Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[O:6]=[C:7]1[C:15](=[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([CH2:25][CH2:26]OS(C)(=O)=O)[O:17]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1.O1CCOCC1.C(N(CC)CC)C>C1COCC1>[N:2]1([CH2:26][CH2:25][CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16](=[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:6])[O:17]2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2C1=C1OC(CCN2CCC2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.05 h

Procedure:
To a slurry of azetidine hydrochloride (126 mg, 1.35 mmol) in THF (1.0 ml) was added a scoop of Aberlite-IRA-93 ion exchange resin, which was shaken 3 minutes to give a solution, dried with anhydrous Na2SO4 and filtered to remove resin. Then methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50.0 mg, 0.135 mmol) was added to the amine solution and heated at 60° C. for 18 hours (no reaction had occurred). After standing at room temperature for 2 days, to the mixture were added dioxane (0.3 ml), azetidine hydrochloride (63 mg, 0.675 mmol), and triethylamine (132 μl, 0.945 mmol). The resulting mixture was stirred at room temperature for 3 days, and heated at 60° C. for 24 hours. The reaction was partitioned between water and EtOAc. The EtOAc layer was extracted with 4% HCl aqueous solution, and then the aqueous layer was basified with saturated NaHCO3 aqueous solution. The basified aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and rotary evaporated to give a film. The film was chromatographed (2.5% to 5% MeOH/CHCl3 gradient) to provide 3-[3-(2-azetidin-1-yl-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow film (8.7 mg, 19%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C@@:6]([CH3:12])([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:8].C[C@]([N+]([O-])=O)([C@@H](O)C)CO>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C@@:6]([CH3:12])([C@@H:9]([OH:11])[CH3:10])[CH2:7][OH:8]
Reactant: C[C@@H](O)[C@](C)(N)CO
Agent: C[C@H](O)[C@@](C)(CO)[N+](=O)[O-]
Solvent: CC(=O)O
Product: C[C@H](O)[C@](C)(N)CO
Yield: 93 %

Procedure:
Using the procedure described for 5E (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (5A) gave (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate (93%) mp 163°-165° (C, H, N).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13]
Reactant: O=C1OCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2c1COC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A suspension of 4-nitroisobenzofuran-1(3H)-one (1.0 g, 5.58 mmol) and 10% Pd/C (0.1 g) in ethyl acetate (30 mL) was purged in 1 atm hydrogen and stirred at 25° C. for 3 hr. The mixture was filtered, and the filtrate was concentrated to give 4-aminoisobenzofuran-1(3H)-one (0.8 g, yield 96%) as a off-white solid. MS (ESI) m/z: 150 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ 3.82 (s, br 1H), 5.19 (s, 3H), 6.91-6.95 (m, 1H), 7.32-7.36 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=[C:9]2[C:8]([CH2:17][C:18]2[S:19][C:20]3[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([F:29])[C:21]=3[N:22]=2)=[CH:7]1)C.[OH-].[Na+].Cl>COCCOC>[CH2:15]([C:12]1[N:11]=[C:10]2[N:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:7]=[C:8]([CH2:17][C:18]3[S:19][C:20]4[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([F:29])[C:21]=4[N:22]=3)[C:9]2=[CH:14][CH:13]=1)[CH3:16]
Reactant: CCOC(=O)Cn1cc(Cc2nc3c(F)c(F)cc(F)c3s2)c2ccc(CC)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CCc1ccc2c(Cc3nc4c(F)c(F)cc(F)c4s3)cn(CC(=O)O)c2n1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
A solution of [6-ethyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetic acid ethyl ester (0.474 g, 1.10 mmol) and BHT (2 mg) in 1,2-dimethoxyethane (10 mL, 1 M) is cooled to 0° C. and treated with 1 N NaOH (5 mL, 5 mmol). After stirring 30 min, the soln is acidified to pH 3-4 with 1 N HCl and extracted with ethyl acetate (3×). The combined organic layers are washed with saturated aq NaCl, dried over MgSO4 and filtered through a layered pad of celite, charcoal and florisil to give [6-ethyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetic acid (0.25 g, 56%). mp 155-157° C.; Rf 0.63 (50% methanol in chloroform) 1H NMR (DMSO-d6, 300 MHz) δ 12.98 (br s, 1 H), 7.87 (d, J=8.1 Hz, 1 H), 7.73-7.64 (m, 1 H), 7.53 (s, 1 H), 6.98 (d, J=8.1 Hz, 1 H), 4.99 (s, 2 H), 4.64 (s, 2 H), 2.76 (q, J=7.8 Hz, 2 H), 1.21 (t, J=7.8 Hz, 3 H); LRMS calcd for C19H14F3N3O2S: 405.4; found 405.0 (M)+. Anal. Calcd for C19H14F3N3O2S: C, 56.29; H, 3.48; N, 10.37; S, 7.91. Found C, 56.12; H, 3.40; N, 10.27; S, 7.91.
Reaction SMILES: Br.Br[CH:3]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][C:4]1=O.[C:11]([NH2:16])(=[S:15])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH:12]([C:11]1[S:15][C:3]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:16]=1)([CH3:14])[CH3:13]
Reactant: O=C1CCNCCC1Br
Reactant: CC(C)C(N)=S
Agent: Br
Solvent: CCO
Product: CC(C)c1nc2c(s1)CCNCC2

