Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=3[Cl:30])[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: C[C@H]1C[C@@H](Oc2cccc(N)c2)CCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 4-(3-amino-phenoxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 39, 0.29 g), triethyl amine (95 mg), and 2-chloro-4-fluorobenzoyl chloride (0.201 g) in THF (10 mL) and stir at room temperature. After 18 hr., partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and dry in vacuum to give the title compound (0.464 g). Mass spectrum (electrospray) m/z=461 (M−1); 1H NMR (CDCl3): 7.87 (br s, 1H), 7.72 (dd, 1H), 7.37 (t, 1H), 7.19 (dd, 1H), 7.13 (dd, 1H), 7.02 (ddd, 1H), 6.97 (dd, 1H), 6.64 (dd, 1H), 4.63 (m, 1H), 4.28 (m, 1H), 3.81 (m, 1H), 3.20 (m, 1H), 1.88 (m, 2H), 1.81 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.24 (d, J=7.1 Hz, 3H). (file: mn4-a01246-76).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OC(=O)C)(=O)C.O.C(N(CC)CC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([OH:20])=[O:19])=[CH:3][CH:4]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=C(C(=O)O)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Triethylamine was added to solution of p-anisaldehyde (10 g) and phenylacetic acid (10 g) in acetic anhydride (25 ml). Reaction mixture was stirred at 90° C. for 8 h. Reaction mixture was cooled and water (600 ml) solution of potassium carbonate (81 g) was added. After addition reaction mixture was heated at 60° C. for an hour. Before neutralising with concentrated hydrochloric acid the reaction mixture was cooled below 10° C. Precipitate was filtered and washed with water. 1H-NMR (400 MHz, d6-DMSO): 12.6 (bs, 1H), 7.67 (s, 1H), 7.4-7.3 (m, 3H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.8-6.7 (m, 2H), 3.70 (s, 3H). (M)+=254 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:17]Cl>>[Cl:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nsc3ccccc23)cc1
Reactant: ClCl
Product: ClCc1ccc(-c2nsc3ccccc23)cc1
Reaction time: 2 h

Procedure:
225 parts of 3-(4-methylphenyl)-1,2-benzisothiazole are heated to 170° C. in a stirred apparatus and 100 parts of chlorine are passedin over 2 hours whilst irradiating the mixture with a UV lamp. The end point of the reaction is determined by gas chromatography (disappearance of the starting material). The reaction mixture is then cooled and the product is filtered off and recrystallized from methanol. 208 parts of 3-(4-chloromethylphenyl)-1,2-benzisothiazole, melting at 86°-89° C., are obtained; this yield corresponds to 80% of theory.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:19]1[CH:20]=[C:21]([C:37]2[N:42]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:40]=[C:39]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:38]=2)[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28](C3C=CC=CN=3)=[CH:27][CH:26]=2)[CH:24]=1.O1[CH2:60][CH2:59]OCC1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[N:38]1[CH:60]=[CH:59][CH:20]=[CH:21][C:37]=1[C:1]1[CH:6]=[CH:5][C:4]([C:19]2[CH:20]=[C:21]([C:37]3[N:38]=[C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:40]=[C:41]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:42]=3)[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: Clc1cc(-c2ccc(-c3ccccn3)cc2)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2cc(-c3ccc(-c4ccccn4)cc3)cc(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
In a stream of argon, 73 mg of phenylboronic acid, 5.8 mg of tris(dibenzalacetone)dipalldium complex and 12 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were suspended in 15 mL of 1,4-dioxane. 0.6 mL of an aqueous 3N potassium phosphate solution was added to the suspension, and the obtained mixture was stirred at room temperature for 10 minutes. To this mixture, 149 mg of 2-[5-chloro-4′-(2-pyridyl)-1,1′-biphenyl-3-yl]-4,6-diphenyl-1,3,5-triazine, synthesized in Example 1, was added, and the resultant mixture was refluxed under heating at 110° C. for 48 hours. Then the reaction mixture was left to stand at room temperature, and was concentrated under a reduced pressure to give a solid. The solid was purified by silica gel chromatography using a hexane/chloroform mixed liquid (50:50-0:100) as a developing solvent, and then recrystallized from dichloromethane/methanol to give 162 mg of 2-{4-(2-pyridyl)-[1,1′:3′,1″]-terphenyl-5′-yl}-4,6-diphenyl-1,3,5-triazine as a white solid (yield: >99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]([CH3:14])[C:12](SC)=[N:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.O[O:18][S:19]([O-:21])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[CH3:31]O>O>[CH3:31][S:19]([C:12]1[N:13]([CH3:14])[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[N:10][N:11]=1)(=[O:21])=[O:18]
