 4-chloro-6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidine (600 mg, 1.825 mmol) and tert-butyl 5-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (770 mg, 1.825 mmol) in p-dioxane/H2O (4:1, 6 mL) followed by Pd(PPh3)4 (105 mg, 0.091 mmol) and potassium carbonate (220 μL, 3.65 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-25% EtOAc in Hexanes) to give tert-butyl 5-bromo-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole-1-carboxylate (445 mg, 0.756 mmol, 41.4% yield) as a half solid. MS (ESI, pos. ion) m/z: 587.8 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O.Cl>C(O)(=O)C>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3cccc(F)c3)cnc21
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4cccc(F)c4)c3cnc21
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
4-Chloro-1-ethyl-5-(3-fluorobenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.60 g) and hydroxylamine hydrochloride (14.0 g) were refluxed in a solution of 250 ml of acetic acid and 4 ml of concentrated hydrochloric acid. After 90 minutes, the solvent was evaporated and the residue distributed between dichloromethane and an aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). Evaporation of the appropriate fractions gave 3.2 g of product, mp 182°-184°. Recrystallization from ethyl acetate gave analytically pure product, mp 183°-184° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 116.5 %

Procedure:
To a solution of 4-nitro-3-(trifluoromethyl)aniline (1.0 g, 4.85 mmol) in CH2Cl2 (15 mL) and TEA (2.95 g, 4.1 mL, 29.11 mmol) in a round-bottom flask at 0° C. was added trimethylacetyl chloride (1.75 g, 1.8 mL, 14.55 mmol) dropwise. The reaction mixture was warmed to room temperature and was quenched by pouring into water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel column chromatography using (0-100% EtOAc/Hex.) to obtain N-(4-nitro-3-(trifluoromethyl)phenyl)pivalamide (1.64 g, 81%). LC/MS: m/z 291.1 (M+H)+ at 1.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[N+:13]([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[NH:13][C:17](=[O:19])[CH3:18]
Reactant: COC(=O)Cc1ccc(OC)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a suspension of (4-methoxy-2-nitro-phenyl)-acetic acid methyl ester (154 mg, 0.68 mmol) in 3 mL of acetic acid was added acetic anhydride (3.0 mL, 30.0 mmol) and zinc (nanopowder, 220 mg, 3.36 mmol) in portions over 5 min at 0° C. The reaction mixture was maintained for 30 minutes at 0° C. and 1.5 h at room temperature. Additional zinc powder (110 mg, 1.68 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After filtration, the mixture was partitioned between 50 mL of ethyl acetate and 10 mL of saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified on a Biotage (Biotage Inc.) 10 g silica column, eluted with 0-40% EtOAc in heptane to provide 49 mg (68%) of (2-acetylamino-4-methoxy-phenyl)-acetic acid methyl ester. 1H NMR (CDCl3) δ 2.23 (s, 3H), 3.57 (s, 2H), 3.73 (s, 3H), 3.81 (s, 3H), 6.66 (dd, 1H), 7.09 (d, 1H), 7.57 (d, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[Cl:18][Si](C)(C)C.C1(C)C(C)=CC=CC=1>C(#N)C>[Cl:18][CH2:9][C:8](=[O:10])[C:4](=[N:3][O:2][CH3:1])[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CON=C(C(=O)O)C(=O)CCl
Temperature: -30 °C
Reaction time: 2 h

Procedure:
