Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]\[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][C:60]=1[CH3:66]>O1CCCC1>[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][N:2]([CH3:1])[CH3:22])=[CH:7][CH:8]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:61][C:60]=1[CH3:66]
Reactant: CN(C)CC#Cc1ccc(/C(=C\CO)c2ccccc2)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(C#CCN(C)C)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above alcohol (291 mg, 0.999 mmol) in dry tetrahydrofuran (30 mL) was added tributylphosphine (0.27 ml, 1.5 mmol). The mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (377.5 mg, 1.5 mmol), and after 10 min (4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (2151 mg, 1.1 mmol) was added. After 1.5 hr at 0° C. the reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was added silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding (4-{(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methyl-phenoxy)-acetic acid methyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH2:19]>>[OH:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10](=[O:11])[NH:19][CH3:18]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)O
Reactant: CN
Agent: Cl
Product: CNC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-tert-Butoxycarbonylamino-3-hydroxy-3-methyl-butyric acid (CAN 105504-72-1) and methanamine hydrochloride as starting materials and isolated (486 mg, 38%); MS (ESI, m/z): 247.2 (M+H+).
Reaction SMILES: NC1C=CC(C(O)=O)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:22]([N:26]([C:64]1[CH:74]=[CH:73][C:67]([C:68]([O:70]CC)=[O:69])=[CH:66][CH:65]=1)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[N:44](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:43]=[N:42][N:41]=2)=[CH:30][CH:29]=1)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]([C:64]1[CH:65]=[CH:66][C:67]([C:68]([OH:70])=[O:69])=[CH:73][CH:74]=1)[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][N:43]=[N:42][N:41]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1ccc(C(=O)OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1ccc(C(=O)O)cc1
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared in analogy to Example 164 starting from 4-aminobenzoic acid instead of 3-aminobenzoic acid. Tosic acid deprotection of ethyl 4-{N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}benzoate followed by ester hydrolysis afforded, after purification by flash chromatography on silica gel eluting with 95:5:0.25 chloroform/ethanol/acetic acid, the title compound (100 mg, 26%) as a solid. 1H NMR (CD3OD, 300 MHz) δ 1.00 (t, 3H), 1.40 (m, 2H), 1.65 (m, 2H), 3.50 (t, 2HO, 4.65 (s, 2H), 6.70 (m, 2H), 7.10 (m, 2H), 7.20 (m, 2H), 7.55 (m, 2H), 7.65 (m, 2H), 7.80 (m, 2H). MS (DCl/NH3) m/e 428 (M+H)+, 445 (M+H+NH3)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]([C:13](=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25]([O:27]C(C)(C)C)=[O:26])=[O:19])[CH:10]=[CH:11][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:25]([C:21]1[N:20]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([N:9]2[CH:10]=[CH:11][CH:12]=[C:8]2[C:6]([OH:7])=[O:5])=[O:32])[CH:24]=[CH:23][CH:22]=1)([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)c1cccn1C(=O)CCCCC(=O)n1cccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccn1C(=O)CCCCC(=O)n1cccc1C(=O)O
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a stirred solution of 55 mg (0.12 mmol) 1-[6-(2-tert-butoxycarbonyl-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylic acid tert-butyl ester in 8 ml dichloromethane at 0° C. was added dropwise 0.15 ml (1.97 mmol) trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded 39 mg (95%) of the title compound as an off-white crystalline solid. MS mle (%): 350 (M+NH4+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]([C:20]1[S:35][C:23]2[N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25](=[O:28])[CH:26]=[CH:27][C:22]=2[C:21]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C(=O)OC(C)(C)C)(=[O:11])=[O:10].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:28]=[C:25]1[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[S:35][C:20]([NH:12][S:9]([CH3:8])(=[O:11])=[O:10])=[C:21]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:22]=2[CH:27]=[CH:26]1
Reactant: CC(C)(C)OC(=O)N(c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of the compound of Example 82 (105 mg, 0.212 mmol) in DCM (2.5 mL) and the reaction mixture stirred for 2 h at r.t. The mixture was added to saturated NaHCO3 solution (20 mL) and the product extracted with DCM (2×20 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by radial chromatography on silica (EtOAc) to give the title compound (62 mg, 74%). δH (CDCl3) 7.6–7.25 (11H, m), 6.58 (1H, d, J 9 Hz), 6.31 (1H, br s), 2.53 (3H, s). m/z (ES+) 397 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([OH:24])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Cl)(Cl)Cl>CC(C)=O.CO>[C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([O:24][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(OCc3ccccc3)c1C2COC(N)=O
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (80 mg) in acetone (1 ml) were added potassium carbonate (55 mg) and benzyl bromide (47 μl), and the mixture was stirred at 50° C. for 90 minutes. The mixture was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (20:1, v/v) to afford 11-acetyl-6-benzyloxy-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (90 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:12]=2)[NH:7][CH:6]=1.O.[OH-].[Li+]>CO>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:12]=2)[NH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc2[nH]cc(CCN(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCc1c[nH]c2ccc(CCC(=O)O)cc12