Reactant: COc1cc(-c2nnc(SC)n2C)ccn1
Reactant: O=S([O-])OO
Reactant: CO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(-c2nnc(S(C)(=O)=O)n2C)ccn1
Reaction time: 5 h
Yield: 93 %

Procedure:
The title compound of example 25.1 (21.97 g, 92.97 mmol) was partially dissolved in methanol (500 mL) and OXONE® (potassium peroxomonosulfate compound, 114.3 g, 186.0 mmol) dissolved in water (500 mL) was added slowly. The reaction mixture stirred for 5 hours. The reaction was partially concentrated, poured into water and extracted with chloroform. The organic extracts were dried, filtered and concentrated to afford the title compound (22 g, 93%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[C:34]1=[O:51]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[C:34](=[O:51])[N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:41]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: COCCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COCCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=481.2.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(-c2ccccc2)cc1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 4-phenylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.55 (br s, 1H), 8.17 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.71 (m, 4H), 7.58 (d, 1H, J=5.0 Hz), 7.32-7.48 (m, 5H), 4.62 (s, 2H). [M+H] calc'd for C19H16N2O2, 305. found 305.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:21][C@@H:22]1[CH2:24][O:23]1>CN(C=O)C>[OH:23][C@H:22]([CH3:24])[CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:13]#[N:14])=[N:8]1
Reactant: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: C[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Temperature: 85 °C
Yield: 96.8 %

Procedure:
5-nitro-1H-indazole-3-carbonitrile (600 mg, 3.19 mmol, Example 391E) was taken up in DMF (3 ml), and K2CO3 (580 mg, 4.20 mmol) and (R)-2-methyloxirane (1.85 ml, 26.4 mmol) were added. The reaction mixture was heated at 85° C. for 1 h. The reaction mixture was partitioned between half-saturated aq. NH4Cl solution and EtOAc. The organic layer was washed with half-saturated aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness. The crude material was purified by flash column chromatography eluting with 0-50% EtOAc/DCM. (R)-1-(2-hydroxypropyl)-5-nitro-1H-indazole-3-carbonitrile (760 mg) was obtained as a colorless film.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][NH:1][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][CH:5]=1)#[N:8]
Reactant: CCCCCCCCC(=O)Cl
Reactant: N#Cc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(=O)NCc1ccc(C#N)cc1
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of 4-(aminomethyl)benzonitrile (5.0 g, 0.038 moles) in 100 mL chloroform is added 3.82 g (0.038 moles) triethylamine. A solution of nonanoyl chloride (6.68 g, 0.038 moles) in 10 mL chloroform is then added dropwise with stirring over a 10 min period and the final mixture stirred at room temperature for 18 hrs. The mixture is extracted with water (100 mL), saturated NaHCO3 (50 mL), 2N HCl (50 mL), dried over Na2SO4 and evaporated to leave 10.2 g crude N-(4-cyanobenzyl)nonanamide. This crude product is taken up in 50 mL dimethylformamide, to which is added 2.47 g (0.038 moles) sodium azide and 2.03 g (0.038 moles) ammonium chloride. The final mixture is heated at 90°-110° C. for 4 hrs after cooling, the mixture is diluted with water (350 mL) and the resultant precipitate recovered by suction filtration, washed with water, and vacuum dried. Recrystallization from ethyl acetate left N-[[4-(1H-tetrazol-5-yl)phenyl]methyl]nonanamide (2.6 g), m.p. 185°-187° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25].O>N1C=CC=CC=1>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][S:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:15]=1
Reactant: COc1ccc(-c2nc3cccnc3[nH]2)cc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2nc3cccnc3[nH]2)cc1NS(=O)(=O)c1cccs1
Reaction time: 8 h
Yield: 19.7 %

Procedure:
5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine (0.5 g, 2.1 mmol prepared as described above in Chemical Example 1) was dissolved in 15 mL pyridine at room temperature. Solid thiophene 2-sulfonyl chloride (0.38 g, 2.1 mmol) was added and the resulting blood red solution was stirred overnight The reaction mixture was poured into 250 mL water, stirred for 30 minutes, and filtered to give a pink solid. The solid was recrystallized from ethyl acetate after treatment with decolorizing charcoal to give 0.16 g of thiophene-2-sulfonic acid [5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-amide as an off-white solid; mp 252-254° C. 1H-NMR (DMSO-d6): δ 13.26 (d, 1H), 9.85 (bs, 1H), 8.27 (m, 2H), 8.02 (m, 2H), 7.87 (d, 1H), 7.43 (d, 1H), 7.16 (m, 3H), 3.59 (s, 3H) ppm. Anal. (C17H14N4O3S2) C,H,N values were within 0.4% of theoretical values.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH2:43][CH2:44][F:45])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.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>[F:45][CH2:44][CH2:43][N:41]1[C:40](=[O:46])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1CCF
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CCF)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 20.8 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.041 mmol), 5-bromo-1-(2-fluoroethyl)pyridin-2(1H)-one (9.2 mg, 0.041 mmol), and Cs2CO3 (2 N, 0.2 mL, 0.41 mmol) in 1,4-dioxane (2 mL) was added Pd(PPh3)2Cl2 (3 mg, 0.0041 mmol) under N2. The mixture was refluxed for 2 h, treated with EtOAc (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by preparative HPLC to give (S)-3-((S)-1-(4-(1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (4.20 mg, 20%). LC-MS Method 2 tR=1.01 min, m/z=515, 493; 1H NMR (CD3OD): δ 0.97 (s, 3H), 1.28 (s, 3H), 1.56 (d, 3H), 2.18 (s, 2H), 2.22 (m, 1H), 2.49 (m, 2H), 3.05 (m, 1H), 4.37 (t, 1H), 4.43 (t, 1H), 4.69 (t, 1H), 4.81 (t, 1H), 5.59 (q, 1H), 6.66 (d, 1H), 7.05 (d, 2H), 7.33 (m, 7H), 7.82 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:15]1([CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=1>O>[O:1]=[C:2]([O-:14])[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:15]1([CH2:23][NH3+:24])[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH3+:22])[CH:16]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Reactant: NCc1cccc(CN)c1
Solvent: O
Product: O=C([O-])[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)[O-]
Product: [NH3+]Cc1cccc(C[NH3+])c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of galactaric acid (5.004 g, 23.811 mmol) in deionized water (50.0 mL), m-xylylenediamine (3.15 mL, 23.868 mmol) was added using a pipette. The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was filtered, washed with several small portions of deionized water, and then dried under vacuum at room temperature for 24 h to give white solid, m-xylylenediammonium galactarate 14, 6.016 g, 17.372 mmol, 72.88%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[C:26]([CH:27]([CH3:32])[C:28]([F:31])([F:29])[F:30])=[CH:25][C:24]3[O:23][CH2:22][C:21]4=[N:20][NH:19][C:18](=[O:33])[CH:17]([CH3:34])[N:16]4[C:15]=3[CH:14]=2)[CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(C(C)C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C(C)C(F)(F)F)c(NC4CNC4)cc3N21
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-[4-methyl-3-oxo-7-(2,2,2-trifluoro-1-methyl-ethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.020 g, 0.041 mmol) in DCM (3 mL) was added in TFA (0.5 mL) and the solution was stirred for 2 h. The solvent was removed in vacuo to give 9-(azetidin-3-ylamino)-1-methyl-8-(1,1,1-trifluoropropan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (0.015 g, 95%). LC/MS (Table 1, Method 5) Rt=2.166 min; MS m/z: 384 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].O1CCC[CH2:23]1.C([Li])CCC.CI>CCCCCC>[CH3:23][N:5]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:21]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Product: COC(=O)N(C)c1cn2cc(Sc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g. (0.0033 moles) of 2-(methoxycarbonylamino)-6-(phenylthio)imidazo [1,2-a] pyridine in 35 ml. of tetrahydrofuran under a argon atmosphere is treated dropwise with 1.35 ml. of a 2.45 molar solution of butyllithium in hexane at -20° C. The resultant solution is stirred for 5 minutes and 0.469 g. (0.0033 moles) of methyliodide is added. The reaction mixture is allowed to warm to room temperature and stirred for 30 minutes. The solution is diluted with ice water and the solids are collected by filtration, washed with water and dried. The solid materials is chromatographed on silica gel and eluted with 1:99 methanol in methylene chloride affording 2-[methyl-N-(methoxycarbonyl)amino]-6-(phenylthio)imidazo [1,2-a] pyridine m.p. 147°-149° C.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[CH:13]3[CH2:14][C:15]([CH3:18])=[CH:16][CH2:17][CH:12]3[C:11]([CH3:20])([CH3:19])[O:10][C:9]=2[CH:21]=1.[CH3:28][Mg]Br.CBr.[Mg]>C(OCC)C>[OH:1][C:2]([CH3:28])([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[CH:13]3[CH2:14][C:15]([CH3:18])=[CH:16][CH2:17][CH:12]3[C:11]([CH3:19])([CH3:20])[O:10][C:9]=2[CH:21]=1