Procedure:
0.4 g (1.47 mmol) 5-Bromo-azepan-4-one hydrobromide, 0.15 g (1.47 mmol) thioisobutyramide in 3 mL ethanol were stirred under reflux for 3 h. The reaction mixture was concentrated and to the residue DCM and a small amount of methanol were added. The precipitate was removed and the filtrate was evaporated to dryness. Yield: 0.36 g (89% of theory). ESI-MS: m/z=197 (M+H)+; Rt(HPLC): 0.79 min (Method J).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:2].[F:47][C:48]1([F:60])[O:52][C:51]2[CH:53]=[CH:54][C:55](B(O)O)=[CH:56][C:50]=2[O:49]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:55]3[CH:54]=[CH:53][C:51]4[O:52][C:48]([F:60])([F:47])[O:49][C:50]=4[CH:56]=3)[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OS(=O)(=O)C(F)(F)F)cc(C(C)=O)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccc4c(c3)OC(F)(F)O4)c2)c1CCC(=O)OCC
Temperature: 90 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a solution of 4-[3-[6-(3-acetyl-5-trifluoromethanesulfonyloxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (500 mg) in 1,2-dimethoxyethane (5 mL) were added 2,2-difluoro-benzo[1,3]dioxole-5-boronic acid (273 mg), 2 M aq. sodium carbonate solution (1.0 mL) and Pd(PPh3)4 (8 mg) and the resulting mixture was stirred at 90° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 300 mg of the title compound (59% yield). HRMS calcd for C38H44O9F2 [M+Na]+ 705.2845, observed 705.2843.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[C:24]([O:30][CH2:31][CH:32]([F:34])[F:33])[C:25]([C:27]([OH:29])=O)=[CH:26][C:19]=2[N:18]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:27]([C:25]2[C:24]([O:30][CH2:31][CH:32]([F:34])[F:33])=[CH:23][C:20]3[N:21]([CH3:22])[C:17]([NH:16][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:18][C:19]=3[CH:26]=2)=[O:29])[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared from 2-(2-chloro-5-{[(tert.butylcarbonyl)amino]methyl}-phenylamino)-6-(2,2-difluoroethoxy)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and 3-chloro-4-fluoro-aniline with HATU and TEA in THF in analogy to example 3e and purified via flash chromatography.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[Cl-].[Na+]>O.CS(C)=O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCCC(=O)C1
Temperature: 180 °C
Yield: 110.8 %

