Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([F:26])[CH:22]=[CH:21][CH:20]=3)[C:14]([OH:27])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[N:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([F:26])[C:24]=4[CH:25]=[C:17]3[C:15]=2[N:16]=1
Reactant: Cc1cccc(Br)c1Br
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccc2c1cc1n2C(c2ccccc2)Oc2ccc(Cl)nc2-1
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
A solution of dibromotoluene (382 mg, 1.527 mmol, prepared using similar method described for Example 1) in DMF (2 mL) was added slowly to a mixture of compound 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (200 mg, 0.763 mmol) and Cs2CO3 (746 mg, 2.289 mmol) in DMF (10 mL) at 100° C. After 10 min, the mixture was concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (25 mL×3). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:ethyl acetate=50:1) to provide 2-chloro-11-fluoro-6-phenyl-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (187 mg, yield: 70.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.43 (s, 1H), 7.23˜7.35 (m, 3H), 7.18 (s, 1H), 7.10 (s, 1H), 7.03˜7.08 (m, 4H), 6.79 (m, 1H), 6.65 (d, J=8.4 Hz, 1H). MS (M+H)+: 351/353.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([C:20]([F:23])([F:22])[F:21])[CH:5]=[C:4]([CH3:24])[N:3]=1.[H-].[Na+]>N1C=CC=CC=1>[CH2:18]([N:17]1[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9](=[O:10])[NH:8][C:7]2[C:6]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:4]([CH3:24])=[N:3][C:2]1=2)[CH3:19]
Reactant: CCNc1ncccc1C(=O)Nc1c(C(F)(F)F)cc(C)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN1c2ncccc2C(=O)Nc2c(C(F)(F)F)cc(C)nc21
Temperature: 150 °C
Yield: 20 %

Procedure:
A solution of 0.5 g of N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-2-ethylamino-3pyridinecarboxamide in 3 ml of pyridine was added to 0.2 g of a 50% dispersion of sodium hydride in oil. The mixture was heated to 150° C. and then cooled and concentrated in vacuo. Water was added to the residue and the product was extracted with ethyl acetate, dried (magnesium sulfate), filtered, and concentrated. The product was purified by column chromatography over silica gel (methylene chloride, then methylene chloride/methanol). After concentrating in vacuo, the residue was crystallized from hexane to give 0.09 g of the title compound, m.p. 150°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:43]=[CH:42][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39](O)=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:45][C@@H:46]([C:55]([O:57]C(C)(C)C)=[O:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([NH:45][C@@H:46]([C:55]([OH:57])=[O:56])[CH2:47][C:48]3[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=3)=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:42][CH:43]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccc(O)cc1
Reactant: NC(=O)CC[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: NC(=O)CC[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine (22 mg, 0.0359 mmol), tert-butyl D-tyrosinate hydrochloride (10 mg, 0.0421 mmol) and N-methylmorpholine (14 mg, 0.138 mmol) were dissolved in methylene chloride (0.5 ml). TBTU (14 mg, 0.0436 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (1 ml). The mixture was stirred at 45-50° C. for 4 h and was then evaporated under reduced pressure. Methanol (10 ml) was added and evaporated. The residue was dissolved in methanol (2 ml). Three drops of TEA were added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 15 mg (54%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.60-2.00 (m, 4H), 2.69-3.0 (m, 4H), 4.09-4.18 (m, 1H), 4.22-4.35 (m, 3H), 4.49 (s, 2H), 4.65-4.78 (m, 1H), 4.97-5.08 (m, 1H), 6.56 (d, 2H), 6.70 (s, 1H), 6.86-7.40 (m, 18H), 7.77-7.91 (m, 1H), 8.12 (d, 1H), 9.10 (bs, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)[Cl:9].O[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>>[Cl:9][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnccc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Temperature: 140 °C
Yield: 76 %

Procedure:
In a reaction flask under nitrogen, were reacted at 70° C., 51.5 g of PCl5 and 75 ml of POCl3. At the same temperature was added carefully 34.6 g of (8). The temperature was increased to 140° C. and the reaction refluxed for 4 hours under nitrogen. To the cooled mixture, evaporated under vacuum, was added 100 ml of iced water. The pH was adjusted to 7.5 by the addition of granular sodium carbonate, and 60 ml of methylene chloride added and the mixture stirred vigorously until all the residue had completely dissolved. The phases were separated and the aqueous part was extracted with more methylene chloride (5×30 ml). The combined organic phases were treated with anhydrous sodium sulphate and evaporated to obtain 29.9 g of (9) as a yellow, waxy solid.
Reaction SMILES: [Cl:1][C:2]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:28][CH2:29][CH3:30].[NH2:31][CH2:32][CH2:33][OH:34].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:31][CH2:32][CH2:33][OH:34])=[O:20])=[CH:16][N:15]=3)[CH2:11][CH2:12]2)=[CH:4][C:3]=1[O:28][CH2:29][CH3:30]
Reactant: NCCO
Reactant: CCOc1cc(CN2CCC(Nc3ccc(C(=O)O)cn3)CC2)cc(OCC)c1Cl
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: CCOc1cc(CN2CCC(Nc3ccc(C(=O)NCCO)cn3)CC2)cc(OCC)c1Cl
Temperature: 60 °C
Yield: 42 %

