Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[CH:23]=[N:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=4[CH3:28])[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:31]([OH:34])[CH2:32][CH3:33])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:34][CH:31]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[N:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=4[CH3:28])[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Acetic anhydride (103 μL, 1.09 mmol) was added to a stirred solution of 1-[9-chloro-1-(6-methoxy-4-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (140 mg, 0.362 mmol) in pyridine (1.2 mL) at room temperature, and the mixture was stirred at room temperature for 19 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (89.9 mg, 0.210 mmol, 58%). Amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Cu][C:16]#[N:17].O.CO>CN1CCCC1=O>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:16]#[N:17])[CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2[nH]c3ccccc3c2c1
Temperature: 200 °C
Yield: 26.3 %

Procedure:
To a solution of 3-bromo-9H-carbazole (4.00 g, 16.3 mmol, 1 equiv) in N-Methyl-2-pyrrolidinone (40 mL) was added copper(I) cyanide (1.6012 g, 17.9 mmol, 1.1 equiv). The mixture was sealed and heated at 200° C. until TLC showed no starting material. The reaction solution was cooled and 60 mL of water was added. The off-white precipitate was filtered off and washed with EtOAc (3×20 mL). This filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), and then dried over Na2SO4. The solvent was removed under reduced pressure to afford red-brown oil. Methanol was added to the crude oil to afford 0.8251 g off-white precipitate as pure product. The mother liquid from the methanol precipitation was concentrated and purified by chromatography (25% EtOAc/Hex) to provide 0.28 g off-white solid. The combined yield was 35.5%.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22](O)=[O:23])[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([NH:4][C:22](=[O:23])[CH:21]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[NH:5][N:6]=[CH:7]3)[CH2:16]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=C(O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCNC(=O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Propylamine (30 mg) and the compound prepared in Example 222 (88 mg) were dissolved in dimethylformamide (1 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (77 mg), and dimethylaminopyridine (5 mg) were added to the solution. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give 72 mg of the title compound as two diastereomers (ratio=ca. 50:50).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][C:9]=3[N:10]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:13]4[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].C([O:32][C:33](=[O:51])/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2([NH3+:50])[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:44])=[CH:38][CH:37]=1)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[Li].O.Cl>CN(C=O)C.CCOC(C)=O.C1COCC1.CO.O>[CH:1]1([C:7]2[C:8]3[S:25][C:24]([C:26]([NH:50][C:45]4([C:43]([NH:42][C:39]5[CH:38]=[CH:37][C:36](/[CH:35]=[CH:34]/[C:33]([OH:51])=[O:32])=[CH:41][CH:40]=5)=[O:44])[CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:27])=[CH:23][C:9]=3[N:10]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:13]4[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2([NH3+])CCCC2)cc1
Reactant: CN1CCn2c(c(C3CCCCC3)c3sc(C(=O)O)cc32)-c2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CN1CCn2c(c(C3CCCCC3)c3sc(C(=O)NC4(C(=O)Nc5ccc(/C=C/C(=O)O)cc5)CCCC4)cc32)-c2ccccc2C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 13-cyclohexyl-6-methyl-5,6,7,8-tetrahydrothieno[2′,3′:4,5]pyrrolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid (1 eq, from Example 3), 1-[({4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]phenyl}amino)carbonyl]cyclopentanaminium chloride (1.3 eq.) and DIPEA (4 eq) in anhydrous DMF (0.025 M) was treated with HATU (1.3 eq.) and stirred overnight at 40° C. The reaction mixture was then diluted with EtOAc, washed with aqueous HCl (1M solution), aqueous NaHCO3 (saturated solution) and brine. The foregoing compound (1 eq.) was dissolved in THF/MeOH/H2O (4:1:1, 0.025 M) and treated with LiOH.H2O (2 eq) at RT for 3 h. The acidified (1N HCl) reaction mixture was purified by RP-HPLC (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min) to afford, after freeze-drying, the title compound (0.16 eq) as a colourless powder. 