Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:38]=[C:37]([F:39])[C:10]([CH2:11][S:12][C:13]2[N:14]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:15]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=3)([CH3:20])[CH3:19])=[CH:16][N:17]=2)=[C:9]([F:40])[CH:8]=1)=[N+]=[N-]>CCO.Cl.O=[Pt]=O>[ClH:27].[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]([C:15]2[N:14]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:13]([S:12][CH2:11][C:10]3[C:9]([F:40])=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH2:1])=[CH:38][C:37]=3[F:39])=[N:17][CH:16]=2)([CH3:20])[CH3:19])=[CH:22][C:23]=1[O:28][CH3:29]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN=[N+]=[N-])cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 5 h
Yield: 173 %

Procedure:
A pressure bottle was charged with a solution of 2-(4-(2-azidoethoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (340 mg, 0.56 mmol) in EtOH (10 mL), conc HCl (0.5 mL) and PtO2 (170 mg). The bottle was purged with hydrogen (2×40 psi), pressurized with hydrogen (45 psi) and was agitated for 5 h. The reaction mixture was filtered through Celite™ and the filtrate was evaporated to give a residue. The residue was triturated with ether, and the solids were collected by filtration and dried to give the title compound (290 mg, 99%). 1H NMR (400 MHz, CD3OD) δ 7.21 (s, 1H), 7.17 (d, J=8.24 Hz, 1H), 6.76 (t, 2H), 6.55 (m, 1H), 6.51 (m, 3H), 6.29 (m, 2H), 4.07 (t, 2H), 3.83 (s, 2H), 3.68 (s, 3H), 3.62 (t, 2H), 1.49 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[CH2:20]([N:23]1[C:27]([CH2:28][OH:29])=[N:26][CH:25]=[N:24]1)[CH2:21][CH3:22]>>[O:17]1[CH:18]=[CH:19][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:29][CH2:28][C:27]4[N:23]([CH2:20][CH2:21][CH3:22])[N:24]=[CH:25][N:26]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:16]1
Reactant: CCCn1ncnc1CO
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Product: CCCn1ncnc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 6-chloro-3-(isoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine (described in Example 34 part b) and 2-propyl-3-hydroxymethyl-1,2,4-triazole prepared as described in WO-A-9804559 using the procedure given for Example 71, 1H NMR (360 MHz, CDCl3) δ 0.95 (3H, t, J=7.4 Hz, Ar—H), 1.91-2.01 (2H, m, CH2), 4.34 (2H, t, J=7.0 Hz, CH2), 5.85 (2H, s, CH2), 7.28 (1H, d, J=1.7 Hz, Ar—H), 7.83 (1H, t, J=8.3 Hz, Ar—H), 7.96-8.01 (2H, m, 2 of Ar—H), 8.21 (1H, d, J=7.9 Hz, Ar—H), 8.62 (1H, s, Ar—H), 8.70 (1H, d, J=7.1 Hz, Ar—H); MS (ES30) m/e 377 [MH]+; Anal. Found. C, 57.12; H, 3.87; N, 29.49. C18H16N8O2.0.05CH2Cl2 requires C, 56.96; H, 4.26; N. 29.44%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[C:26]2=[O:34])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH2:29][CH2:28][N:27]([CH2:30][C:31](=[O:32])[N:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:5]4[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=4)[CH2:8][CH2:9]3)[C:26]2=[O:34])=[CH:21][CH:20]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-(trifluoromethyl)benzyl)piperazine (0.24 g, 1.00 mmol) in dichloromethane (25 mL) under nitrogen was added 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D, 0.33 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.39 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.59 (m, 4H), 7.27-7.35 (m, 4H), 6.96-7.03 (m, 4H), 4.18 (s, 2H), 3.59-3.63 (m, 2H), 3.53 (s, 2H), 3.51 (t, J=6.6 Hz, 2H), 3.41-3.45 (m, 2H), 2.77 (t, J=6.5 Hz, 2H), 2.40-2.44 (m, 2H), 2.31-2.35 (m, 2H); MS (DCI+) m/z 558 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[S:18]([O:1][N:2]=[C:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: N#CC(=NO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccccc2)cc1

