Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:35](Cl)(=[O:57])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:35](=[O:57])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1Oc1ccc(C)cc1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with docosanoyl chloride there is obtained 3-(docosanoyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methaneusalfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(docosanoyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [O:1]1[C:3]2([CH2:12][CH2:11][C:6]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:5][CH2:4]2)[CH2:2]1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH2:2][C:3]1([OH:1])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: C1COC2(CCC3(CC2)CO3)O1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCC2(CC1)OCCO2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 196 g (1.15 mol) 1,7,10-trioxadispiro[2.2.4.2]dodecane (prepared according to Synthetic Communications, 2003, vol. 33, #12, p. 2135-2144) in 2 L methanol were added 2 L sodium methanolate (25% in methanol) and the mixture was stirred at 60° C. for 8 hours. The solvent was removed, ethyl acetate added and washed with brine. The organic layer was dried over sodium sulfate. After filtration and removal of the solvent 272 g (max. 100%) of the title compound were obtained that was used without further purification.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[NH:10].[N:16](=[C:18]([C:24]#[N:25])[C:19](OCC)=[O:20])[OH:17].O>CO.C(O)(=O)C>[NH2:25][C:24]1[N:10]=[C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][C:19](=[O:20])[C:18]=1[N:16]=[O:17]
Reactant: COc1ccccc1C(=N)N
Reactant: CCOC(=O)C(C#N)=NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Reaction time: 4.5 h
Yield: 67.4 %

Procedure:
A stirred solution of sodium methoxide in dry methanol [prepared from sodium (10.7 g.) and dry methanol (150 ml.)] maintained at 0° C. was treated with 2-methoxybenzamidine hydrochloride (21.6 g.) followed by ethyl α-oximinocyanoacetate (16.5 g.). The mixture was then heated to reflux with stirring for 4.5 hours, and then poured into water (1000 ml.) and brought to pH6 by the addition of glacial acetic acid. The resultant green solid was filtered off and recrystallised from aqueous acetic acid to give 4-amino-2-(2-methoxyphenyl)-5-nitrosopyrimid-6-one (19.2 g.), m.p. 210°-211° C. (with decomposition). A further quantity of less pure 4-amino-2-(2-methoxyphenyl)-5-nitrosopyrimid-6-one (2.9 g.) was obtained by concentration of the mother liquors of the recrystallisation.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(C(C)C)C(C)C.Cl.[CH3:46][N:47]([CH2:49][C:50](Cl)=[O:51])[CH3:48]>C(Cl)Cl>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:50](=[O:51])[CH2:49][N:47]([CH3:48])[CH3:46])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 14, step (b), 655 mg, 1.30 mmol) in DCM (15 mL) was cooled to 0° C. and DIEA (0.92 mL, 5.2 mmol) was added. Dimethylaminoacetyl chloride hydrochloride (211 mg, 1.3 mol) was then added portion wise over 10 min. The reaction mixture was stirred at 0° C. for 30 min and allowed to warm to RT and stirred for 2 h. Solvent was removed in vacuo and the resulting residue was partitioned between brine and DCM. The organic layer was separated, dried (Na2SO4) and concentrated. The residue obtained was purified on silica (5% MeOH: DCM) to obtain 432 mg (70%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.49 (s, 1H), 8.24 (d, 1H, J=2.3 Hz), 7.70 (s, 1H), 7.12 (dd, 1H, J=8.4, 2.1 Hz), 7.01 (s, 1H), 5.82 (m, 1H), 4.75 (d, 1H, J=13.4 Hz), 4.13 (d, 1H, J=13.4 Hz), 3.57 (d, 1H, J=14.2 Hz), 3.18 (d, 1H, J=14.2 Hz), 3.12 (td, 1H, J=13.3, 2.4 Hz), 2.73 (dddd, 1H, J=11.9, 11.9, 3.8, 3.8 Hz), 2.65 (ddd, 1H, J=13.3, 13.3, 2.4 Hz), 2.40 (s, 6H), 2.18-2.32 (m, 4H), 1.60-1.98 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C26H32N6O2, 461.3 (M+H). found 461.2.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([CH2:37][S:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:37][S:38]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccn4)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccn4)cc2)CCN3CCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.30 g) was dissolved in methylene chloride (15 ml), m-chloroperbenzoic acid (83 mg) was added to the solution at −30° C., and the mixture was stirred for 1 hour at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 181) (97 mg).
