Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=1)[CH2:3][CH3:4].[C:23]([O:27][C:28](=[O:36])[NH:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH:32]=O)([CH3:26])([CH3:25])[CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:23]([O:27][C:28](=[O:36])[NH:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH2:32][NH:1][CH:2]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=1)[CH2:3][CH3:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: CCC(N)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(NCCC(C)(C)NC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a solution of 36 (136 mg, 0.433 mmol) in MeOH (5 ml) was added (1,1-dimethyl-3-oxo-propyl)-carbamic acid tert-butyl ester(105 mg, 0.522 mmol) followed by NaBH(OAc)3 (138 mg, 0.65 mmol). The reaction mixture was stirred at room temperature overnight, quenched with water. Solvent was removed in vacuo, the residue was purified by preparative HPLC to give 37 (86 mg) at the yield of 41% for the two steps. 1H-NMR (500 MHz, CDCl3): δ 7.23–7.39 (m, 5H), 5.89 (d, J=16.0 Hz, 1H), 5.01 (d, J=16.0 Hz, 1H), 4.66 (t, J=5.77 Hz, 1H), 4.43 (brs, 1H), 2.86 (s, 3H), 2.45 (m, 2H), 2.11 (m, 1H), 1.96 (m, 2H), 1.74 (m, 1H), 1.30 (s, 9H), 1.13 (s, 3H), 1.01 (s, 3H), 0.88 (t, J=7.42 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24](OC3C=CC=CC=3)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16]C(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)CC2)CCCCC1.C([O:56][C:57](=[O:67])[CH2:58]CSC1SC(N)=NC=1)C>>[CH:1]1([N:7]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[CH2:25][CH2:26]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:58][C:57]([OH:67])=[O:56])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](Oc3ccccc3)CC2)s1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: c1ccc(O[C@H]2CC[C@H](NC3CCCCC3)CC2)nc1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](Oc3ccccn3)CC2)s1

Procedure:
Prepared in a similar manner {2-[3-cyclohexyl-3-(trans-4-phenoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-[trans-4-(pyridin-2-yloxy)-cyclohexyl]-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:57]=[CH:56][C:27]([CH2:28][P:29](=[O:55])([O:33][CH2:34][CH2:35][CH2:36][N:37]4[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[N:39]=[N:38]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:58][CH3:59])[N:14]=2)=[CH:4][CH:3]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:31]([O:30][P@@:29]1(=[O:55])[CH2:28][C:27]2[CH:56]=[CH:57][C:24](=[C:25]([O:58][CH3:59])[CH:26]=2)[NH:23][C:15]2=[N:14][C:13](=[C:18]([C:19]([F:20])([F:21])[F:22])[CH:17]=[N:16]2)[NH:12][C:5]2[CH:4]=[CH:3][C:2](=[N:7][C:6]=2[C:8]([NH:9][CH3:10])=[O:11])[C:40]2=[CH:41][N:37]([N:38]=[N:39]2)[CH2:36][CH2:35][CH2:34][O:33]1)[CH3:32].[CH2:31]([O:30][P@:29]1(=[O:55])[CH2:28][C:27]2[CH:56]=[CH:57][C:24](=[C:25]([O:58][CH3:59])[CH:26]=2)[NH:23][C:15]2=[N:14][C:13](=[C:18]([C:19]([F:20])([F:21])[F:22])[CH:17]=[N:16]2)[NH:12][C:5]2[CH:4]=[CH:3][C:2](=[N:7][C:6]=2[C:8]([NH:9][CH3:10])=[O:11])[C:40]2=[CH:41][N:37]([N:38]=[N:39]2)[CH2:36][CH2:35][CH2:34][O:33]1)[CH3:32]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCCOP(=O)(Cc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccc(Br)nc4C(=O)NC)n3)c(OC)c2)OCC)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CCO[P@@]1(=O)Cc2ccc(c(OC)c2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cn(nn2)CCCO1
Product: CCO[P@]1(=O)Cc2ccc(c(OC)c2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cn(nn2)CCCO1
Temperature: 100 °C
Yield: 24 %

Procedure:
A mixture of ethyl 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 64A, 0.331 mmol assumed) and Pd(PPh3)2Cl2 (11.6 mg, 0.0166 mmol) in 1,4-dioxane (8 mL) was evacuated and refilled with nitrogen (3×), then heated at 100° C. for 5 h. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (ISCO system: MeOH/DCM-EtOAc (1:1)=0-15%) to give the desired product as a white solid, (51 mg, 24% yield over 2 steps). 1H NMR (CDCl3, 400 MHz): δ 10.86 (s, 1H), 8.53 (s, 1H), 8.48 (m, 1H), 8.36 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.79 (br s, 1H), 7.56 (d, J=7.8 Hz, 1H), 6.66 (s, 1H), 6.25 (d, J=8.4 Hz, 1H), 4.66-4.77 (m, 2H), 4.05-4.11 (m, 2H), 3.89-3.97 (m, 2H), 3.84 (s, 3H), 3.09 (dd, J=21.2, 2.2 Hz, 2H), 3.04 (d, J=5.0 Hz, 3H), 2.36-2.49 (m, 2H), 1.28 (t, J=7.1 Hz, 3H). MS (ESI): m/z 648.69 [M+H]+. UPLC: tR=1.08 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCC1>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:4]2[N:3]=1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)N1