In 15 ml of acetonitrile was dissolved 725 mg of 2-methoxyimino-3-oxobutyric acid, followed by addition of 2.8 ml of triethylamine. Then, 2.5 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 2 hours. After addition of 10 ml of xylene, the reaction mixture was concentrated under reduced pressure and the residue was suspended in 15 ml of tetrahydrofuran. The suspension was filtered in a nitrogen gas stream to remove insolubles. This filtrate containing trimethylsilyl 2-ethoxyimino-3-oxobutyrate trimethylsilyl enol ether (i.e. trimethylsilyl 2-methoxyimino-3-trimethylsilyloxy-3-butenoate) was cooled to -30° C. and 0.45 ml of sulfuryl chloride was added dropwise thereto. After the temperature of the mixture was increased to 20° C., the reaction mixture was concentrated under reduced pressure and the residue was diluted with 20 ml of water and stirred for 10 minutes for hydrolyzing the trimethylsilyl ester. Then, 2N aqueous sodium hydroxide solution was added dropwise to adjust the reaction mixture to pH 9.0. The reaction mixture was washed twice with 20 ml portions of methylene chloride and the aqueous layer was adjusted to pH 0.5 by dropwise addition of concentrated hydrochloric acid. The aqueous layer was saturated with sodium chloride and extracted 3 times with 20 ml portions of ether. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The above procedure gave 4-chloro-2-methoxyimino-3-oxobutyric acid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][N:27]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: CNCC(=O)OC
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Temperature: 25 °C

Procedure:
To a 20 mL scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30.0 μL 0.176 mmol). Following 4, hours of stirring at room temperature, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.98-1.20 (m, 2 H), 1.38-1.55 (m, 2 H), 1.70-1.93 (m, 5 H), 2.20-2.33 (m, 2 H), 2.78-2.88 (m, 1H), 3.01-3.10 (m, 3 H), 3.64 (s, 3 H), 4.08 (s, 2 H), 7.03-7.19 (m, 1 H), 7.28-7.41 (m, 2 H), 7.66-7.76 (m, 2 H), 13.80-14.09 (m, 1H); MS (ESI) m/z 438 [M+H]f;
Reaction SMILES: CC(C)(C)[C@H](NC(=O)[C@@H](NC)C)C(N1[C@H](C(N[C@H]2C3C(=CC=CC=3)CCC2)=O)CC2C(=CC([C@H]3C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C3)=CC=2)C1)=O.[C@H:70]1([NH:80][C:81]([C@@H:83]2[CH:87]=[C:86](OS(C(F)(F)F)(=O)=O)[CH2:85][N:84]2[C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])=[O:82])[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[CH2:73][CH2:72][CH2:71]1.CC1(C)C(C)(C)OB([C:111]2[CH:120]=[C:119]3[C:114]([CH2:115][C@@H:116]([C:128]([O:130][CH3:131])=[O:129])[N:117]([C:121]([O:123][C:124]([CH3:127])([CH3:126])[CH3:125])=[O:122])[CH2:118]3)=[CH:113][CH:112]=2)O1>>[C:99]([O:98][C:96]([N:84]1[C@H:83]([C:81](=[O:82])[NH:80][C@H:70]2[C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[CH2:73][CH2:72][CH2:71]2)[CH:87]=[C:86]([C:111]2[CH:120]=[C:119]3[C:114]([CH2:115][C@@H:116]([C:128]([O:130][CH3:131])=[O:129])[N:117]([C:121]([O:123][C:124]([CH3:127])([CH3:126])[CH3:125])=[O:122])[CH2:118]3)=[CH:113][CH:112]=2)[CH2:85]1)=[O:97])([CH3:102])([CH3:100])[CH3:101]
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: COC(=O)[C@@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1C(=O)OC(C)(C)C
Agent: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: COC(=O)[C@@H]1Cc2ccc(C3=C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)cc2CN1C(=O)OC(C)(C)C
Yield: 83.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D of Example 22, (S)-tert-butyl 2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (683 mg, 1.39 mmol) and (S)-2-tert-butyl 3-methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (726 mg, 1.74 mmol) were converted to the title compound (730 mg, 83%). MS (ESI+) m/z 632.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH2:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1

Procedure:
A stirred mixture of 3-nitro-1,2-phenylenediamine (1.00 g, 6.53 mmol) and p-toluenesulfonyl chloride (1.25 g, 6.53 mmol) in pyridine (50 ml) was heated at reflux for 1 h, then concentrated to dryness in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=308 (M+1).