Procedure:
α-Tosyloxyiminobenzyl cyanide is prepared from α-hydroxyiminobenzyl cyanide and p-toluenesulfonyl chloride in accordance with a procedure analogous to that of Example 1d. Melting point: 179°-181° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][C:11]([CH3:14])([CH3:13])[C:10](/[CH:16]=[CH:17]/[Sn](CCCC)(CCCC)CCCC)([OH:15])[C:9]([CH3:31])=[CH:8]2)[O:3]1.[F:32][C:33]([F:43])([F:42])/[C:34](/I)=[CH:35]/[C:36]([O:38][CH2:39][CH3:40])=[O:37].[F-].[K+]>CC#N.CC#N.Cl[Pd]Cl.CN(C)C=O>[OH:15][C:10]1(/[CH:16]=[CH:17]/[C:34](/[C:33]([F:32])([F:42])[F:43])=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:11]([CH3:14])([CH3:13])[CH2:12][C:4]2([O:5][CH:6]([CH3:7])[CH:2]([CH3:1])[O:3]2)[CH:8]=[C:9]1[CH3:31]
Reactant: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)(CCCC)CCCC
Reactant: CCOC(=O)/C=C(\I)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Under argon, 2,3,7,9,9-pentamethyl-8-[(E)-2-(tributylstannyl)vinyl]-1,4-dioxaspiro[4.5]dec-6-en-8-ol (300 mg, 0.55 mmol) and ethyl (2Z)-4,4,4-trifluoro-3-iodobut-2-enoate (163 mg, 0.55 mmol) in a round-bottom flask that had been dried by heating were dissolved in abs. N,N-dimethylformamide (4 ml), dichlorobis(acetonitrile)palladium(II) (7 mg, 0.03 mmol) was added and the mixture was stirred at room temperature for 3 h. After the addition of potassium fluoride solution, the reaction mixture was stirred further at room temperature overnight. The aqueous phase was then repeatedly extracted thoroughly with diethyl ether, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E,4E)-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-3-(trifluoromethyl)penta-2,4-dienoate (150 mg, 61% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.47 (d, 1H), 6.29 (d, 1H), 6.25 (s, 1H), 5.48 (s, 1H), 4.26 (q, 2H), 3.68 (m, 1H), 3.59 (m, 1H), 1.93 (d, 1H), 1.83 (br. m, 1H, OH), 1.77 (d, 1H), 1.69 (s, 3H), 1.32 (t, 3H), 1.25 (m, 3H), 1.18 (m, 3H), 1.10 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:22]1[CH2:27][CH2:26][NH:25][C:24]([CH3:29])([CH3:28])[CH2:23]1)=O)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH3:28][C:24]1([CH3:29])[CH2:23][NH:22][CH2:27][CH2:26][N:25]1[C:12]([C:9]1[N:10]=[N:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:14]
Reactant: O=C(O)c1nnn(-c2ccccc2)n1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1nnn(-c2ccccc2)n1

Procedure:
This intermediate was prepared from 2-phenyl-2H-tetrazole-5-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CS(C)=O.[CH3:18][C@H:19]1[C@@H:23]([OH:24])[CH2:22][CH2:21][NH:20]1.C(=O)([O-])[O-].[Li+].[Li+]>>[OH:24][C@H:23]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[C@H:19]1[CH3:18]
Reactant: C[C@@H]1NCC[C@@H]1O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)cc1C(F)(F)F

Procedure:
Using 4-fluoro-3-(trifluoromethyl)benzonitrile (398 mg), 0.9 mol/L (2S,3S)-2-methylpyrrolidin-3-ol dimethyl sulfoxide solution (2.35 mL) and lithium carbonate (156 mg), the title compound was obtained as yellow crystals (yield: 135 mg) by an operation similar to that in Example 3.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=3)[CH:22]=2)=[C:15]([Cl:33])[CH:14]=1)[NH:5]C(=O)C(F)(F)F.Br.C(O)(=O)C.[OH-].[Na+]>O>[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:33])[C:16]=1[O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:31])[CH:27]=2)[CH:22]=1)[CH2:12][C@@H:4]([C:3]([OH:34])=[O:2])[NH2:5]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(Oc2ccc3cc(OC)ccc3c2)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N[C@@H](Cc1cc(Cl)c(Oc2ccc3cc(O)ccc3c2)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A mixture of 3,5-dichloro-N-trifluoroacetyl-O-[(6-methoxy)-2-naphthyl]-L-tyrosine methyl ester (160 mg, 0.31 mmol), 47% hydrobromic acid (3 ml) and acetic acid (2 ml) was heated under reflux for 5 hrs. The reaction mixture was diluted with water (10 ml), adjusted to pH 4-5 with 4N sodium hydroxide under ice cooling and then stirred at room temperature for 30 min. The precipitates were collected by filtration, washed with water and dried under reduced pressure to give 3,5-dichloro-O-[(6-hydoxy)-2-naphthyl]-L-tyrosine (92 mg, 76%) as a pale orange powder.
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([OH:10])=O)O)O)(O)=O.[C:11]([C:14]([C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])[NH2:12]>C(O)(=O)C.[Pd]>[C:11]([C:14]([C@@H:27]1[CH2:31][CH2:30][N:29]([CH2:23][CH2:22][C:21]2[CH:14]=[CH:15][C:16]3[O:10][CH2:8][CH2:6][C:4]=3[CH:1]=2)[CH2:28]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])[NH2:12]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Reaction time: 6 h