Temperature: 70 °C
Yield: 33.2 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (400 mg, 1.70 mmol) in EtOH was added hydantoin (186 mg, 1.86 mmol) and pyrrolidine (14 μL, 0.17 mmol). The reaction was stirred at 70° C. over weekend. Precipitate was filtered and air dried to yield 180 mg (33% yield) 5-((5-chloro-7-(cyclopropylamino)pyrazolo-[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=319)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:10](=[NH:21])([O-:20])[C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13](=N)[O-:14].[K+].[K+].O.C(Cl)Cl>CN(C=O)C>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:21]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:14]
Reactant: OCCCCCCCBr
Reactant: N=C([O-])c1ccccc1C(=N)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCCCCO
Reaction time: 4 h

Procedure:
585 mg of 7-bromoheptanol was dissolved in 5 mL of DMF. 833 mg of potassium phthalimidate was added, and the mixture was stirred for 4 h. 50 mL of water and 50 mL of DCM were added to the reaction system, which was violently vibrated and then isolated. The water layer was once again extracted with 50 mL of DCM. The two organic layers were combined, successively washed with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution, dried over 5 g of anh. MgSO4 for 30 min, and concentrated via a rotary evaporator to obtain a pale yellow transparent oily liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=O)=[N:9][NH:8][C:7]2=[O:23].[CH2:24]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:18]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH2:24][CH3:25])[CH2:28][CH2:29]3)=[O:20])[CH:21]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: CCOC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)ccc2F)CC1
Reaction time: 1 h
Yield: 19.5 %

Procedure:
5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzoic acid (103) (0.2 g, 0.60 mmol), 4-ethoxypiperidine (0.078 g, 0.60 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.251 g, 0.78 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.136 mL, 0.78 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam (0.052 g, 19.49%); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 1.59-1.48 (1H, m), 1.81-1.63 (2H, m), 1.94-1.89 (1H, m), 3.16-3.07 (1H, m), 3.57-3.45 (4H, m), 4.09-4.00 (1H, m), 4.65 (2H, s), 6.99 (1H, t), 7.17-7.13 (2H, m), 7.26 (1H, s), 7.66 (1H, t), 7.80 (1H, dd), 8.49 (1H, dd); NH missing; m/z (LC-MS, ESI+), RT=2.08 (M+H 444).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14]O)[N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Se:32]C#N)([O-:25])=[O:24].C(P(CCCC)CCCC)CCC>C1COCC1.N1C=CC=CC=1.CC(OC)(C)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][Se:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])[N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(CCO)N1C(=O)OC(C)(C)C
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(CC[Se]c2ccccc2[N+](=O)[O-])N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of 4.18 g of alcohol 184 (13.3 mmol) in 50 ml of anhydrous THF and 17 ml of anhydrous pyridine was added with 3.31 g of ortho-nitrophenyl selenocyanate (14.6 mmol, 1.1 eq.). Slow dropwise addition of 4.30 ml of tri-n-butylphosphine (17.3 mmol, 1.3 eq.) with cooling in an ice bath resulted in a dark-red solution. After stirring for 30 min at RT, the batch was diluted with 200 ml of MTBE and filtered over a small amount of silica gel. Concentrating the filtrate afforded a brownish-yellow residue that was purified using silica gel column chromatography (EE/CH 1:4), thereby isolating 6.06 g of the selenyl ether 47 (12.1 mmol, 92%) as an intensely yellow colored oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([Cl:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[ClH:35].