Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)O1.I[C:28]1[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:49])=[O:48])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[C:30](=[O:52])[CH:29]=1>COCCOC.CO.C(OCC)(=O)C>[CH3:51][C@@:36]([S:47]([CH3:50])(=[O:48])=[O:49])([CH2:35][CH2:34][N:31]1[CH:32]=[CH:33][C:28]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:19][CH:20]=2)=[CH:29][C:30]1=[O:52])[C:37]([NH:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:38]
Reactant: CC1(C)OB(c2ccc(-n3cccn3)cc2)OC1(C)C
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@@](CCn1ccc(-c2ccc(-n3cccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Trisdibenzylidine dipalladium (29 mg, 0.049 mmol) was added to a mixture of potassium carbonate (343 mg, 2.46 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole (133 mg, 0.49 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (245 mg, 0.49 mmol), which may be synthesized as described in Preparation 2B in 1,2-dimethoxyethane-methanol (5.0 mL, 1:1). The reaction was heated to 80° C. and allowed to stir overnight. The reaction was diluted with ethyl acetate (10 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography (1:0-9:1 ethyl acetate/methanol) to provide a colorless residue (58 mg, 23%). MS (LCMS) m/z 513.7 (M−1).
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH:4]([OH:6])[CH:3]=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.N1C=CC=CC=1.O1CCCC1>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:6][C@@H:4]1[CH2:5][C@H:1]([OH:7])[CH:2]=[CH:3]1
Reactant: C1=COCCC1
Reactant: OC1C=CC(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a solution of 5.0 g of 2-cyclopentene-1,4-diol in 300 ml of methylene chloride was added 5 ml of a solution of p-toluenesulfonic acid in tetrahydrofuran (1 millimole/100 ml). A solution of 4.2 g of 2,3-dihydropyran in 30 ml of methylene chloride was then added dropwise with stirring over a period of 1 hour. After stirring overnight at room temperature, 8 drops of pyridine were added. The methylene chloride was evaporated and the residue was dissolved in diethyl ether, washed with water and dried. The residual obtained by evaporating the solvent was chromatographed on silica gel (200 g) using chloroform as an eluent. First, the diether product flowed out. The subsequent effluent was treated in a customary manner to afford 6.6 g of cis-4-tetrahydropyranyloxy 2-cyclopentenol as colorless oily substance boiling at 84° C. (0.7 mmHg).
Reaction SMILES: N1C=CC(C)=CC=1.C([N-]C(C)C)(C)C.[Li+].C(OC(=O)NCC(C1N[C:29]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][CH3:40])[CH:33]=2)N=1)(C)C)(C)(C)C.[Cl-].[NH4+].[O:50]1CCCC1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:50])[CH2:29][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:33][C:34]=1[O:39][CH3:40]
Reactant: C1CCOC1
Reactant: COc1cc(-c2nc(C(C)(C)CNC(=O)OC(C)(C)C)[nH]c2-c2ccncc2)ccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccncc1
Product: COc1cc(C(=O)Cc2ccncc2)ccc1Cl
Temperature: 25 °C
Yield: 64 %

Procedure:
4-Picoline (16.9 ml, 0.174 mol) was added dropwise to a stirred solution of lithium di-isopropylamide (110 ml, 0.22 mol, 2M solution in heptane, ethylbenzene, tetrahydrofuran) in dry tetrahydrofuran (150 ml) at −78° C. After stirring at −78° C. for 15 min a solution of the product of Step 1 (40.0 g, 0.174 mol) in tetrahydrofuran (100 ml) was added dropwise and the reaction allowed to warm to room temperature over 3 hours. The solution was then cooled in ice, saturated ammonium chloride solution added and the aqueous mixture extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The resulting gum was triturated with cold diethyl ether/hexane (1:1, 300 ml) and the solid collected to give the title compound as a pale yellow solid (29 g, 64%); MS(ES+) m/e 262/264 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylate (3.00 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (30 mL) and ethanol (30 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylic acid (2.63 g, yield 92%). The crystals were recrystallized from acetone-hexane. melting point: 209-210° C.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2].[C:31](C1SC=C(CN2CC[C@H](NS(C3C=CC4C(=CC(OC)=CC=4)C=3)(=O)=O)C2=O)C=1)#N>>[C:1]([C:3]1[S:7][C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH3:31])[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc(C#N)s4)C3=O)cc2c1

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as in EXAMPLE 148, Part A, in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide.
Reaction SMILES: NO.C(Cl)CCl.[CH:7]1[CH:8]=[CH:9][C:10]2N(O)N=[N:13][C:11]=2[CH:12]=1.C(N[C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH:27](C)C)(OC(C)(C)C)=O>C(Cl)Cl.C(OCC)(=O)C>[N:13]1[C:11]2[C:10](=[CH:9][CH:8]=[CH:7][CH:12]=2)[CH:27]=[CH:26][C:25]=1[C:30]([OH:32])=[O:31]
Reactant: On1nnc2ccccc21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: NO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(O)c1ccc2ccccc2n1
Temperature: 25 °C
Yield: 212 %