Reactant: CCCCCC(=O)C=Cc1cc(O)c2c(c1)OC(C)(C)C1CC=C(C)CC21
Reactant: C[Mg]Br
Agent: CBr
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC(C)(O)C=Cc1cc(O)c2c(c1)OC(C)(C)C1CC=C(C)CC21

Procedure:
A solution of 1.0 g (0.0028 mole) of 3-(3-oxo-1-octenyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol in diethyl ether was added dropwise to a solution of methyl magnesium bromide in ether prepared by bubbling methyl bromide into 0.78 g (0.032 mole) of magnesium. After the addition was complete, the mixture was refluxed for 3 hours and then decomposed by the careful addition of a mixture of methanol/diethyl ethr followed by dilute acid. The ethereal layer was separated and washed consecutively with water, 5% sodium bicarbonate and again water. It was dried and evaporated to leave 0.95 g of a gum which was chromatographed on magnesium silicate and eluted with graded mixtures of ether/petroleum ether. This furnished 0.28 g of 3-(3-hydroxy-3-methyl-1-octenyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol as a resinous material. The infrared and nuclear magnetic resonance spectra were consistent with the structure of the desired hydroxy compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:12])[CH2:11][O:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:13][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([OH:12])[CH2:9][O:10][CH2:11]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C2(O)COC2)c(F)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2(O)COC2)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a stirred solution of 3-(4-amino-2-fluorophenyl)oxetan-3-ol (0.93 g, 5.08 mmol, 1.0 eq) in acetone (10 mL) was added pyridine (0.82 mL, 10.16 mmol, 2.0 eq) and phenyl chloroformate (0.7 mL, 5.59 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 1 h. The solvents was evaporated and the crude product was extracted with EtOAC (25 mL), diluted with water (15 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The resulting residue was washed with diethyl ether (25 mL) to get phenyl 3-fluoro-4-(3-hydroxyoxetan-3-yl)phenylcarbamate (0.892 g, 59%) as a off white solid (TLC system: 100% EtOAc, Rf: 0.55).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]3[CH:16]([C:17]([OH:19])=O)[CH2:15][CH2:14][N:13]3[CH3:20])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:47]1[O:58][C:57]2[CH:56]=[CH:55][C:51]([CH2:52][CH2:53][NH2:54])=[CH:50][C:49]=2[O:48]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[O:58]1[C:57]2[CH:56]=[CH:55][C:51]([CH2:52][CH2:53][NH:54][C:17]([CH:16]3[CH2:15][CH2:14][N:13]([CH3:20])[CH:12]3[C:10]3[CH:9]=[C:8]([CH3:21])[N:7]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:11]=3)=[O:19])=[CH:50][C:49]=2[O:48][CH2:47]1
Reactant: Cc1cc(C2C(C(=O)O)CCN2C)nc(-n2ccnc2)n1
Reactant: NCCc1ccc2c(c1)OCO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2C(C(=O)NCCc3ccc4c(c3)OCO4)CCN2C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid (31.9 mg, 0.111 mmol) was dissolved in DMF (1 mL). Next, the HBTU (64.0 mg, 0.167 mmol) was added. The reaction was stirred at room temperature for 30 minutes prior to addition of 3,4-methylenedioxyphenethyl amine hydrochloride (22.4 mg, 0.111 mmol) and triethylamine (50 μL). The reaction was stirred at rt for 12 h then heated to 60° C. for 16 h. After this period, the reaction mixture was transferred to a separatory funnel with ethyl acetate (20 mL). The organic layer was washed with sat. NaHCO3 (aq) (30 mL) and H2O (30 mL). The aqueous layers were back extracted with ethyl acetate (25 mL) and all of the organic portions were combined, dried over Na2SO4 and concentrated down under vacuum. The material was purified by Flash Chromatography (10 g, 0-10% methanol/DCM gradient) to afford 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide. Product isolated as a mixture of diasteromers; [M+H]+ 435.63.