Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH2:5][C:6]([OH:8])=O)([CH3:4])[CH3:3].O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=CC=[C:12]2[C:11]1=[O:20].C1C[O:24][CH2:23][CH2:22]1.O1CCOCC1>>[Si:2]([C:5]1[C:6]([O:8][C:23](=[O:24])[CH3:22])=[C:12]2[C:11](=[O:20])[NH:10][C:14](=[O:15])[C:13]2=[CH:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C[Si](C)(C)CC(=O)O
Reactant: C1CCOC1
Solvent: C1COCCO1
Product: CC(=O)Oc1c([Si](C)(C)C)ccc2c1C(=O)NC2=O
Reaction time: 3 h

Procedure:
Trimethylsilylacetic acid (0.1 mmole) and N-hydroxyphthalimide (0.1 mmole) were weighed under N2 and placed in a conical flask with 2 side arms (flask A). Dry THF/dioxane (0.5 mL) was added and removed carefully under vacuum to dry the substrates. THF (0.4 mL) was added and mixed to dissolve the substrates. DCC (95 μL, 1 M solution in methylene chloride) dried on activated molecular sieves was added and mixed. The reaction was stirred 3 hours, and a precipitate formed after 10 minutes. THF was removed under vacuum to dryness. Dry ether was added (1 mL) and mixed to dissolve the product of coupling, the reaction was left for 5 minutes for the by-product dicyclohexylurea to settle. The upper layer was transferred and filtered into the second flask. Dry ether (0.5 mL) was added, mixed and the upper layer was again transferred as above. The ether was removed under vacuum to leave the TMS-acetoxyphthalimide as a white solid.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:16])[CH2:15][CH2:14][CH2:13]2)=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18])=O.CO.C(=O)([O-])[O-].[K+].[K+].O>>[CH3:16][C:12]1([C:9]2[CH:10]=[CH:11][C:6]([NH2:5])=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=2)[CH2:13][CH2:14][CH2:15]1
Reactant: CC1(c2ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(c2ccc(N)c([N+](=O)[O-])c2)CCC1
Temperature: 45 °C
Yield: 102.1 %

Procedure:
A solution of 2,2,2-trifluoro-N-[4-(1-methylcyclobutyl)-2-nitrophenyl]acetamide (580 mg. 1.9 mmol) in Methanol (18 ml, 440 mmol) was treated with a solution of Potassium carbonate (788 mg, 5.70 mmol) in Water (4.5 ml, 250 mmol) and the mixture was heated at 45° C. for 50 minutes The reaction mixture was cooled to RT and the methanol was removed in vacuo. The remaining aqueous phase was diluted with 10 ml H2O and extracted with three 20 ml portions of EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to yield an oil. The material was placed on high vacuum where upon it solidified giving the desired compound (400 mg). The material was used directly in the next step 1H NMR (400 MHz. CDCl3) d ppm 7.90 (d, J=2.07 Hz, 1 H), 7.23 (dd, J=8.50, 2.28 Hz, 1 H), 6.77 (d, J=8.71 Hz, 1 H), 5.96 (br. s., 2 H), 2.33 (m, 2 H), 2.13 (m, 1 H), 2.04 (m, 2 H), 1.84 (m, 1 H), 1.43 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[CH:9]=1)[CH:5]=O.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+]>C1COCC1>[C:11]1([C:8]2[CH:9]=[C:2]([CH:20]=[O:23])[CH:3]=[C:4]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2)cc(-c2ccccc2)c1

Procedure:
21.38 g (0.081 mol) of 3,5-dibromobenzaldehyde, 16.82 g (0.162 mol) of phenylboronic acid and 1.04 g (0.90 mmol) of tetrakispalladium are initially introduced. 500 ml of 1 M sodium carbonate solution and 300 ml of THF are added, and the reaction is brought to reaction under reflux for 24 h.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6](OCC)[CH:5]=1)([O-])=O.[C:20](OCC)(=[O:22])[CH3:21]>[Pd].[H][H]>[CH2:20]([O:22][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:21]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1OCC
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(N)cc1)OCC
Yield: 60 %

Procedure:
Ethyl p-nitro-2-ethoxycinnamate obtained in step (i) was hydrogenated using 10% Pd—C—H2 (60 psi) (11 g) in ethyl acetate (150 mL) at room temperature and chromatographed using ethyl acetate/hexane to yield the title compound as viscous oil (9.41 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.C(N(CC)CC)C.Cl.[CH:39]12[CH2:44][CH:43]1[CH2:42][NH:41][CH2:40]2.Cl>C1COCC1.CO>[ClH:1].[CH:39]12[CH2:44][CH:43]1[CH2:42][N:41]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([NH:15][CH2:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:11][N:10]=1)[CH2:40]2
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: C1NCC2CC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 72.4 %