Procedure:
To a solution of the amino alcohol of Example 1e (720 mg, 2.72 mmol) in CH2Cl2 was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction was maintained at room temperature until complete consumption of the starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with 1N HCl, sat. K2CO3, water, brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3% methanol:dichloromethane) gave 1.0 g of the title compound: MS(EI) 478 (M+H+).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1OC(C(OC)=O)=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1ccc(Br)o1
Product: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)o1
Yield: 99 %

Procedure:
Methyl 5-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)furan-2-carboxylate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (82 mg, 0.125 mmol) and methyl 5-bromofuran-2-carboxylate following General Procedure A. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (62 mg, 99%): 1H NMR (CDCl3, 400 MHz) δ 7.42 (s, 1H), 7.29-7.25 (m, 3H), 7.19-7.16 (m, 3H), 6.70 (d, 1H, J=3.6 Hz), 4.83 (t, 1H, J=6.0 Hz), 3.92 (s, 3H), 2.60 (t, 2H, J=7.6 Hz), 1.96-1.85 (m, 2H), 1.71-1.57 (m, 2H), 1.40-1.33 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.8, 151.9, 149.1, 147.8, 147.5, 133.4, 133.2, 130.6, 129.3, 124.6, 113.6, 113.5, 73.6, 57.1, 41.3, 40.9, 36.4, 34.1, 30.7, 30.7, 30.1, 23.2, 0.0, −0.1.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[CH:14][N:15]([CH3:16])[C:11]=3[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:1][C:2]1([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[CH:14][N:15]([CH3:16])[C:11]=3[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:4][CH2:3]1
Reactant: Cn1cnc2ccc(C3(O)CCC(=O)CC3)cc21
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cn1cnc2ccc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)cc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-methyl-3H-benzoimidazol-5-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:36](O)=[O:37])=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:29]=2)[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:36]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:37])=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:29]=2)[CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1c(-c2ccccc2)nc2ccc(Cl)cn12
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1c(-c2ccccc2)nc2ccc(Cl)cn12

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 6-Chloro-2-phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=2)[CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32].CC(O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[ClH:32].[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=2)[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc1ccccc1)C2
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)C[C@@H](C(=O)OCc1ccccc1)NC2
Temperature: 40 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a suspension of crude (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(tert-butyloxycarbonyl)-3-isoquinolinecarboxylic acid benzyl ester (example 5) (335 g, 0.7836 mol) in ethyl acetate (335 mL) and toluene (335 mL) was added 20% HCl solution in IPA (357 g, 1.959 mol) at 15-20° C. The reaction mixture then was heated to 40° C. over 1-2 h, and stirred at this temperature for 2 h. A 20% HCl solution in IPA (71.4 g, 0.3918 mol) was added, and the stirring was continued for another 2 h. The reaction mixture was cooled to 15-20° C., and stirred at this temperature. The mixture was filtered, and washed with ethyl acetate (2×670 mL). The white solids were dried under vacuum at 40° C. to give 278.6 g (99% yield, ee=98%) of (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid benzyl ester, hydrochloride. 1H NMR (DMSO-d6) δ: 3.10 (dd, J=16.64, 10.74 Hz, 1H, CHHCHCOOH), 3.24 (dd, J=16.64, 5.10 Hz, 1H, CHHCHCOOH), 3.72 (s, 6H, OCH3), 4.23 (br s, 2H, CH2N), 4.58 (dd, J=10.74, 5.10 hz, 1H, CHCOOH), 5.27 (d, J=12.48 Hz, 1H, PhCHH), 5.33 (d, J=12.48 Hz, 1H, PhCHH), 6.85 (br s, 2H, PhH), 7.35-7.46 (m, 5H, PhHCH2), 10.19 (br s, 2H, NH.HCl).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccc(Br)s1
Temperature: 25 °C

