Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]3)[O:18][N:17]=2)[N:3]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH3:15][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][CH:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[O:18][N:17]=2)[N:5]=1
Reactant: Oc1ccccc1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCC(O)CC3)n2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCC(Oc4ccccc4)CC3)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.3 %

Procedure:
To a solution of 4-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)cyclohexan-1-ol (Example 424, 0.1 g, 0.272 mmol) in THF (4 mL) was added phenol (0.03 g, 0.272 mmol), triphenylphosphine (0.09 g, 0.327 mmol) and N-{[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (0.08 g, 0.327 mmol). The reaction mixture was stirred at room temperature 16 h. The mixture was then concentrated and purified by preparative HPLC, Method D, to afford the title compound (0.010 g, 8%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>CN(C=O)C>[N:1]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Temperature: 95 °C

Procedure:
A solution of imidazole (13.6 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (8.0 g, 60% dispersion in oil) in dry DMF (250 ml) at ambient temperature under nitrogen for 2.5 hours. A slurry of N-(4-bromobutyl)phthalimide (53.6 g) in dry DMF (80 ml) was added and the mixture heated at 95° C. for 16 hours. The solvent was evaporated off under vacuum and the residue was extracted with hot toluene. The combined toluene extracts were evaporated to dryness and the residue triturated with ether and dried to give N-[4-(imidazol-1-yl)butyl]phthalimide, m.p. 76°-79° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C@@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:28][C:24]1[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[C:22]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCNC1
Yield: 31.5 %

Procedure:
A solution of (3R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (80 mg) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 30 min. The solvent was neutralized by adding satd aq NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and evaporated to give N-(2-((R)-(6-fluoro-3′-methylbiphenyl-2-yl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide (20 mg, 32%).
Reaction SMILES: C(NC1C=CN([C@@H]2O[C@H](CO)[C@@H](OC(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)C2)C(=O)N=1)(=O)C1C=CC=CC=1.[C:48]([NH:56][C:57]1[CH:116]=[CH:115][N:60]([C@@H:61]2[O:91][C@H:65]([CH2:66][O:67][C:68]([C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)([C:77]3[CH:82]=[CH:81][C:80]([O:83][CH3:84])=[CH:79][CH:78]=3)[C:69]3[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=3)[C@@:63](C(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)([OH:64])[CH2:62]2)[C:59](=[O:117])[N:58]=1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:48]([NH:56][C:57]1[CH:116]=[CH:115][N:60]([C@@H:61]2[O:91][C@H:65]([CH2:66][O:67][C:68]([C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)([C:69]3[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=3)[C:77]3[CH:82]=[CH:81][C:80]([O:83][CH3:84])=[CH:79][CH:78]=3)[C@@H:63]([OH:64])[CH2:62]2)[C:59](=[O:117])[N:58]=1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@]2(O)C(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: COc1ccc(C(O[C@H]2C[C@H](n3ccc(NC(=O)c4ccccc4)nc3=O)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
To a solution of N4-benzoyl-2′-deoxycytidine (119.0 g) in pyridine (1.5 L), 4, 4′-dimethoxytritylchloride (113.5 g) was added over two hours and the mixture was stirred at room temperature for a further four hours. Sodium hydrogencarbonate (33.8 g) was added and stirred for two hours, and then the reaction solution was condensed. Ethyl acetate (1.2 L) and water (300 mL) were added to the residue and the mixture was stirred. A small amount of saturated saline solution was added to the mixture and the resultant liquid was separated. The extracted organic layer was washed with water, and dried with anhydrous magnesium sulfate. The mixture was filtered and then the solvent was removed. The residue was purified by silica gel column chromatography with ethyl acetate as a solvent. A fraction including the target substance was added dropwise to diisopropyl ether (2.0 L) with vigorous stirring, and then the resultant mixture was stirred at room temperature for two hours. The filtrate was dried in a vacuum at 50° C. to yield non-hydrated N4-benzoyl-5′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine (153.3 g). The XRD pattern showed that the free product was amorphous. Furthermore, the component contained N4-benzoyl-2-deoxycytidine, which was the raw material, N4-benzoyl-3′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine, and N4-benzoyl-3′, 5′-O-bis(4, 4′-dimethoxytrityl)-2′-deoxycytidine, both of which were byproducts, and the rates of the respective peak areas were 1.0%, 0.15%, and 2.2%, respectively.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])O[C:2]1=[O:11].[CH2:12]1[C@@H:15](C(O)=O)[NH:14][CH2:13]1>CN(C)C=O.C(O)(=O)C>[S:9]1[C:5]2[C:4](=[O:10])[N:14]3[CH2:15][CH2:12][C@H:13]3[C:2](=[O:11])[NH:1][C:6]=2[CH:7]=[CH:8]1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2ccsc2C(=O)N2CC[C@@H]12
Yield: 42.7 %