1H NMR (400 MHz, DMSO, 300 K, δ) 12.36 (bs, 1H), 10.02 (bs, 1H), 9.68 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.92-7.47 (m, 9H), 6.40 (d, J 15.8, 1H), 4.47-4.39 (m, 2H), 4.02-3.15 (m, 4H, partially hidden by H2O signal), 3.07 (s, 3H), 2.50 (m, 1H, hidden by the DMSO signal), 2.38-1.05 (m, 18H); MS (ES+) m/z 651 (M)+.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C:20](=[O:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]1)[CH2:11][CH2:10]3)#[N:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C:20](=[O:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@@H:14]2[O:31][C@@H:15]2[CH2:16]1)[CH2:11][CH2:10]3)#[N:2]
Reactant: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 17β-cyano-5α-androst-2-en-11-one (2.8g.) and 85% m-chloroperbenzoic acid (2.0g.) in chloroform (50 ml.) was stirred for 1.5 hour at room temperature and then diluted with chloroform (75 ml.). This solution was washed with aqueous 10% sodium bicarbonate and water prior to drying. Filtration and evaporation afforded a solid (3.18g.) which was recrystallised from ether/petrol to afford the pure title compound; m.p. 206°-208°; [α]D + 93°, (c 0.7).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=[CH:12]2.[O:21]=[C:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH:32]=O)=[CH:30][C:25]=2[CH2:24][O:23]1.[Na]>C(O)(=O)C.C(Cl)Cl>[O:2]=[C:3]1[CH2:8][N:7]([CH2:32][CH2:31][C:29]2[CH:28]=[CH:27][C:26]3[C:22](=[O:21])[O:23][CH2:24][C:25]=3[CH:30]=2)[CH2:6][CH2:5][N:4]1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=[CH:12]2
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)ccc2c1
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc2cc(N3CCN(CCc4ccc5c(c4)COC5=O)CC3=O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25 mL pear shaped flask charged with 6-(2-Oxopiperazin-1-yl)naphthalene-2-carbonitrile hydrochloride [I-5] (30 mg, 0.10 mmol) and a stir bar was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde [I-1] (28 mg, 0.16 mmol), sodium triacetocyborohydride (22 mg, 0.10 mmol), DCM, and a few drops of acetic acid. The mixture was allowed to stir at RT for 16 hours. The title product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 412 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C.C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1CC
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 2-ethylphenol (244 mg) in acetonitrile (20 ml) was treated with cesium carbonate (650 mg) and ethyl bromoacetate (0.221 ml) and the mixture stirred at 60° C. for 6 hours and then at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate; the suspension filtered and the title compound isolated by evaporation in vacuo of the filtrate as a colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].Br.Br[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CN(C=O)C.C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:22])=[C:12]([CH3:21])[N:13]2[CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:18][CH:17]=1
Reactant: BrCc1cccnc1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Cl)cc2n1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The recovered crude material, along with an additional portion of the starting material, 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.075 g, 0.23 mmol), were dissolved in DMF:THF (1:1, 4 mL) and the reaction was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.95 mmol) was added and after five minutes 3-(bromomethyl)pyridine hydrobromide (0.57 mmol) was added and the ice bath was removed. After 10 minutes, LCMS of the reaction mixture indicated that the starting material was consumed and that the product was also hydrolyzed to from the methyl ester to the free acid in situ. Standard aqueous workup and purification by preparatory HPLC (10-100% ACN in H2O) afforded the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:13]([O-])=O>C(O)C.[Pd]>[NH2:13][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[NH:2][CH3:1])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CNc1c(N)cnc2ccccc12
Yield: 41.4 %