Procedure:
10% Palladium-on-carbon (10 mg) was added to a solution of 3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(benzofuran-5-yl)ethyl]pyrrolidine (0.1 g—see Example 7) in acetic acid (2 ml) and the mixture was hydrogenated at 40° C. and atmospheric pressure for 6 hours. The catalyst was filtered off and washed with water (20 ml). The combined filtrate and washings were transferred to a separating funnel, dichloromethane (20 ml) was added, and the mixture was basified by the addition of 10% aqueous sodium hydroxide. The layers were separated and the aqueous layer was further extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless solid which was purified by column chromatography on silica eluting with dichloromethane containing methanol (4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glass, yield 0.048 g, which was characterised spectroscopically to be identical to the product of Example 1(B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]3[OH:23])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[P:32](Cl)(=[O:40])([O-:39])[O:33]CC(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]3[O:29][C@H:28]([CH2:30][O:31][P:32]([OH:40])([OH:39])=[O:33])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]3[OH:23])=[CH:19][CH:20]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=P([O-])(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1ccc(/C(C#N)=C/c2ccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc([C@@H]3O[C@H](COP(=O)(O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1OC
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Compound 44 (100 mg) and (2,2,2-trichloroethyl) phosphorochloridate (256 mg) were dissolved in pyridine (2 mL), and the resultant solution was stirred for two hours. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system. The thus-purified product was dissolved in a pyridine-acetic acid (4:1) solvent mixture, and zinc powder (140 mg) was added to the resultant solution, followed by stirring for two hours. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (83 mg, yield: 70%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([OH:25])=O)[CH:20]=[CH:19][S:18]2.[C:28]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)([CH3:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:27][C:2]([CH3:1])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:37][C:34]1[S:35][CH:36]=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:33]=1)=[O:25])[CH:20]=[CH:19][S:18]2
Reactant: CC(C)(C)c1csc(N)n1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(C)(C)C)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (150 mg, 0.388 mmol) with 4-tert-butyl-1,3-thiazol-2-amine (72 mg, 0.465 mmol) in the presence of EDCI hydrochloride (148 mg, 0.776 mmol) and DMAP (71 mg, 0.582 mmol) in a mixture of DCM and DMF (4:1, 10 mL) to give 70 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 1.33 (s, 9H), 3.57 (s, 2H), 3.80 (s, 3H), 6.58 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.32-7.34 (m, 1H), 7.41 (d, J=4.5 Hz, 1H), 7.87 (d, J=16.8 Hz, 1H), 8.11 (d, J=16.5 Hz, 1H), 8.79 (d, J=3.9 Hz, 1H), 12.68 (br s, 1H); ESI-MS (m/z) 525.43 (MH)+.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1.[CH2:16]([CH:24]1[CH2:26][O:25]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[OH:25][CH:24]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: Oc1ccc(SC2CCCNC2)cc1
Reactant: c1ccc(CCC2CO2)cc1
Agent: Br
Product: Oc1ccc(SC2CCCN(CC(O)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=358.2 (M+H+) was prepared from (RS)-4-(piperidin-3-yl-sulfanyl)-phenol hydrobromide and (RS)-2-phenethyl-oxirane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:18][CH2:17][C:16]([F:25])([F:24])[F:15])[CH:6]=1)[CH3:2]
Reactant: CS(=O)(=O)OCCC(F)(F)F
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC)c(OCCC(F)(F)F)c1