Procedure:
In absolute anhydrous THF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (100 mg, 0.22 mmol). Triethylamine (0.22 g, 2.2 mmol) was added dropwisely, and 3-azabicyclo[3.1.0]hexan hydrochloride salt (42 mg, 0.35 mmol) was added. The reaction mixture was heated to reflux overnight. The solvent was removed by rotary evaporation, and water was added, followed by extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1) to give a solid. The solid was dissolved in methanol (0.05 mL), and hydrochloric acid (1 mol/L) was added. The solvent was removed to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide hydrochloride (40 mg, 39% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH:9]=O)=[C:7]([CH3:14])[C:6]=1[CH3:15])[CH:2]=[CH2:3]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH:9]=[CH:3][CH2:2][CH:1]=[O:4])=[C:7]([CH3:14])[C:6]=1[CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)c(C=O)c(C)c1C
Solvent: CC(C)=O
Product: C=CCOc1cc(C)c(C=CCC=O)c(C)c1C

Procedure:
The 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphonium bromide employed as the starting material can be prepared by the procedure of Example 3. This procedure is carried out by alkylation of 1,3,5-trimethylphenol with allyl bromide to give 1,3,5-trimethyl-phenyl allyl ether (boiling point 76°-80° C/0.05 mmHg), by formylation of the ether obtained to give 4-allyloxy-2,3,6-trimethyl-benzaldehyde (boiling point 90°-102° C/0.15 mmHg), by condensation of the aldehyde obtained with acetone to give 4-(4-allyloxy-2,3,6-trimethyl-phenyl)-but-3-en-1-al (boiling point 135°-138° C/0.05 mmHg), by reaction of the ketone obtained with acetylene to give 5-(4-allyloxy-2,3,6-trimethyl-phenyl-3-methyl-3-hydroxy-penta-4-en-1-yne, by partial hydrogenation of the tertiary acetylene carbinol obtained to give 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-1,4-diene and by reaction of the tertiary ethylene carbinol obtained with triphenylphosphine hydrobromide. There is obtained 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-triphenylphosphonium bromide which melts at 114°-116° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:18][C:19]([OH:21])=[O:20])([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([CH2:7][C:8]([CH2:18][C:19]([OH:21])=[O:20])([C:14]([CH3:15])([CH3:16])[CH3:17])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccccc1)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(CC(=O)O)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Dissolve 3-phenyl-2-t-butylcarboxymethylpropionic acid, ethyl ester (2.68 g, 9.17 mmol) in ethanol (95%, 60 mL) and water (30 mL). Treat with potassium hydroxide (2.94 g, 52 mmol). Stir at room temperature for 3 hours. Add water (75 mL) and extract with ethyl ether (2×50 mL). Extract the combined ethereal phases with water (75 mL) and acidify the combined aqueous phases with aqueous 1 M tartaric acid (pH 2-3). Extract with ethyl acetate (2×125 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Take the residue up in methylene chloride and filter to give 3-phenyl-2-t-butylcarboxymethylpropionic acid as a pale yellow solid (1.96 g, 81%).
Reaction SMILES: O1C2C(=CC=CC=2)[C@H]([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C@H:24]4[CH2:28][C@@H:27]([C:29](=[O:41])[NH:30][C@H:31]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH2:34][CH2:33][CH2:32]5)[N:26]([C:42](=[O:55])[C@@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:25]4)=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:56](=[O:69])[C@@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:13])CC1.C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1C[C@@H](C2C=C3C(C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](N(C(OC(C)(C)C)=O)C)C)C(C)(C)C)C3)=CC=2)C[C@H]1C(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)=O)=O)=O)(C)(C)C.[C:154]1([CH2:160][C@@H:161]([C:163]2[NH:167][N:166]=[N:165][N:164]=2)N)[CH:159]=[CH:158][CH:157]=[CH:156][CH:155]=1.C(O)(C(F)(F)F)=O>>[CH3:46][C:44]([CH3:47])([CH3:45])[C@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:42]([N:26]1[CH:27]([C:29]([NH:30][C@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][CH2:32]2)=[O:41])[CH2:18][C:19]2[C:24](=[CH:28][C:22]([C@H:17]3[CH2:23][C@@H:14]([C:12](=[O:13])[NH:11][C@H:161]([C:163]4[NH:167][N:166]=[N:165][N:164]=4)[CH2:160][C:154]4[CH:159]=[CH:158][CH:157]=[CH:156][CH:155]=4)[N:15]([C:56](=[O:69])[C@@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:58]([CH3:59])([CH3:61])[CH3:60])[CH2:16]3)=[CH:21][CH:20]=2)[CH2:25]1)=[O:55]
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCOc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Reactant: N[C@@H](Cc1ccccc1)c1nnn[nH]1
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H](Cc4ccccc4)c4nnn[nH]4)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2CC1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Yield: 33 %