Reaction SMILES: C(O[N:6]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=4[F:43])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:15]=1)=[O:12])[C:7](C)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:52]>Cl>[ClH:52].[ClH:52].[CH3:7][NH:6][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=4[F:43])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[CH:15]=1)=[O:12]
Reactant: CC(=O)N(CC(=O)Nc1ccc(C)c(C2CCN(Cc3ccc(Oc4cc(F)c(F)cc4F)cc3)CC2)c1)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)Nc1ccc(C)c(C2CCN(Cc3ccc(Oc4cc(F)c(F)cc4F)cc3)CC2)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
2-[(tert-butoxy)-N-methylcarbonylamino]-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy) phenyl]methyl}(4-piperidyl))phenyl]acetamide was dissolved in CH2Cl2 (15 mL) and trifluoroacetic acid (5 mL) was added dropwise to the stirred solution. Stirring was continued for 30 minutes then the reaction mixture was concentrated in vacuo to give a gum. This was partitioned between CH2Cl2 (2×30 mL) and saturated aqueous NaHCO3 (30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the free base. This was dissolved in methanolic hydrogen chloride (1.6 M, 5 mL), and concentrated in vacuo to yield 2-(methylamino)-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]acetamide dihydrochloride (292 mg, 88% yield) as a white solid. LCMS (method A): 7.35 min, 498.3 (M+H)+; 1H NMR (D6-DMSO) δ 11.20 (br s, 1H), 10.68 (s, 1H), 9.03 (m, 2H), 7.84 (td, J=10.7, 7.7 Hz, 1H), 7.67 (m, 2H), 7.59 (dt, J=11.0, 8.0 Hz, 1H), 7.40 (m, 2H), 7.13 (d, J=8.5 Hz, 1H), 7.09 (m, 2H), 4.27 (d, J=5.1 Hz, 2H), 3.90 (t, J=5.7 Hz, 2H), 3.39 (d, J=11.8 Hz, 2H), 3.06 (m, 2H), 2.95 (m, 1H), 2.61 (t, J=5.4 Hz, 3H), 2.26 (s, 3H), 2.04 (m, 2H,), 1.86 (d, J=13.4 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][C:18]=1[F:23]
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate (1.31 g, 4.12 mmol) in DMF (40 ml) was added N-iodosuccinimide (1.39 g, 6.17 mmol) and TFA (2.4 ml). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 1.71 g (93%) of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate as a brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.Cl.[CH3:13][C:14]1[N:15]=[C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][C:27]3[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=3)[O:30][CH2:31][C:32](O)=[O:33])[CH:23]=[CH:22][N:21]=2)[S:17][CH:18]=1.Cl>CCOCC>[CH3:13][C:14]1[N:15]=[C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][C:27]3[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=3)[O:30][CH2:31][CH2:32][OH:33])[CH:23]=[CH:22][N:21]=2)[S:17][CH:18]=1
Reactant: Cc1csc(Nc2cc(Oc3cccc(OCC(=O)O)c3)ccn2)n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(Nc2cc(Oc3cccc(OCCO)c3)ccn2)n1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
Lithium aluminum hydride in ether (1.0 M, 3.86 ml, 3.86 mmol) was added to a solution of THF (50 mL) at 0° C., 2-(3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenoxy)acetic acid hydrochloride (Example 66; 0.380 g, 0.965 mmol) was added portionwise. The reaction was stirred for one hour, and then quenched with an excess of solid saturated sodium sulfate decahydrate. The reaction was stirred overnight and filtered, and the solid cake was washed several times with THF. The combined filtrates were concentrated and the residue was purified by MPLC (Biotage), eluting with ethyl acetate to afford the product as the free base. The free base was dissolved in ether, and 1M HCl in ether was added. The mixture was diluted with hexanes, filtered, and washed with hexanes to afford the title compound (0.065 g, 17.7% yield) as a white powder. 1H NMR (d6-DMSO) δ 2.22 (s, 3H), 3.66 (t, 2H), 3.95 (t, 2H), 6.60-6.76 (m, 5H), 6.85 (d, 1H), 7.35 (t, 1H), 8.19 (d, 1H).
Reaction SMILES: [C-:1]1([C:6]2([CH2:11][CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][CH2:8][O:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]>FC(F)(F)C(O)=O>[C-:1]1([C:6]([CH2:10][CH2:9][CH2:8][OH:7])=[CH:11][CH2:12][CH2:13][OH:14])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: OCCCC1([c-]2cccc2)CCCO1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: O=C(O)C(F)(F)F
Product: OCCC=C(CCCO)[c-]1cccc1
Reaction time: 8 h
Yield: 63 %

Procedure:
2-Ferrocenyl-2-(3-hydroxypropyl)tetrahydrofuran (II), 20.5 g (0.065 mole), was dissolved in 100 ml of trifluoroacetic acid at 25°C with external cooling (in an ice bath). After 5 hours about half of the trifluoroacetic acid was removed under reduced pressure at 25°C. The residue was dissolved in 200 ml of tetrahydrofuran (THF). Then 100 ml of 6N NaOH was added with cooling and the mixture was stirred overnight. The THF phase was separated and the THF removed under reduced pressure. The product crystallized out in the form of plates. The plates were suspended in 500 ml of water, filtered and then washed twice on the filter with 50 ml portions of water. The wet cake was removed from the filter, triturated with 50 ml of ether and then filtered to give 11.0 grams of V, mp 85°-88°C. An additional 2.0 g of material, mp 85°-88°C, was recovered from the liquid phases to give a total yield of 4-ferrocenyl-3heptene-1,7-diol of 13.0 g (63% yield).