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCN(c2ccc(N)c3ccccc23)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCN(C)CC3)c3ccccc23)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-methyl-1-piperazinyl)-1-naphthylamine (prepared according to methods A and B) (0.099 g, 0.409 mmol) and pyridine (231 μL, 2.86 mmol) in CH2Cl2 (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.078 g, 0.409 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and then washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (SiO2, CHCl3→CHCl3/MeOH/NH3 9:1:0.4%) to give the pure base which was converted to its HCl-salt: yield 110 mg (62%); 1H NMR (DMSO-d6) δ 10.86 (br s, 1H), 10.02 (s, 1H), 8.11-8.03 (m, 2H), 7.60-7.56 (m, 2H), 7.55-7.44 (m, 2H), 7.33-7.30 (m, 2H), 7.09-7.06 (m, 1H), 7.04-7.01 (m, 1H), 3.55-3.32 (m, 6H), 3.19-3.10 (m, 2H), 2.86 (s, 3H), 2.34 (s, 3H); MS (posES-FIA) m/z=395.1665 (M+H) (calc 395.1667).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][Si:20]([CH3:22])([CH3:21])[C:23]#[C:24][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
Add copper (I) iodide (48.2 mg, 0.25 mmol), bis(triphenylphosphine)palladium (II) dichloride (155.8 m g, 0.22 mmol) and triethylamine (2.51 mL, 17.8 mmol), to a solution of 1-bromo-3-trifluoromethylbenzene (0.62 mL, 4.44 mmol) and trimethylsilylacetylene (0.81 mL, 5.78 mmol), in ethyl acetate (4 mL). Stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify the residue by silica gel chromatography, eluting with hexanes, to give the title compound (1.1 g, 100%).
Reaction SMILES: CC(O)=[O:3].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([CH:17]2[CH2:19][O:18]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1(C)C=CC=CC=1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([C@H:17]([OH:3])[CH2:19][OH:18])[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C2CO2)C1
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R,R)-(−)-N,N′-Bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexanediaminocobalt (II) (32.6 mg, 53.9 μmol) was dissolved in toluene (2.0 mL). AcOH was added (6.1 μL), and the resulting mixture was stirred at room temperature for 1 hour under air. The mixture was then concentrated and dried under high vacuum. (S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (2.3 g, 10.8 mmol) was added, followed by water (97.1 μL), and the resulting mixture was stirred vigorously for 6 hours. Hexanes (15 mL) was added. The resulting solid was manually crushed and additional hexanes was added and stirred until the red solid became a yellowish precipitate. The precipitate was filtered and washed with 2 portions of hexanes. The precipitate was dried under vacuum to yield (S)-3-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester as an off-white solid (1.3 g). The filtrate was concentrated and purified by SiO2 flash chromatography (0-100% EtOAc in hexanes) to yield (S)—(R)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (970 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][N:32]([S:38]([NH:41][C:42]1[S:43][C:44]([F:47])=[CH:45][N:46]=1)(=[O:40])=[O:39])[CH2:33]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[F:47][C:44]1[S:43][C:42]([NH:41][S:38]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[C:19]3[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=3[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)[CH2:33]2)(=[O:39])=[O:40])=[N:46][CH:45]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)CC1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.020 g, 0.028 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.078 g, 0.350 mmol), 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.150 g, 0.280 mmol), and potassium phosphate (0.237 g, 1.119 mmol) in 2 mL dioxane 1 mL water, was heated to 110° C. 2 hours. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with 1N citric acid. The organic layer was then concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave N-(5-fluorothiazol-2-yl)-5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.044 g, 0.080 mmol). [M+H]+=553.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.72 (d, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.03-7.14 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.58-6.64 (m, 1H), 5.92 (br. s., 1H), 4.53 (d, J=17.3 Hz, 1H), 4.19 (d, J=17.6 Hz, 1H), 3.71-3.84 (m, 2H), 3.13-3.46 (m, 4H), 2.86-2.99 (m, 1H), 2.75-2.86 (m, 1H), 2.53-2.60 (s, 3H), 1.94-2.19 (m, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=3[O:39][CH3:40])[C:33](Cl)=[O:34])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.O>C1COCC1>[C:20]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=3[O:39][CH3:40])[C:33]([O:12][C:10]3[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=3)=[O:34])[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(O)cc1O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.4 %