Reaction SMILES: CS(O[C@@H:6]1[CH2:15][O:14][C@H:13]2[C@@H:8]([O:9][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:11][CH2:12]2)[CH2:7]1)(=O)=O.[N-:22]=[N+]=[N-].[Na+].CP(C)C.[N-]=[N+]=[N-]>CN(C=O)C.C1COCC1>[C:16]1([CH:10]2[O:9][C@H:8]3[CH2:7][C@@H:6]([NH2:22])[CH2:15][O:14][C@@H:13]3[CH2:12][O:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: CP(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl methanesulfonate (109 mg, 0.347 mmol) under nitrogen in anhydrous DMF (2.0 mL) was added sodium azide (90 mg, 1.387 mmol). The mixture was heated to 80° C. After 24 hours, the mixture was concentrated under reduced pressure. The resultant oil was chromatographed using a Biotage™ 10 g silica gel cartridge eluted with 0-50% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The product fractions were combined and concentrated under reduced pressure. The resultant white solid (67 mg, 0.256 mmol) was dissolved in anhydrous THF (2.0 mL) under nitrogen and a IM solution of trimethylphosphine (0.51 mL, 0.51 mmol) was added. The mixture was allowed to stir at room temperature for 40 minutes until the azide was consumed, then saturated aqueous ammonium hydroxide (0.5 mL) was added. After stirring for 30 minutes, the mixture was concentrated under reduced pressure and dried under high vacuum. The resultant residue was dissolved in acetonitrile (2 mL), frozen at −78° C., and lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C13H17NO3 235.12, observed m/e: 236.19 (M+H)+ (Rt 0.45/4 min).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC(OC)(C)C>[CH:12]1([NH:18][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1nc2cccc(Cl)n2n1
Reactant: NC1CCCCC1
Solvent: COC(C)(C)C
Product: Nc1nc2cccc(NC3CCCCC3)n2n1
Yield: 59 %

Procedure:
A suspension of 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 10.0 g; 59.32 mmol; 1.0 eq.) in cyclohexylamine (60 mL) was heated to reflux for 52 h. Reaction mixture was taken up in MTBE and filtered. The resulting cake was washed with MTBE and filtrate was concentrated to dryness. Residue was purified by flash chromatography (Hept/EtOAc, 1:1) to give the title compound as a beige powder (8.08 g, 59%). HPLC, Rt: 2.46 min. (purity 98.9%). LC/MS, M+(ESI): 231.9.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>C1C2C(=CC=CC=2)CCN1.C(O)C>[CH2:22]1[C:20]2[C:5](=[CH:4][CH:3]=[CH:2][CH:21]=2)[CH2:6][CH2:26][N:23]1[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1,2,3,4-tetrahydroisoquinoline in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=419.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH:15](=O)[CH3:16].[CH2:18]([O:25][C:26](=[O:30])[NH:27][CH:28]=[CH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:30])[NH:27][C@H:28]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C@@H:15]([CH3:16])[CH2:29]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: CC=O
Reactant: C=CNC(=O)OCc1ccccc1
Agent: FB(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1
Temperature: -25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
Aniline (3.64 mL, 39.97 mmol, 1.0 equ) was dissolved in methylene chloride (100 mL) and Na2SO4 (2 g) was added and cooled to −25° C. Acetaldehyde (2.23 mL, 39.97 mmol, 1.0 equ.) was added to the solution and stirred for 1 h at −25° C. Sodium sulfate was filtered off and N-vinyl-carbamic acid benzyl ester (7.07 g, 39.97 mmol, 1.0 equiv) was added to the filtrate at −25° C., followed by boron triflouride diethyl etherate (0.50 mL, 3.9 mmol, 0.1 equ). The reaction was allowed to stir at −25° C. for 1 h and then warmed to room temperature and stirred for 10 h. The reaction was evaporated in vacuo and the residue was purified by Biotage flash system (20% ethyl acetate/80% hexane) to yield 4.0 g, 33% of (±)-cis-(2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH:41]1[CH:46]=[CH:45][C:44](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:43][CH:42]=1>C(Cl)Cl>[C:18]1([N:13]2[C:12]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1

Procedure:
2-Phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a stirred solution of the above compound (1.79 g) in 35 mL of CH2Cl2 was added 3.0 mL of i-Pr2NEt and 3.05 g of N-phenyltrifluoromethanesulfonimide. The mixture was heated at reflux for 24 h and then was concentrated in vacuo. Chromatography on SiO2 (0 to 75% EtOAc/hexanes) afforded 1.88 g of the desired compound. MS (ESI): exact mass calculated for C19H22F3N3O5S, 461.12; found, m/z 407.1 [M+H]+.