Procedure:
A solution of 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate (28.50 g, 111.20 mmol, 1.00 equiv) and sodium chloride (7.02 g, 1.10 equiv) in a mixture of water (4 mL) and DMSO (80 mL) was heated for 24 h at 180° C. in an oil bath. After cooling to r.t, the reaction was diluted with water and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the desired ethyl 2-(3-oxocyclohexyl)acetate (22.7 g, crude) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:6][C:7]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
2-[(4-chlorophenyl)carbonyl]-3,6-difluorobenzoic acid (3.20 g, 11.00 mmol) was dissolved while heating in concentrated.sulfuric acid (15 ml) and it was cooled to 0° C. A solution of fuming nitric acid (0.5 ml, 11.00 mmol) in concentrated.sulfuric acid (3.0 mL) was added dropwise and the reaction mixture was stirred at 0° C. for 60 minutes. It was poured into crushed ice. The product was precipitated. It was collected by filtration then it was dissolved in ethyl acetate (100 mL); it was washed with water (2×40 mL), brine (40 mL) and dried over anhydrous sodium sulfate. Filtration and concentration resulted in a crude product, which was triturated with hexane. The crystalline product was collected by filtration to give 2-[(4-chloro-3-nitrophenyl)carbonyl]-3,6-difluorobenzoic acid (2.73 g, 74% yield). 1H NMR (400 MHz, CD3OD): 8.28 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.53-7.42 (m, 2H); MS (EI) for C14H7ClF2NO5: 341 (M−).
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[C:5]([N+:11]([O-])=O)[C:3]=1[NH2:4].C(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.[Fe]>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:11])[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Br
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(Cl)c(Br)c1N
Temperature: 0 °C
Yield: 79.1 %

Procedure:
2-Bromo-3,4dichloro-6-nitroaniline (48.3 g, 168.9 mmol), iron powder (30.0 g, 537.2 mmol) and ethanol (1 L) were combined and the resulting suspension was cooled to 0° C. Concentrated hydrochloric acid (37%, 193.0 mL, 2.36 mol) was then added dropwise over 15 min by means of an addition funnel. The resulting mixture was heated to reflux for 1 h, after which time it was allowed to cool to room temperature. The mixture was diluted with water (1.5 L) and the pH was adjusted to approximately 8 by the addition of sodium carbonate. The product was extracted with ethyl acetate (1 L), dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure using a rotary evaporator. The product was crystallized from a methanol/water mixture to afford 34.21 g (79%) of a brown solid; m.p. 128-129° C. Anal. Calcd for C6H5BrCl2N2: C, 28.16; H, 1.97; N, 10.95. Found: C, 28.29; H, 1.96; N, 10.79.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[CH:20]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)C=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (90 μL) and methanesulfonyl chloride (60 μL) were added dropwise to a solution of [4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 5(5), 100 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (123 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].[N+](=[CH:66][C:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:68])=[N-]>ClCCl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:66][C:67]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[O:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (500 mg) and rhodium acetate (5 mg, 2 mol %) in dichloromethane (4 ml) was added α-diazoacetophenone (159 mg, 2 eq.) in dichloromethane (2 ml) dropwise. The reaction mixture was stirred for 15 minutes after the addition and then filtered through a silica gel pad washing with ethyl acetate. The filtrate was concentrated and purified by column chromatography on silica gel eluting with 60% hexane:40% ethyl acetate to give the desired product (188 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.B(O)(O)[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C.CC(N(C)C)=O>[S:27]1[CH:26]=[C:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:3]=2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3csc4ccccc34)nc21
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-(2-(2-chloro-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol (950 g), thianaphthene-3-boronic acid (561 g), dichlorobis(triphenylphosphine)palladium(II) (10.1 g), potassium carbonate (791 g), water (3.25 L), and DMA (3.25 L) was stirred under a nitrogen atmosphere for 10 min. The stirred mixture was then heated at 70° C. for 14 h. Ethyl acetate (6.5 L) and water (3.25 L) were added, and the mixture was filtered through Celite (125 g) at 50° C., rinsing with ethyl acetate (1.0 L). The layers were separated, and the aqueous layer was extracted at 50° C. with additional ethyl acetate (7.5 L). The combined organic layers were washed with water (3×2.5 L), then distilled to remove about 2.5 L of solvent. Tetrahydrofuran (2.5 L) and silica bond thio silica gel (200 g) were added. The mixture was stirred at 70° C. for 16 hr, then was filtered, washing the pad with ethyl acetate (1.0 L). The combined filtrates were concentrated at atmospheric pressure to a volume of about 5 L, then the mixture was allowed to cool. The resulting solid was collected and washed with ethyl acetate (2×1.0 L) to provide the title compound.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]([NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=4)=[N:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:14]=3[CH:13]=2)=[O:10])=CC=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>O1CCOCC1>[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[CH3:46][C:42]1[CH:41]=[C:40]([C:18]2[C:15]3[CH:16]=[N:17][C:12]([NH:11][C:9]([NH2:8])=[O:10])=[CH:13][C:14]=3[NH:20][N:19]=2)[CH:45]=[CH:44][N:43]=1
Reactant: COc1ccc(CNC(=O)Nc2cc3c(cn2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3cc(NC(N)=O)ncc23)ccn1
Reaction time: 5 h
Yield: 19 %