Procedure:
To a mixture of 6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid (65.09 mg, 0.15 mmol, 1.0 equiv; example 70) and 2-amino-ethanol (46.4 mg, 0.25 mmol, 1.67 equiv; commercially available) in dry DMF (2.0 mL) and N-ethyl diisopropylamine (0.3 mL) was added HATU (68.44 mg, 0.18 mmol, 1.2 quiv; commercially available) and the reaction stirred at 60° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 30.1 mg (42%) of the title compound. MS (ISP): 477.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[OH:11])=[N:6][C:7]=1[O:8][CH3:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)=[O:11])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1nc(C(O)c2ccc(SC)cc2)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1nc(C(=O)c2ccc(SC)cc2)ccc1Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Manganese dioxide (8.34 g) was added to a solution of (5-chloro-6-methoxypyridin-2-yl)[4-(methylsulfanyl)phenyl]methanol (1.42 g) in chloroform (40 mL), and the mixture was stirred at 65° C. for one hour. The reaction solution was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give the title compound as a yellow powder (1.02 g, 71%).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][CH2:26][C:27](=[S:29])[NH2:28])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO.CCOC(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][CH2:26][C:27]2[S:29][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[N:28]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(CBr)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(N)=S)CC1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(OCc2nc(-c3ccncc3)cs2)CC1

Procedure:
A solution of 2-bromo-1-pyridin-4-yl-ethanone hydrobromide (35 mg, 1241 mol) and 4-thiocarbamoylmethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 18, 34 mg, 124 μmol) in methanol (2 ml) was heated at 60° C. for 1.5 h. The reaction mixture was diluted with EtOAc (60 ml), washed with saturated aqueous NaHCO3 (15 ml) and brine (15 ml) then dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (EtOAc) to afford the title compound: RT=2.95 ml, m/z (ES+)=376.1 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[C:9]([F:14])[C:7]=1N.[C-:15]#[N:16].[K+].C(=O)(O)[O-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].C1C=CC=CC=1.C(O)(=O)C>[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[C:9]([F:14])[C:7]=1[C:15]#[N:16]
Reactant: [C-]#N
Reactant: Nc1c(F)cc(I)cc1F
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: N#Cc1c(F)cc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12 g of sodium nitrite was dissolved in 91 ml of sulfuric acid and cooled to 10° C or less, and then 100 ml of acetic acid was added. At 20 to 25° C, 39 g of the 2,6-difluoro-4-iodoaniline from Step 3 was added to the solution, and then the solution was agitated for one hour. A second solution was made by dissolving 37 g of copper sulfate pentahydrate in 91 ml of water to which was added 62 g of ice, and this solution was added to the first. A third solution containing 39 of potassium cyanide dissolved in 92 ml of water, 221 g of sodium bicarbonate, and 91 ml of benzene was added to the first solution, and a diazonium salt sulfuric acid solution was added therein. After agitation at room temperature for 3 hours, a sodium hydroxide aqueous solution was added to dissolve the crystals. After being extracted with chloroform, the crystals were washed three times alternating with a 10% sodium hydroxide solution and water. After distillation of the chloroform, the residue was extracted with hexane, and the hexane was distilled off. This residue was recrystallized with methanol to obtain 6.7 g of 1,3-difluoro-2-cyano-5-iodobenzene.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39][O:40]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:25][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:40][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:26])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared, acording to the procedure of Example 16, Step C, using 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester to produce a white solid (19%). MS [EI+] 520 (M+H)+, [EI−] 518 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[C:22]4[C:21]([NH:23][C@H:24]([C:26]5[N:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:30](=[O:38])[C:29]6=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]6[N:27]=5)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=4[N:16](COCC[Si](C)(C)C)[CH:15]=3)[CH:10]=[C:11]([OH:13])[CH:12]=2)=[N:4][N:3]=1.FC(F)(F)C(O)=O.N>>[NH2:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[C:22]4[C:21]([NH:23][C@H:24]([C:26]5[N:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:30](=[O:38])[C:29]6=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]6[N:27]=5)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=4[NH:16][CH:15]=3)[CH:10]=[C:11]([OH:13])[CH:12]=2)=[N:4][N:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(-c5nnc(N)o5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(-c6nnc(N)o6)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 14.9 %