Procedure:
The mixture of 3-hydroxy-4-methoxy-benzoic acid ethyl ester (1.75 g, 8.92 mmol), methanesulfonic acid 3,3,3-trifluoro-propyl ester (2.06 g, 10.7 mmol) and anhydrous K2CO3 (2.49 g, 17.8 mmol) in acetone (20 mL) is heated with stirring at reflux temperature overnight. After cooling, the mixture is diluted with AcOEt followed by washing of the organic phase with 2N aqueous NaOH and brine. The organic layer is dried over Na2SO4 and evaporated, and the crude product is purified by silica gel chromatography (eluent: hexane/AcOEt 5:1) to give the title compound as oil. TLC, Rf (hexane/AcOEt 1:1)=0.59. MS: 293.0 [M+H]+. 1H-NMR (CDCl3): δ 1.42 (t, 3H), 2.74 (m, 2H), 3.96 (s, 3H), 4.33 (m, 2H), 4.40 (m, 2H), 6.94 (m, 1H), 7.59 (s, 1H), 7.77 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][C:14]([O-])(C)[CH3:15].[K+].IC(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:14]([CH3:15])[CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 0 °C
Yield: 48 %

Procedure:
To a solution of methyl 2-(4-bromophenyl)acetate, 13-a, (2.29 g, 10 mmol) in DMF (40 ml) was added dropwise a mixture of t-BuOK (1.12 g, 10 mmol) in DMF (20 mL) with stirring at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 30 min, 2-iodopropane (1.70 g, 10 mmol) was added dropwise. Then the resulting solution was stirred overnight and ice-water was added. The aqueous layer was extracted by EA. The combined organic layers were washed by brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to afford the title compound, 13-b, (1.3 g, 48%). 1H NMR (300 MHz, CDCl3) δ 0.70-0.72 (m, 3H), 1.02-1.04 (m, 3H), 2.27-2.32 (m, 1H), 3.10-3.14 (m, 1H), 3.65 (s, 3H), 7.19-7.24 (m, 2H), 7.42-7.45 (m, 2H). LC-MS: (M+H)+ 254, 256.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(OCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1OCCc1ccccc1
Temperature: 70 °C

Procedure:
3-Benzyloxy-4-cyano-benzoic acid methyl ester from step 1 (84 mg, 0.30 mmol) was dissolved in THF (1.5 ml). LiBH4 in THF (2 M, 300 μl, 0.60 mmol) was added. The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:8][CH2:9]2)=[O:32])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccccc1CN1CCC(O)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1
Yield: 92.6 %

Procedure:
0.5 g (0.00212 mol) of 1-(2-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.561 ml (0.00424 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.696 g (93%) of 1-(2-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 86°-87°.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([C:9]([O:11]C)=[O:10])[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>>[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1nc2ccc(O)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A mixture of methyl 6-hydroxybenzo[d]thiazole-2-carboxylate (0.21 g, 1 mmol) and 1N aqueous sodium hydroxide (2 mL) was stirred at room temperature overnight. The reaction mixture was then carefully acidified with concentrated hydrochloric acid. The precipitate formed was filtered, washed with water, and dried under reduced pressure to afford 6-hydroxybenzo[d]thiazole-2-carboxylic acid as a white solid (0.20 g, 99%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.20 (s, 1H), 7.96 (m, 1H), 7.44 (m, 1H), 7.06 (m, 1H) ppm; MS (ESI): 196.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@H:22]([C:27](O)=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([N:35](CC)CC)C.CCN(C(C)C)C(C)C.Cl.CN.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:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@H:22]([C:27]([NH:35][CH3:33])=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)[C@H](C(=O)O)C1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
(2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylic acid (15) (145 mg, 0.32 mmol) was dissolved in DMF (10 ml) under nitrogen. Triethylamine (0.13 ml, 0.95 mmol) was added, followed by DIPEA (0.055 ml, 0.32 mmol) and methylamine hydrochloride (0.043 g, 0.63 mmol). The mixture was cooled in an ice/water bath and HATU (180 mg, 0.47 mmol) was then added portionwise such that the temperature remained <10° C. The reaction mixture was stirred at room temperature overnight and evaporated to dryness. The residues were dissolved in EtOAc, washed with water (10 ml), brine (10 ml), dried over MgSO4, filtered and evaporated. The crudes were purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0-90/10). Fractions containing the desired product were combined and evaporated. The resulting solids were dissolved in methanol, loaded onto an SCX column and eluted with MeOH (20 ml) followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated to give the title product as a white solid (69 mg, 40%): 1H NMR Spectrum: (DMSO-d6) δ1.63-1.69 (2H, m), 2.15-2.21 (6H, m), 2.55-2.62 (4H, m), 2.93-2.98 (1H, m), 3.94 (3H, s), 4.43-4.51 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.49-7.56 (2H, m), 7.68-7.72 (1H, m), 7.86 (1H, s), 8.39 (1H, s), 9.57 (1H, s); Mass Spectrum: (M+H)+ 474.