Procedure:
A crude mixture of 1-(4-methoxybenzyl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea prepared according to Scheme 6 (35 mg, 0.055 mmol) in 1,4-dioxane (0.25 mL) was treated at room temperature with TFA (0.25 mL) and the reaction mixture stirred for 5 h, then additional TFA (0.25 mL) was added and the reaction mixture stirred for 16 h at room temperature and then concentrated in vacuo. The residue was purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA), to give 1-(3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea TFA salt as a yellow solid (4 mg, 0.01 mmol, 19%). MS ESI calc'd. for C13H13N6O [M+H]+ 269, found 269. 1H NMR (600 MHz, DMSO-d6) δ 13.82 (br s, 1H), 9.31 (s, 1H), 9.19 (s, 1H), 8.70 (s, 1H), 8.30-8.15 (m, 2H), 7.88 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1>CN(C=O)C.ClCCl>[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
To a solution of N-Cbz-valine (2.5 g, 10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) and triethylamine (2.0 g, 20 mmol) in DMF (10 mL) is added dropwise a solution of proline methyl ester hydrochloride (1.8 g, 11 mmol) in DMF (5 mL). The solution is stirred at room temperature and the reaction monitored by TLC until the disappearance of N-Cbz-valine. The reaction solution is then diluted with dichloromethane (30 mL) and the organic layer is extracted with 0.1 N HCl (20 mL), water (20 mL), then dried over Na2SO4. The solvent is removed in vacuo to afford the desired compound.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1>CO>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:17])([F:18])[F:16])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: Cc1cccc([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1F
Solvent: CO
Product: Cc1cccc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Temperature: 50 °C
Yield: 89.5 %

Procedure:
To a solution of N-((4S,6S)-4-(2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.69 g, 4.10 mmol) in MeOH (20 mL) was added dbu (0.741 ml, 4.92 mmol) and the resulting mixture was heated at 50° C. for 17 h. The reaction went to completion. The mixture was concentrated and chromatographed on silica gel using 0-30% EtOAc/hexanes to afford a white foam as (4S,6S)-4-(2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.13 g, 3.67 mmol, 89% yield). MS m/z=308.9 [M+H]+. Calculated for C13H13F5N2O: 308.09.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH:22]=O)=[CH:7]2.[CH2:24]([NH2:33])[C:25]1[CH:32]=[CH:31][C:28]([O:29][CH3:30])=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:30][O:29][C:28]1[CH:31]=[CH:32][C:25]([CH2:24][NH:33][CH2:22][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:26][CH:27]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2ccccc2C(F)(F)F)cc1

Procedure:
Prepared according to Procedure F using 8-methyl-2-(2-(trifluoromethyl)phenyl)-quinoline-3-carbaldehyde (1 g, 3.17 mmol), DCE (16 mL), PMBNH2 (0.62 mL, 4.75 mmol, 1.5 eq), and NaBH(OAc)3 (2.0166 g, 9.52 mmol, 3 eq). After purification, N-(4-methoxybenzyl)(8-methyl-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methanamine was obtained as light yellow syrup. 1H NMR (DMSO-d) δ ppm 8.48 (1H, s), 7.87 (2H, t, J=7.2 Hz), 7.64-7.77 (2H, m), 7.48-7.62 (3H, m), 7.14 (2H, d, J=8.6 Hz), 6.81 (2H, d, J=8.6 Hz), 3.71 (3H, s), 3.44-3.62 (4H, m), 2.61 (3H, s), 2.54 (1H, s). Mass Spectrum (ESI) m/e=437.2 (M+1).