Procedure:
(S)-2-(1-((5-(3-(5-Amino-1,3,4-oxadiazol-2-yl)-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (40 mg, 0.06 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 1 ml, 59 mmol) according to the method described in Example 27. The residue was purified by reverse phase chromatography using SP1® Purification System to give 5 mg (15% yield) of the title compound. Purity 98%.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:15]2[S:19][C:18]([C:20](OC(C)(C)C)=[O:21])=[CH:17][CH:16]=2)[CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.CN(C([O:43][N:44]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Si](ON)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C=O.ClCCCl>[OH:43][NH:44][C:20]([C:18]1[S:19][C:15]([C@H:13]([NH:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH3:14])=[CH:16][CH:17]=1)=[O:21]
Reactant: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)[Si](C)(C)ON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)NO)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
To a 2-dram vial containing crude (R)-tert-butyl 5-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)thiophene-2-carboxylate from Step 2 was added 1,2-dichloroethane (2 mL), and trifluoroacetic acid (0.246 mL, 3.20 mmol). After shaking at rt for 4 h, the mixture was evaporated to dryness to give a solid which was azeotroped with toluene (2×5 mL). To the resulting solid residue in another microwave vial was added HATU (0.0912 g, 0.240 mmol), N,N-dimethylformamide (1.5 mL), and triethylamine (0.178 mL, 1.28 mmol). The mixture was stirred for 10 min then O-(tert-butyldimethylsilyl)hydroxylamine (0.0471 g, 0.320 mmol) in DCM (0.5 mL) was added. The solution was shaken at rt for 2 h and then evaporated to dryness to afford a brown oil. To this oil in a microwave vial was added hydrochloric acid (3.5 mL, 1% in IPA). After shaking at rt for 30 min, solid NaHCO3 was added to quench the excess acid and the solvent was then removed. To the resulting solid residue was added DMSO (1.2 mL). After filtration, the DMSO solution was filtered and purified by Gilson prep-HPLC to give the title compound (0.0148 g, 23%) as a white solid. LC-MS: (FA) ES− 393. 1H NMR (Methanol-d4, 300 MHz) δ 7.92 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 7.24 (m, 1H), 6.77 (d, J=4.1 Hz, 1H), 4.78 (q, J=7.0 Hz, 1H), 1.44 (d, J=6.8 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:29][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (0.454 g, 1.24 mmol) (from example 97, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.050 g, 1.24 mmol) dissolved in water (1 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.076 mL, 1.24 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (6 mL, 36.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow oil. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.268 g, 64.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.47-1.75 (m, 2H), 1.85-2.14 (m, 2H), 2.71-3.00 (m, 2H), 3.02-3.16 (m, 2H), 3.40-3.76 (m, 3H), 4.22 (d, br., 1H), 4.59 (d, br., 1H), 5.64 (s, 1H), 6.95-7.03 (m, 2H), 7.15 (s, br., 2H). MS m/z 335 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:44])[C:3]1[CH:11]=[C:10]([CH:12]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH3:13])[C:9]2[C:5](=[CH:6][N:7](COCC[Si](C)(C)C)[N:8]=2)[CH:4]=1>FC(F)(F)C(O)=O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:16]2([CH2:15][O:14][CH:12]([C:10]3[C:9]4[C:5](=[CH:6][NH:7][N:8]=4)[CH:4]=[C:3]([N:2]([CH3:1])[CH3:44])[CH:11]=3)[CH3:13])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:30][CH:31]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(N(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(N(C)C)cc2c[nH]nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
(±)-tert-Butyl 4-((1-(5-dimethylamino-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (206 mg, 0.329 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 3.5 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 124 mg of (±)-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-N,N-dimethyl-2H-indazol-5-amine (95%). The crude amine (124 mg, 0.313 mmol) in dichloromethane (2.7 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (137 mg, 0.625 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (18%→45% EtOAc/Hex) to give 138 mg (89%) as clear oil. LC/MS (HPLC method 3): tR=2.816 min, 497.50(MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][CH2:9][N:10]([CH:30]([CH3:32])[CH3:31])[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:39]N1C(=O)CCC1=O>CN(C=O)C>[Cl:39][C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]([CH3:31])[CH3:32])=[N:18][C:17]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=1
Reactant: CC(C)N(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)cc2)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)N(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(3,3-diphenylpropyl)-1-isopropyl-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)urea (0.101 g, 0.18 mmol) in DMF (1 mL) at room temperature was added 1-chloropyrrolidine-2,5-dione (0.035 g, 0.26 mmol). The reaction mixture was stirred at room temperature for 2 d. Direct purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes) gave N-(4-(5-chloro-2-(((3,3-diphenylpropyl)(1-methylethyl)carbamoyl)amino)-1,3-thiazol-4-yl)phenyl)methanesulfonamide 69. Mass spectrum, calculated for C29H31ClN4O3S2 582.2; found 583.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(N(CC)CC)C.[CH2:27]([C:34]1[CH:38]=[CH:37][NH:36][C:35]=1[CH2:39]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:39][C:35]1[NH:36][CH:37]=[CH:38][C:34]=1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: OCc1[nH]ccc1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by 3-benzylpyrrolylmethyl alcohol (2.0 mmol) in ether over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give 3-benzylpyrrolylmethyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.