Procedure:
A solution of 26.9 g (0.171 mol) of 2H-thieno-[3,2-d][1,3]-oxazine-2,4(1H)-dione and 16.1 g (0.171 mol) of L-azetidine-2-carboxylic acid in 200 ml of dimethylformamide and 40 ml of acetic acid was stirred at 120° for 3 hrs. The brown solution was evaporated and the brown residue obtained was crystallised from ethanol. There were obtained 15.2 g (43%) of (S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione as colorless crystals; m.p. 274°.
Reaction SMILES: ClCCl.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH:22]([CH:25]4[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]4)[O:21][CH:20]3O)=[C:15]([F:35])[C:14]=2[F:36])=[C:9]([F:37])[C:8]=1[F:38])[CH3:5].C([SiH](CC)CC)C>O>[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:20][O:21][CH:22]([CH:25]4[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]4)[CH2:23][CH2:24]3)=[C:15]([F:35])[C:14]=2[F:36])=[C:9]([F:37])[C:8]=1[F:38])[CH3:5]
Reactant: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(O)O2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)CO2)CC1
Reaction time: 3 h
Yield: 36.1 %

Procedure:
Dichloromethane (30 ml) was added to 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-ol (12) (2.29 g) prepared in the tenth step. Triethylsilane (1.93 g) and a boron trifluoride-diethyl ether complex (2.37 g) were added dropwise to the solution at −30° C. After 3 hours of stirring, water (30 ml) was added to give two layers. The organic layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=80/20 by volume) and then by recrystallization (heptane/ethyl acetate=90/10 by volume) to give 5-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-2-(4-propylcyclohexyl)tetrahydropyran (13) (0.8 g) in 36% yield.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([F:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([F:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(c1cc(F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-5-fluoro-2-methylbenzoate (269 mg, 0.701 mmol) in dichloromethane (5 mL) and acetic acid (500 uL) was added acetaldehyde (124 mg, 2.80 mmol) and sodium triacetoxyborohydride (469 mg, 2.10 mmol) at 0° C. The reaction mixture was stirred at rt for 12 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (277 mg, 96% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.19-7.36 (m, 6H), 6.97 (dd, J=2.4, 10.4 Hz, 1H), 3.89 (s, 3H), 3.86 (d, J=10.4 Hz, 1H), 3.39 (d, J=10.4 Hz, 1H), 3.02-3.10 (m, 4H), 2.74-2.80 (m, 1H), 2.43 (s, 3H), 1.74-1.82 (m, 1H), 1.51-1.63 (m, 2H), 1.32-1.40 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.93 (d, J=7.2 Hz, 3H), 0.86 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 413.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](N)=[N:6][CH:7]=1.[BrH:10].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>>[Br:10][C:5]1[C:4]([CH3:9])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Br
Reactant: Cc1cc(Br)cnc1N
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(Br)cnc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-methyl-pyridin-2-ylamine (1.0 eq.) was added portionwise to aqueous HBr (48%; 1.0M). The mixture was stirred 1 h at rt then cooled to −20° C. Bromine (2.8 eq.) was added dropwise followed by a aqueous solution of NaNO2 (1.0M; 2.7 eq.). The final mixture was warmed to rt and stirred for 2 h. The mixture was cooled back to −20° C. then aqueous NaOH (1.0M; 3.0 eq.) was added dropwise over 1 h. The final mixture was warmed to rt and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11].Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.CNCCNC>O1CCOCC1.[Cu]I>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:12][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:22][CH:23]=1)=[O:11]
Reactant: Cc1oc(-c2ccccc2)nc1-c1ccc(Br)cc1
Reactant: NC(=O)c1ccccc1Cl
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1-c1ccc(NC(=O)c2ccccc2Cl)cc1
Temperature: 110 °C