Procedure:
A mixture of Methyl 3-[2-(Dimethylamino)ethyl]-1H-indole-5-propanoate (4.6 g) and lithium hydroxide hydrate (0.7 g) in aqueous methanol (1:1) (80 ml) was stirred under reflux for 4.5 h. The solvent was removed by evaporation to leave a foam which was purified by flash chromatography (E). Evaporation of the appropriate fractions gave a solid which was triturated with ether to present the title compound as a powder (2.92 g) m.p. 195°-200°.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:30]1[C:43]2[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=2[O:37][C:36]2[CH2:35][C:34]([CH3:48])([CH3:47])[CH2:33][C:32](=[O:49])[C:31]1=2.[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:54][S:51]([CH3:50])(=[O:53])=[O:52])=[O:29])[CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:30]1[C:43]2[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=2[O:37][C:36]2[CH2:35][C:34]([CH3:47])([CH3:48])[CH2:33][C:32](=[O:49])[C:31]1=2
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cccc(C(=O)NS(C)(=O)=O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 2 h
Yield: 56.1 %

Procedure:
1,1′-Carbonyldiimidazole (54.6 mg, 0.34 mmol) was added to a solution of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 1-2 (130 mg, 0.26 mmol) in DMF (2.6 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, methanesulfonamide (32.1 mg, 0.34 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.050 ml, 0.34 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 71 hours. Thereafter, an aqueous solution of citric acid (249 mg, 1.30 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). Ethanol was added to the fraction thus obtained, and the generated solid was then collected by filtration and dried to obtain the title compound (84.4 mg, yield: 56%).
Reaction SMILES: C1(C(N)=O)CC1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8].[CH:12]1([C:15]2N(C)[C:18]([CH:21]=[O:22])=[CH:17][N:16]=2)[CH2:14][CH2:13]1>>[C:7]([N:11]1[C:18]([CH:21]=[O:22])=[CH:17][N:16]=[C:15]1[CH:12]1[CH2:14][CH2:13]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: Cn1c(C=O)cnc1C1CC1
Agent: NC(=O)C1CC1
Product: CC(C)(C)n1c(C=O)cnc1C1CC1

Procedure:
3-tert-Butyl-2-cyclopropyl-3H-imidazole-4-carbaldehyde was prepared from cyclopropyl carboxamide and tert-butylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:4]([O:17][C:18]([F:21])([F:20])[F:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:12])[CH3:11])=[C:4]([O:17][C:18]([F:21])([F:19])[F:20])[CH:3]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1OC(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO[Si](C)(C)C(C)(C)C)c(OC(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-hydroxy-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxybenzene (3.2 g, 10 mmol) from Step 4 above and triphenylphosphine (3.9 g, 15 mmol) in THF (50 mL) at 0° C. was added a solution of N-tert-butyloxycarbonyl-4-piperidinol (3.0 g, 15 mmol) and DEAD (2.6 g, 15 mmol) in THF (25 mL) dropwise over a period of 1 h. The mixture was stirred at 0° C. for 3 h and then at ambient temperature for 12 h. The solvent was removed under reduced pressure and the residue was suspended in ether. The solid triphenylphosphine oxide was removed by filtration and the filtrate was purified by pressurized silica gel column chromatography using a gradient elution of 5-10% EtOAc:hexanes as eluant to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-1-(tert-butyldimethylsilyloxy-methyl)-2-trifluoromethoxybenzene as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27][CH3:28].[BrH:32]>>[BrH:32].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:30][CH2:29][N:25]([CH3:24])[CH2:26][CH2:27][CH3:28])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CCCN(C)CCCl
Agent: Br
Agent: Cl
Product: CCCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21