Procedure:
Into a round bottom flask, there are introduced 1.68 g (10 mmoles) of methyl 2,4-dihydroxybenzoate, 1.55 ml (11 moles) of triethylamine and 50 ml of THF. There is then slowly added a solution of 3 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 50 ml of THF and the mixture is stirred at ambient temperature for 12 hours. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted by a 50:50 mixture of dichloromethane and hexane. After evaporation of the solvents, 2.55 g (59% yield) of methyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate having a melting point of 125°-127° C. are recovered.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:20][O:21][CH3:22])[NH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])([CH3:10])[CH3:9].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:15]=1[C:16]([O:18][CH3:19])=[O:17])([CH3:9])[CH3:10]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
194 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 359 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethylimidazole-5-carboxylate [prepared as described in Preparation 2(v)] in 5 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 15 minutes. At the end of this time, a solution of 1.32 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was added. The mixture was first stirred at room temperature for 4 hours and then at 50° C. for a further 2 hours. The reaction mixture was then mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 848 mg of the title compound as crystals, melting at 120°-137° C. (with decomposition).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].O1CCCC1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:12]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1NCCN1C(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
8.6 parts by weight of imidazolid-2-one in 100 parts by volume of dry tetrahydrofurane were treated with 15.5 parts by weight of benzoyl chloride in 30 parts by volume of tetrahydrofurane over the course of 15 minutes, at 5°-10°C, and the mixture was subsequently stirred for 3 hours at 10°C. The solvent was stripped off, the residue was shaken with a mixture of chloroform and aqueous NaHCO3 solution for 15 minutes, the chloroform was separated off, the water was again extracted with chloroform and the combined organic phases were washed with water, dried over MgSO4 and evaporated. The residue was recrystallized from ethyl acetate/ether.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:9]=1[C:10]#[N:11].CCO.O>CC(O)=O.[Fe]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:8]([O:7][CH2:6]/[CH:5]=[CH:4]/[CH2:3][O:2][CH3:1])[C:9]=1[C:10]#[N:11]
Reactant: COC/C=C/COc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC/C=C/COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.1 %

Procedure:
To a solution of (E)-2-(4-methoxybut-2-enyloxy)-6-nitrobenzonitrile (Example 199c) (0.25 g, 1.00 mmol) in a mixture of AcOH, EtOH and water (33 mL, 1:1:1) was added iron powder (0.56 g, 10.00 mmol) at rt. The obtained mixture was stirred at rt for 20 min, then was heated to 50° C. for a further 15 min, and allowed to cool. The suspension was concentrated under reduced pressure; the residue was treated with water (50 mL) and extracted with EtOAc (4×50 mL). The combined extract was washed with saturated aqueous NaHCO3 and brine, and was dried over anhydrous MgSO4. The filtrate was evaporated and the residue was purified by silica gel flash chromatography using gradient hexanes→hexanes/EtOAc (1:1), to give 0.19 g (86%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) 7.17 (t, J=8.4 Hz, 1H), 6.34 (d, J=8.8 Hz, 1H), 6.22 (d, J=8.4 Hz, 1H), 6.00 (broad s, 2H), 5.82-5.96 (m, 2H), 4.56-4.62 (m, 2H), 3.88-3.93 (m, 2H), 3.23 (s, 3H).