Procedure:
To a mixture of potassium carbonate (0.898 g, 6.50 mmol), copper(I) iodide (0.0309 g, 0.162 mmol), 2-chlorobenzamide (0.607 g, 3.90 mmol) and 4-(4-bromophenyl)-5-methyl-2-phenyloxazole (1.021 g, 3.25 mmol) in 10 mL 1,4-dioxane was added N,N′-dimethylethylenediamine (0.0350 ml, 0.325 mmol). The reaction was purged with nitrogen twice (evacuated-backfill) then heated in a 110° C. oil bath. After ca. 72 h the reaction was filtered and the filtrate concentrated under reduced pressure. The concentrate was triturated several times with ethyl acetate and the collected solid was discarded. The product was purified from the filtrate by chromatography on silica gel, eluting with 20-60% ethyl acetate in hexane, to afford product as a faintly yellow solid. ESI+ m/z=389.0 [MH]+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)(C)C.[CH2:17]([O:35][CH2:36][CH:37]1[O:39][CH2:38]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[ClH:40]>O>[ClH:40].[OH:39][CH:37]([CH2:36][O:35][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:38][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Yield: 39.5 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 32.6 g (0.1 mols) of octadecylglycidyl ether (made by Sakamoto Yakuhin Kogyo Co., Ltd.) were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 21.2 g of N-(2-hydroxy-3-octadecyloxypropyl)-L-arginine hydrochloride (yield 42.3%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([CH3:24])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:12]([C:13]1([CH3:24])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)N1CCC(C)(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(C)(C=O)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a 100 mL round bottom flask was added DCM (30 mL) and oxalyl chloride (0.88 mL; 10.13 mmol). The solution was cooled to −78° C. and treated with DMSO (1.19 mL; 16.88 mmol). The solution was stirred at −78° C. for 20 minutes and then treated with ethyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (1.7 g; 8.44 mmol, dissolved in 10 mL of DCM). The solution was stirred for 30 minutes at −78° C. and then treated with Et3N (3.53 mL; 25.32 mmol). The solution was stirred at −78° C. for 20 min and then slowly warmed to room temperature and stirred at room temperature for an additional 2 hours. The solution was then treated with saturated aqueous NaHCO3 (50 mL), diluted with DCM (50 mL), and the layers were separated. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the product as an oil that was used without further purification. LC/MS m/z (M+1) 200.0, retention time 2.23 minutes; (10-99% CH3CN—H2O gradient with 0.03% TFA, 5 min). 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.66 (dt, J=13.6, 4.7 Hz, 2H), 3.09 (dd, J=10.1, 3.5 Hz, 1H), 3.06 (dd, J=10.2, 3.4 Hz, 1H), 1.86 (dt, J=13.6, 4.4 Hz, 2H), 1.42-1.30 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 1.02 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:4]=2[O:3]1.[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:15][CH3:14])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(C=O)c2O1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cccc2c1OC(C)(C)C2
Reaction time: 3 h
Yield: 99.6 %

Procedure:
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carbaldehyde (281 mg, 1.59 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.63 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (61.5 mg, 1.63 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (2,2-Dimethyl-2,3-dihydro-benzofuran-7-ylmethyl)-methyl-amine (303 mg, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.02 (m, 2H), 6.76-6.71 (m, 1H), 3.52 (s, 2H), 2.97 (s, 2H), 2.24 (s, 3H), 1.39 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[N:33]=[C:34]([NH:37][CH:38]([CH3:40])[CH3:39])[S:35][CH:36]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:41]([O:43]C(C)(C)C)=[O:42])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[N:33]=[C:34]([NH:37][CH:38]([CH3:40])[CH3:39])[S:35][CH:36]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:41]([OH:43])=[O:42])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)C[C@H]1C(=O)O)C(=O)OCC

Procedure:
To a solution of compound 74 (20 mg, 30 umol) in CH2Cl2 (2 mL) was added TFA (2 mL) and Et3SiH (10 uL, 63 umol). After 2 h the volatiles were evaporated and the product was used without any purification step. Compound 75: 18 mg, quant. as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([NH:14][S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 100.8 %

Procedure:
3-Chlorosulfonyl-benzoic acid (300 mg, 1.36 mmol), and aniline (0.30 mL, 3.29 mmol) were stirred at room temperature in anhydrous CH2Cl2 (10 mL) overnight under N2. The reaction mixture was concentrated in vacuo. Purification of the residue on IR-120 ion exchange resin column (eluted with methanol) afforded the title compound (380 mg, 100%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(OC)nc1
Temperature: 90 °C

Procedure:
A solution of the 5-bromo-2-methoxypyridine (1-2) (74.3 g, 0.4 mol), ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08 mol), palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20 g, 0.066 mol) in 100 mL acetonitrile was degassed with argon for 10 minutes. The mixture was heated at 90° C. for 12 hr, then the volatiles were removed in vacuo. Toluene (300 mL) was added and the mixture concentrated again. Diethyl ether (300 mL) was added and the mixture filtered through a pad of silica gel eluting with 800 mL of diethyl ether. After removal of the diethyl ether, the residue was chromatographed on silica gel eluting with EtOAc/hexane, 1:19 then 1:14 then 1:9 to give 1-3 as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:18]=[CH:17][N:16]=[C:15]([CH:19]=[O:20])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BH4-].[Na+]>CO>[OH:20][CH2:19][C:15]1[CH:14]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc(-c2cc(C=O)ncn2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2cc(CO)ncn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3,4,5-Trimethoxyphenyl)pyrimidine-4-carboaldehyde (364 mg) was dissolved in methanol (50 mL), and to the solution sodium borohydride (25 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[C:3](=[O:24])[C@@H:4]1[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6][N:5]1C(C(OC(C)(C)C)=O)[C@@H]1CCCN1.Cl>CCOC(C)=O>[CH3:1][N:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[C:3](=[O:24])[C@@H:4]1[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6][NH:5]1
Reactant: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)N(C)Cc1cccc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H]1CCN[C@@H]1C(=O)N(C)Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline-N-methyl-N-(3-chlorophenylmethyl) amide (0.150 g, 0.32 mmol) was dissolved in EtOAc (15 mL), cooled to -20° C. and saturated with HCl gas. The solution was stirred at 0° C. for 1 h, then at 25° C. for 1 hour, then concentrated to dryness to give pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline-N-methyl-N-(3-chlorophenylmethyl) amide which was used without further purification.