Procedure:
Following procedures analogous to those for the preparation of Compounds F and G of Example 46, (S)-2-((2S,4R)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidine-2-carboxamido)-3-phenylpropanoic acid (Compound D of Example 46, 30 mg, 0.030 mmol) and (S)-2-phenyl-1-(1H-tetrazol-5-yl)ethanamine, TFA (17 mg, 0.059 mmol) were converted to the title compound (10 mg, 33% over 2 steps). MS (ESI+) m/z 987.8 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([NH:11][CH3:12])=[CH:9][C:8]([Cl:13])=[N:7][CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.C(OCC)(=O)C>C1COCC1>[Cl:13][C:8]1[N:7]=[CH:6][C:5]([CH2:4][OH:3])=[C:10]([NH:11][CH3:12])[CH:9]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(Cl)ncc1CO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-Chloro-4-methylaminonicotinic acid ethyl ester (33 g, 156 mmol) was dissolved in anhydrous THF (500 mL) and cooled to −78° C. To the solution was slowly added a solution of LAH (12.5 g, 330 mmol) in THF (500 mL). After the addition was complete, the reaction was kept at −78° C. for 1 h. The mixture was warmed to rt and a small amount of MeOH/ethyl acetate (1/1) was slowly added to destroy the excess LAH. The crude reaction mixture was filtered through a celite plug, washing twice with ethyl acetate. The filtrate was concentrated, and the crude residue was purified by silica gel chromatography (1:1 hexanes/ethyl acetate eluant). The title compound was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 6.48 (s, 1H), 5.55 (bs, 1H), 4.63 (s, 2H), 2.89 (d, J=5.1 Hz, 3H).
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc([N+](=O)[O-])cc12
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc([N+](=O)[O-])cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methyl]amino}benzoic acid (1.54 g) synthesized above, ethyl 3-(methylamino)propanoate (593 mg), 1-hydroxybenzotriazole monohydrate (692 mg), triethylamine (1.26 mL) and N,N-dimethylformamide (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (867 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (1.41 g, 72%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21]C[N:19]([C:22]([O:24][C:25]([CH3:28])(C)C)=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].ClC1N=C(N2CCOC[C@@H]2C)C2CN(C(OCC)=O)CC=2N=1.[F:59]C1C=C(C=CC=1B1OC(C)(C)C(C)(C)O1)N>>[CH2:25]([O:24][C:22]([N:19]1[CH2:21][C:15]2[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])=[N:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:36])=[CH:11][C:10]=3[F:59])=[N:17][C:16]=2[CH2:18]1)=[O:23])[CH3:28]
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)c(F)c1
Yield: 44 %