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.CC([O-])=O.[Na+].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[C:19]([OH:24])[N:18]=1>O>[NH2:16][C:17]1[NH:22][C:21]2=[N:23][CH:1]=[CH:2][C:20]2=[C:19]([OH:24])[N:18]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(O)c2ccnc-2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of 136.7 g of bromoacetaldehyde diethylacetal, 347 mL of water, and 17.3 mL of concentrated HCl was heated to about 90° C. with vigorous stirring for about 30 minutes, at which time a clear solution was obtained. The solution was cooled to room temperature and 68.3 g of NaOAc was added. The resulting solution was added, with stirring, to a suspension of 100 g of 2,4-diamino-6-hydroxypyrimidine and 34.2 g of NaOAc in 739 mL of water, which had been heated to 70°-85° C. The reaction was allowed to proceed for 2 hours at 70°-85° C., at which time the reaction was complete. The mixture was cooled to 0° C. and held for about 1.5 hours. The mixture was then filtered and the collected product was washed with 500 mL of water and 500 mL of acetone, and dried, affording 72.3 g (79%) of 2-amino-4-hydroxypyrrolo[2,3-d]pyrimidine. A small sample was further purified by slurry in hot methanol, filtration, and drying, mp>300° C. 1H NMR (300 MHz, DMSO-d6) δ6.03 (s, 2 H), 6.13 (m, 1 H), 6.56 (dd, J=3.3, 2.3 Hz, 1 H), 10.23 (bs, 1 H), 10.93 (bs, 1 H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.[CH3:21][O:22][C:23](=[O:45])[CH:24]([O:43][CH3:44])[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33]CC2C=CC=CC=2)=[C:29]([O:41][CH3:42])[CH:28]=1)O>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:45])[CH:24]([O:43][CH3:44])[CH2:25][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([O:41][CH3:42])[CH:28]=1
Reactant: COC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)c(OC)c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)c(OC)c1)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
Trifluoroacetic anhydride (0.62 mL, 4.36 mmol) and triethylamine (0.62 mL, 4.36 mmol) were added to a solution of 3-(4-benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester (1.01 g, 2.91 mmol) in methylene chloride (30 mL) at 0° C. The resulting mixture was stirred for 4 hours at room temperature and was concentrated under vacuum. The residue was dissolved in ethyl acetate (30 mL), and 10% palladium on carbon (0.3 g) was added to the solution. The mixture was stirred under hydrogen pressure (4 atm) for 16 hours. The mixture was filtered through Celite and concentrated under vacuum. The residue was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate 7:3) to produce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid methyl ester as an oil (598 mg, 86%). 1H-NMR (200.15 MHz, CDCl3): δ 6.80 (d, 1H, J=7.8), 6.7 (s, 1H), 6.62 (d, 1H, J=7.8), 3.96 (dd, 1H, J=7.8, 4.0), 3.80 (s, 3H), 3.68 (s, 3H), 3.30 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd, 1H, J=14.2, 7.8).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[O:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:25](O)=[O:26])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.CCN(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.C(OCC)(=O)C>[O:15]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:25]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)=[O:26])[CH2:18][CH2:17]2)[O:12][CH2:13][CH2:14]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1N1CCC2(CC1)OCCO2
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
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of 3-Trifluoromethyl-phenylamine (24.1 mg, 0.15 mmol), 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-benzoic acid [as prepared in reference 3] (41.5 mg, 0.15, and DIPEA (78 μl, 0.45 mmol) in DMF was added HATU (59 mg, 0.15 mmol), and the reaction mixture was stirred for 3 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 43.1 mg (68.6%) of 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide [25] as a pale yellow solid.