Procedure:
2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1.13 g of 2-(N-methyl-N-n-propylamino)ethyl chloride hydrochloride are treated in the same manner as described in Example 5. The product is converted to its hydrobromide and recrystallized from a mixture of ethanol and ether. 2.1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-n-propylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide are thereby obtained as colorless prisms.
Reaction SMILES: [CH:1]1([CH2:5][S:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>O>[CH:1]1([CH2:5][S:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH:20]3[O:22][CH2:21]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(CCSCC2CCC2)cc1
Reactant: BrCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(OCC2CO2)ccc1CCSCC1CCC1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
13 g (0.058 mol) of p-(2-cyclobutylmethylthioethyl)-phenol suspended in 80 ml of water are introduced into an Erlenmeyer flask placed under nitrogen. The temperature is kept below 20° C. and 2.72 g (0.068 mol) of sodium hydroxide pellets are added. The solution becomes homogeneous. It is stirred for about 30 minutes and 11.92 g (0.087 mol) of epibromohydrin are then added dropwise at ambient temperature. The batch is stirred at ambient temperature for about 4 hours. The solution becomes cloudy. The oily phase is extracted with ether and the ether phase is washed with 2 N sodium hydroxide solution and then with water. The ether is dried over magnesium sulphate and then evaporated. The residue is distilled on a bulb still at a temperature of 160° C. under a pressure of 0.04 mm Hg. 6.2 g (yield: 38.8%) of 1-[4-(2-cyclobutylmethylthio-ethyl)-phenoxy]-2,3-epoxy-propane are obtained, and this material is used directly.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[NH:7][N:6]=[N:5][N:4]=1.[C:10](Cl)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>C(#N)C>[C:10]([N:4]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:7][N:6]=[N:5]1)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: FC(F)(F)c1nnn[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)n1nnnc1C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
6.9 g of 5-trifluoromethyl-1,2,3,4-tetrazole and 13.7 g of palmitoyl chloride were dissolved in 100 ml of acetonitrile while cooling with ice and to the solution was added dropwise 4.5 ml of pyridine over a period of about 10 minutes. After the completion of the dropwise addition, the mixture was stirred at about 5° C. for 30 minutes and then at room temperature for 1 hour, and to the mixture was added dropwise about 100 ml of ice water. The crystals thus-deposited were collected by filtration to obtain 8.2 g of 1-hexadecanoyl-5-trifluoromethyl-1,2,3,4 -tetrazole. A melting point was 66° to 69° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:26]=[C:25]([CH:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[O:24][N:23]=1.C(N(C(C)C)CC)(C)C>C(O)CCCCC>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([N:28]2[CH2:29][CH2:30][CH2:31][CH:27]2[C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: c1ccc(-c2cc(C3CCCN3)on2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCCO
Product: Cc1cc(Nc2nc(N3CCCC3c3cc(-c4ccccn4)no3)ncc2Cl)n[nH]1
Yield: 109.5 %

Procedure:
A mixture of 2,5-dichloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 10 of WO 03/048133) (158 mg, 0.648 mmol), 2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine (Method 12) (212 mg, 0.972 mmol) and di-isopropylethylamine (282 μL, 1.62 mmol) was stirred and heated at 140° C. in n-hexanol (7.0 ml) under nitrogen for 9 hours. The bulk of the hexanol was then removed by evaporation and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with 1.0 molar phosphate buffer pH 4 (×2), then water and finally brine. The organic layer was dried (Na2SO4), filtered and evaporated and the crude product was absorbed onto a 10 g isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with dichloromethane/2M methanolic ammonia (4:1) to elute the product. The purified product was dissolved in the minimum volume of DCM and to the stirred solution a slight excess of 1.0 M ethereal hydrogen chloride was added. Further diethyl ether was added and the solid product collected by filtration, washed with diethyl ether and dried to give the hydrochloride salt of the title compound (300 mg, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([N:3]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(CCc1ccccn1)C(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCc1ccccn1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
N-Ethyl-3-(4-hydroxyphenyl)-N-(2-pyridin-2-ylethyl)propanamide (0.35 g, 1.17 mmol) and methyl 2-(bromomethyl)benzoate (0.30 g, 1.29 mmol) were dissolved in acetonitrile (5 ml) and potassium carbonate (324 mg, 2.34 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymer supported trisamine (0.3 eqv) was added and stirred overnight. The polymer was filtered off, solvent was removed by evaporation, EtOAc (10 ml) was added and the organic phase was washed with three portions of water. After drying the organic layer (MgSO4), the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 135 mg of methyl 2-[(4-{3-[ethyl(2-pyridin-2-ylethyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (yield 25.8%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:41])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[C:28]([C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=3[OH:40])=[N:29][N:30]([CH3:32])[CH:31]=2)=[CH:21][CH:20]=1)=[O:10])(C)(C)C.Cl>CCO>[OH:40][C:34]1[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:33]=1[C:28]1[C:27]([C:26]#[C:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:17]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:9](=[O:10])[C@@H:8]([NH2:7])[CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:41])=[CH:24][CH:23]=2)=[CH:31][N:30]([CH3:32])[N:29]=1
Reactant: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)[C@@H](N)Cc3ccccc3)cc2)c1
Temperature: 25 °C

Procedure:
A solution of compound 6 (9.9 g) in EtOH (80 mL) was cooled to 0° C. with ice-water bath. Concentrated hydrochloric acid (37%, 40 mL) was added into the above solution slowly at 0° C. The ice-bath was removed and the mixture was stirred at rt until the reaction was complete as indicated by LCMS (ca. 5 h). A solution of NaHCO3 (40 g) in water (200 mL) was added slowly with stirring. The final mixture was extracted with EtOAc (˜200 mL), and the organic layer was washed with brine and dried over sodium sulfate. It was filtered, and the solvent was removed with rotavapor. The residua was dried under high vacuum to provide the title compound as pale yellow gum-like powder (6.5 g, 77.4%) and was used for next step without further purification. LCMS (ESI) m/z 562.39 (MH+), 259.26 (100); HPLC: tR=5.05 min.