Procedure:
Step 1 Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by prep HPLC (high pH) yielding the title compound (54.7 mg, 0.13 mmol, 44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[S:22]([OH:25])(=[O:24])=[O:23]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[C:16]([S:22]([OH:25])(=[O:24])=[O:23])[CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)cc1
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-methoxy-phenyl)-3-phenyl-propionic acid methyl ester (prepared according to the procedure reported in Tetrahedron (2006), 62(41), 9610-9621) (2.50 g, 9.25 mmol) in DCM (250 mL) at 0° C. is added chlorosulfonic acid (30.7 ml, 462.5 mmol). The reaction mixture is allowed to warm to RT and is stirred at this temperature for 2 h. Ice water is added to cause precipitation of the product. The solvents are decanted and the residual solid is washed with ice water. The solid is then dried under vacuum to afford the title compound that is used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:38])([F:37])[C:11]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH2:34]([N:33]([CH2:32][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)([OH:31])[C:10]([F:9])([F:37])[F:38])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH2:35][CH3:36]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccsc1
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 1 from 3-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([N:41]1[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[Cl:48][C:49]1[N:54]=[CH:53][N:52]=[C:51]2[NH:55][N:56]=[CH:57][C:50]=12>O1CCCC1.C1(C)C=CC=CC=1>[C:37]([O:36][C:34]([N:41]1[CH2:46][CH2:45][CH:44]([N:55]2[C:51]3=[N:52][CH:53]=[N:54][C:49]([Cl:48])=[C:50]3[CH:57]=[N:56]2)[CH2:43][CH2:42]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A solution of triphenylphosphine (30.5 g, 116.3 mmol) in anhydrous tetrahydrofuran (450 mL) was cooled to 0° C. under nitrogen. Diisopropylazodicarboxylate (22.9 mL, 116.3 mmol) was added dropwise over 10 min. The mixture was stirred at 0° C. for 15 min and then 1-Boc-4-hydroxy-piperidine (Aldrich, 20.3 g, 100 mmol) was added. The mixture was stirred at 0° C. for 10 min and then solid 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 30; 13.0 g, 84 mmol) was added in portions. The flask containing Intermediate 30 was rinsed with THF and the washings were added to the reaction mixture. The reaction mixture was stirred in the ice-bath for 3 h, and then stored in the refrigerator overnight. The reaction mixture was evaporated to dryness and the residue was taken up in a mixture of ether and hexanes (2:1; 1 L). The mixture was stirred at room temperature for 20 min, and then the white solid was filtered off and washed with a mixture of ether and hexanes (2:1). The filtrate was evaporated to dryness to give a yellow solid. This was taken up in toluene with warming, applied to a column of flash silica gel (90 mm×6″) and eluted with 20-25% ethyl acetate/hexanes to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (11.0 g, 39%) along with mixed fractions which were repurified by flash chromatography.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([O:13][PH:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=[PH](O)CCCCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[PH](CCCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110 %

Procedure:
To a solution of the compound of example 80 (1.75 g, 8.83 mmol) in dry CH2Cl2 (40 mL) was added benzyl alcohol (1.83 mL, 17.7 mmol), DMAP (108 mg, 0.88 mmol) and EDC (1.91 g, 10.0 mmol). The mixture was then stirred at room temperature for 18 h. The mixture was concentrated in vacuum, taken-up in ethyl acetate and washed with NaHCO3 (5%) and H2O. Drying (Na2SO4) and concentration gave 2.8 g of a pale yellow oil which was purified by flash chromatography (SiO2, ethyl acetate:hexane (1:1)) to give 1.92 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([N:49]1[C:58]2[C:53](=[CH:54][C:55]([C:59]([NH:61]O)=[NH:60])=[CH:56][CH:57]=2)[C@H:52]([NH:63][C:64](=[O:69])[O:65][CH:66]([CH3:68])[CH3:67])[CH2:51][C@@H:50]1[CH3:70])(=[O:48])[CH3:47]>CN(C)C=O.CCOC(C)=O>[CH3:68][CH:66]([O:65][C:64](=[O:69])[NH:63][C@H:52]1[C:53]2[C:58](=[CH:57][CH:56]=[C:55]([C:59]3[N:61]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[O:12][N:60]=3)[CH:54]=2)[N:49]([C:46](=[O:48])[CH3:47])[C@@H:50]([CH3:70])[CH2:51]1)[CH3:67]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)N1c2ccc(C(=N)NO)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3noc(CNC(=O)OC(C)(C)C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
A flask was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}glycine (72.4 mg, 0.413 mmol) and HATU (170 mg, 0.448 mmol) then filled with N,N-dimethylformamide (DMF) (2 mL). DIPEA (0.180 mL, 1.033 mmol) was added and the resulting pale yellow solution was stirred for 5 min. 1-Methylethyl {(2S,4R)-1-acetyl-6-[(hydroxyamino)(imino)methyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 56) (120 mg, 0.344 mmol) in N,N-dimethylformamide (DMF) (2 mL) was then added via syringe and the resulting mixture was stirred at room temperature for 1 h. The mixture was then stirred at 100° C. under nitrogen for 3.5 h then cooled to room temperature and dissolved in AcOEt. The organic phase was washed with water. The aqueous phase was extracted with AcOEt. The combined organic phases were washed three times with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 on a 10 G silica cartridge (gradient 23 to 63% AcOEt in Hexanes) gave 1-methylethyl((2S,4R)-1-acetyl-6-{5-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1,2,4-oxadiazol-3-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (132 mg, 0.271 mmol, 79% yield) as a white foam. LCMS (method A): Retention time 1.07 min, [M−H]−=486.23