Reaction SMILES: I.[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]1=[NH:13])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[N:13]\[C:27](=[O:28])[C:26]1[CH:30]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[O:31][CH3:32])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1c(C)c(C)sc1=N
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (312 mg, ˜1 mmol) and triethylamine (0.42 mL, 3 mmol) in CH2Cl2 (15 mL) at 0° C. was added 5-chloro-2-methoxybenzoyl chloride (Waterstone, 205 mg, 1 mmol), the mixture was allowed to warm to room temperature and was stirred for 14 hours. The solution was washed sequentially with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.93 (t, J=7 Hz, 3H), 1.35 (sextet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.21 (s, 3H), 2.26 (s, 3H), 3.78 (s, 3H), 4.26 (t, J=7 Hz, 2H), 7.10 (d, J=9 Hz, 1H), 7.44 (d-d, J=9 Hz, 3 Hz, 1H), 7.70 (d, J=3 Hz, 1H); MS (ESI+) m/z 353 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH:14](N(CC)C(C)C)(C)C.CI>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)COc1ccc(CO)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COc1ccc(CO)cc1
Reaction time: 3 h

Procedure:
18.2 g of 4-hydroxymethylphenoxyacetic acid are dissolved together with 17.1 ml of N,N-diisopropylethylamine in 50 ml of DMF, and then 6.1 ml of methyl iodide are added to the stirred solution. The mixture warms slightly during this. The reaction is complete after 3 h. The solvent is removed in vacuo. The residue is taken up in ether, and the solution is extracted once with 0.5 N hydrochloric acid. The aqueous phase is then extracted three times with ether, and the combined ether phases are washed with aqueous sodium bicarbonate solution and concentrated. The residue is dissolved in ethyl acetate and filtered through a short silica gel column. The pale yellowish oil which is obtained after concentration crystallizes on being left to stand.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21](O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CC(O)=O>[I:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:1][C:2]3[CH:3]=[C:4]([CH2:5][N:6]4[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]4)[CH:13]=[CH:14][C:15]=3[N:16]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CN1CCN(Cc2ccc(N)c(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
A mixture of 1-(3,4-diaminobenzyl)-4-methylpiperazine (10 mmol), 3-iodo-4-methylbenzoic acid (2.6 g, 10 mmol), EDCI (11 mmol), and HOBt (11 mmol) in dry DMF (25 mL) was stirred at ambient temperature for 24 hrs. The mixture was then evaporated in vacuo and the crude residue was dissolved in CH2Cl2 (100 mL) was washed with water (100 mL), brine (100 mL) and then dried by Na2SO4, filtered and concentrated. The residue obtained was dissolved in AcOH (30 mL) and heated at reflux for 3 hrs. The reaction mixture was eavporated in vacuo and the residue was purified by silica gel chromatography (eluent: 10% MeOH in CH2Cl2, MeOH was added 0.5% Et3N) to give a yellow solid (1.35 g, 30.3%). 1H NMR (300 MHz, CDCl3) δ: 8.50 (1 H, s), 7.94-7.97 (1 H, d, J=9.0 Hz), 7.53-7.56 (1 H, d, J=9.0 Hz), 7.52-7.55 (1 H, d, J=9.0 Hz), 7.30 (1 H, s), 7.20-7.23 (1 H, d, J=9.0 Hz), 3.60 (2 H, s), 2.54 (8 H, brs), 2.45 (3 H, s), 2.32 (3 H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]([F:21])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccccc1
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24j (124.9 mg, 0.50 mmol) was added 1.25 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (225 μL, 2.5 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (40 μL, 0.5 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warning, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 114.8 mg of a mixture of 24j and 25j as an off-white solid. FTIR (film) 1849.3 cm−1.