Procedure:
3 g (15.7 mmol) of 5-bromo-thiophene-2-carbaldehyde were dissolved in 30 ml of pyridine and 1.96 g (18.8 mmol) of malonic acid and 133 mg (1.6 mmol) of piperidine was added. The reaction mixture was boiled under reflux for 6 h. After cooling to room temperature, it was poured into a mixture of ice and concentrated aqueous hydrochloric acid whereupon the product precipitated. The product was isolated by filtration, dissolved in ethyl acetate, and the solution was washed with 0.1 M hydrochloric acid. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. Yield: 3.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(#N)C.N>[CH3:36][C:35]([Si:32]([CH3:34])([CH3:33])[O:31][CH2:30][C:12]1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:20]([NH:19][CH2:18][CH3:17])=[O:21])[CH:3]=2)=[N:10][CH:11]=1)([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2cccc(N)c2)nc1NCCCNC(=O)OCc1ccccc1
Agent: N
Solvent: CC#N
Product: CCNC(=O)Nc1cccc(Nc2ncc(CO[Si](C)(C)C(C)(C)C)c(NCCCNC(=O)OCc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of phenylmethyl [3-[[2-[(3-aminophenyl)amino]-5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]pyrimidin-4-yl]amino]propyl]carbamate (225 mg) in acetonitrile (5 ml) ethyl isocyanate (33 μl) was added and the mixture stirred for 18 h at room temperature. Then 5 drops of ammonia solution (25%) were added and the precipitated title compound isolated by filtration (158 mg).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([O:19]CC)=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ncccc1Nc1cc(C(C)(C)C)nn1-c1c(C)cccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Temperature: 40 °C
Yield: 84.6 %

Procedure:
To a solution of ethyl 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylate (2.10 g, 5.35 mmol) in a mixture of ethanol (5 mL) and THF (5 mL) was added lithium hydroxide monohydrate (1.12 mg, 26.8 mmol) in water (10 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid, and the mixture was concentrated to dryness. The crude mixture was redissolved in methanol and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 1.65 g (85%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.22 (br, s, 1H), 9.52 (s, 1H), 8.03 (dd, 1H), 7.86 (dd, 1H), 7.50 (dd, 1H), 7.30 (dd, 1H), 7.18 (d, 2H), 2.02 (s, 6H), 1.37 (s, 9H); ES-MS m/z 321.3 (MH+); HPLC RT (min.) 2.56.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[N+:15]([CH3:18])([O-:17])=[O:16]>O>[OH:14][C:7]1([CH2:18][N+:15]([O-:17])=[O:16])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 12 h

Procedure:
5-nitroisatin (0.081 g) and nitromethane (0.15 ml) were added to water (2 ml) and the reaction mixture was vigorously stirred at a temperature of 30° C. for 12 hours. The product was extracted with ethyl acetate and recrystallized with MeOH to afford pure product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].C(Br)(C)(C)C.[CH3:34][S:35]([CH3:37])=O>C(OCC)(=O)C>[CH3:34][S:35][CH2:37][O:17][C:16](=[O:18])[CH:15]([O:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)[CH3:19]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: CS(C)=O
Agent: CC(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CSCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 g (0.03 mol) of 2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenoxy]-propionic acid and 252 g (3.0 mol) of sodium bicarbonate are suspended in 2.5 liters of dimethyl sulphoxide and thereafter treated slowly with 336.5 ml (3.0 mol) of tert.butyl bromide. The mixture is stirred at room temperature overnight. The mixture, including the separated thick precipitate, is subsequently taken up in 5 liters of ethyl acetate. The ethyl acetate solution is washed twice with 1 liter of water, dried over sodium sulphate and evaporated. The residue is chromatographed on a 10-fold amount of silica gel with hexane/ethyl acetate (7:1) and the eluate is evaporated. There is obtained 2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenoxy]-propionic acid [(methylthio)methyl]ester in the form of an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([NH:1][CH2:2][CH2:3][C:4]1[CH:46]=[CH:45][CH:44]=[CH:43][C:5]=1[O:6][CH2:7][CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:20][CH:21]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:11]1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
A solution of 0.25 g of tert-butyl 3-{2-[2-(2-aminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12 ml of dichloromethane is admixed at room temperature with a solution of 0.12 ml of triethylamine in 1 ml of dichloromethane. Subsequently, a solution of 0.034 ml of methanesulphonyl chloride in 1 ml of dichloromethane is added dropwise. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane, washed with 1M aqueous potassium bisulphate solution (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.07 (1:2 EtOAc-heptane); Rt=5.78.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=1)(=O)[NH2:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(N)=O)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(C#N)n1
Temperature: 0 °C
Yield: 62 %

Procedure:
To a round bottom flask charged with tert-butyl (6-carbamoylpyridin-2-yl)carbamate (0.940 g, 3.96 mmol) in dichloromethane (7.92 ml) was added triethylamine (1.380 ml, 9.90 mmol). The reaction mixture was cooled to 0° C. and trifluoroacetic anhydride (0.671 ml, 4.75 mmol) was added dropwise. The reaction mixture was stirred at 0° C. 90 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (2×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the Isco system (40 g, 0-15% EtOAc/Hex) to provide tert-butyl (6-cyanopyridin-2-yl)carbamate (0.538 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: BrCc1ccc2ccccc2c1
Product: CCOC(=O)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 85 %

Procedure:
In an analogous procedure to that described in Example 1, 2-bromomethylnaphthalene was reacted with ethyl 3-hydroxybenzoate to give ethyl 3-(naphth-2-ylmethoxy)benzoate in 85% yield, m.p. 45°-46.5° C.