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:32]([N:39]([CH2:41][C:42]([OH:44])=O)[CH3:40])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[NH2:45][C:46]1[C:55]([NH2:56])=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49]>CN(C=O)C.O>[NH2:45][C:46]1[C:55]([NH:56][C:42](=[O:44])[CH2:41][N:39]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH3:40])=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1cccc(NC(=O)CN(C)C(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
First N-methyl-morpholine (4 eq.) and then HATU (2.0 eq.) was added to a solution of N-Boc-sarcosine (30.12 mmol, 1.0 eq.) in DMF (3 ml/mmol) at 0° C. The reaction mixture was stirred at room temperature for 15 min and then cooled again to 0° C. in order to add a solution of methyl 2,3-diaminobenzoate (30.12 mmol, 1.0 eq.) in DMF (1 ml/mmol). The reaction mixture was then stirred at room temperature for 16 h. For working up, the reaction mixture was diluted with water and extracted with ethyl acetate and the organic phase was washed with sat. NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over Na2SO4 and concentrated in vacuo in order to obtain the crude product. This was purified by a column chromatography (silica gel) to obtain the desired product. Yield: 60%
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C@@H:7]2[C@@H:10]([C:13]([F:16])([F:15])[F:14])[O:11][CH2:12][C@:6]2([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:5]=[C:4]1[NH:24]C(=O)OC(C)(C)C)[CH3:2].[OH-].[Na+].[N+:34]([O-])([OH:36])=[O:35]>>[NH2:24][C:4]1[N:3]([CH2:1][CH3:2])[C:8](=[O:9])[C@@H:7]2[C@@H:10]([C:13]([F:14])([F:16])[F:15])[O:11][CH2:12][C@:6]2([C:17]2[CH:22]=[C:21]([N+:34]([O-:36])=[O:35])[CH:20]=[CH:19][C:18]=2[F:23])[N:5]=1
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2ccccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc([N+](=O)[O-])ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl ((4aS,5S,7aS)-3-ethyl-7a-(2-fluorophenyl)-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (300 mg, 0.67 mmol) was taken up in fuming nitric acid (2 mL) at RT. The mixture was stirred at RT for 24 h, then poured on to ice and basified slowly with 50% aq. NaOH (˜3 mL). The aqueous mixture was extracted with DCM (×4). The combined extracts were dried by passing through a hydrophobic frit and then evaporated to give the title compound (200 mg, pale yellow foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (t, J=7.20 Hz, 3H) 3.69-3.80 (m, 1H) 3.83-3.94 (m, 2H) 4.29 (dd, J=8.08, 1.77 Hz, 1H) 4.41-4.50 (m, 2H) 4.67 (br. s., 2H) 7.25 (dd, J=10.61, 9.09 Hz, 1H) 8.23 (ddd, J=8.84, 4.04, 2.78 Hz, 1H) 8.32 (dd, J=6.69, 2.91 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([C@H:22]4[C@H:26]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=5[F:34])[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)=[O:21])[CH2:16][CH2:15]3)=[CH:12][C:11]([CH3:42])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([C@H:22]4[C@H:26]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=5[F:34])[CH2:25][NH:24][CH2:23]4)=[O:21])[CH2:18][CH2:19]3)=[CH:12][C:11]([CH3:42])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C2CCN(C(=O)[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3c3ccc(F)cc3F)CC2)n(-c2ccc(F)c(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2CCN(C(=O)[C@@H]3CNC[C@H]3c3ccc(F)cc3F)CC2)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The product from step A was dissolved in CH2Cl2 (5 mL) and treated with TFA (2.5 mL). The mixture was stirred at rt for 6 h, concentrated and purified by RP-HPLC (C-18, acetonitrile, H2O, 10 to 100% over 12 min, 0.05% TFA) to afford the title compound. HPLC/MS: 503.2/505.2 (M+1); Rt=1.62 min (LC4).