Procedure:
A suspension of 1.7 g of 4-methylamino-3-nitroquinoline in 75 ml of ethanol is hydrogenated in the presence of 300 mg of 10% palladium on carbon at atmospheric pressure. After hydrogen absorption is complete, the catalyst is removed by filtration and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel. Elution with chloroform-methanol (2:1 v/v) affords 600 mg (41%) of 3-amino-4-methylaminoquinoline A15 as an oil.
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:50])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([O:43][CH:44]([CH3:46])[CH3:45])=[C:35]([CH:47]=O)[C:34]=2[CH3:49])=[CH:27][CH:26]=1>O1CCCC1>[CH3:21][O:22][C:23](=[O:50])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([O:43][CH:44]([CH3:45])[CH3:46])=[C:35]([CH:47]=[CH2:1])[C:34]=2[CH3:49])=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Yield: 38 %

Procedure:
A solution of methylidene triphenyl phosphorane [5 mL of 0.1M solution, 0.5 mmol, generated from methyl triphenylphosphonium bromide (2.5 g, 7 mmol) and 1.6M n-butyllithium solution in hexanes (2.9 mL, 4.7 mmol) in 50 mL of tetrahydrofuran] was added to a solution of [4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 144, 0.052 g, 0.13 mmol) in tetrahydrofuran (1 mL). After 1 h the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil that after flash column chromatography over silica gel (230–400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound (0.02 g, 39%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:28](Cl)=[C:27]([N:30]3[CH2:35][C@@H:34]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C@@H:32]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:31]3)[N:26]=[C:25]([NH:52][C:53]3[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=3)[C:24]=2Cl)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][N:11]([C:23]2[CH:28]=[C:27]([N:30]3[CH2:31][C@@H:32]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:33][C@@H:34]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35]3)[N:26]=[C:25]([NH:52][C:53]3[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=3)[CH:24]=2)[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)cc3)c(Cl)c(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2Cl)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(N)cc3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2)C1
Reaction time: 16 h
Yield: 47 %

Procedure:
4,6-Bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-3,5-dichloro-2-(4-aminophenyl-amino)-pyridine (167) (0.127 g, 0.144 mmol) was dissolved in MeOH (15 mL). Pd/C (0.33 g, 10%, wet) was added followed by ammonium-formate (0.66 g). The mixture was shaken in a Teflon septum capped 40 mL I-Chem vial, with occasional venting, for 16 hours. LC-MS indicated complete de-chlorination at this point. The mixture was filtered through a plug of Celite and the filtrate was concentrated and purified by flash chromatography on silica gel (eluting with 15–100% EtOAc in hexane for 30 minutes followed by 100% EtOAc for 10 minutes) to give the desired product (168) as an off-white powder (0.055 g, 0.0677 mmol, 47% yield). LC-MS (ESI): (exact mass: 811.5) m/e=812.6 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[BrH:21].C(=O)([O-])O.[Na+]>C(O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][Br:21])[OH:16])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC1C(O)CCC(O)(CBr)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of fumagillol (230 mg) in ethanol (2 ml) was added a 5% aqueous solution of hydrobromic acid (1 ml), and the mixture was stirred for one hour at room temperatures. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=7:3) to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy1-bromomethyl-1,4-cyclohexanediol (242 mg: yield 80%) as a colorless oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.CN(C=O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:29]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1
Yield: 86.7 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (93.7 mg, 0.27 mmol); 1-azido-3,5-bis(trifluoromethyl)benzene (82.5 mg, 0.32 mmol); CuSO4 (0.6 mg, 0.01 mmol); NaAsc (3.5 mg, 0.02 mmol); TBTA (15.0 mg, 0.03 mmol); in t-BuOH/EtOH/H2O (4:4:2) with an additional 3 drops of DMF; afforded the 43 as a while solid (142 mg, 87.8%). 1H NMR (CDCl3, 400 MHz): δ 8.77 (s, 1H); 8.25 (s, 2H); 8.09 (s, 1H): 7.96 (s, 1H); 7.77-7.75 (d, 1H, J=7.09 Hz); 7.34-7.32 (t, 1H); 7.11 (s, 1H); 4.81-4.76 (q, 1H); 4.59-4.57 (d, 2H, J=5.90 Hz); 4.31-4.25 (m, 2H); 3.72-3.711 (d, 1H, J=1.64 Hz); 3.55-3.54 (d, 1H, J=1.64 Hz); 3.41-3.17 (m, 2H); 1.01-0.99 (t, 3H). 13C NMR (DMSO-d6, 100 MHz): 170.62, 167.49, 165.37, 154.06, 153.24, 146.92, 138.31, 124.57, 122.37, 121.85, 121.09, 116.21, 61.97, 53.44, 52.97, 51.74, 34.64, 33.49, 14.29.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)([CH3:6])[CH2:3][OH:4]
Reactant: COc1ccc(C(C)(N)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(N)CO)cc1
Temperature: 25 °C

Procedure:
A solution of 15.0 mmol of 2-amino-2-(4-methoxyphenyl)propionic acid [74279-63-3] in 15 ml of tetrahydrofuran is added dropwise to a suspension of 30.0 mmol of lithium aluminium hydride in 5 ml of tetrahydrofuran. The reaction mixture is heated to reflux for 1 hour. It is quenched with a little water and 1M NaOH and stirred at room temperature. The suspension is filtered through Hyflo. The filtrate is evaporated. The title compound is obtained as a pale yellowish oil, which may crystallize, and is employed without further purification in the next stage. Rt=1.97 (gradient I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C([O-])(=O)C.[NH4+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([B:13]([OH:14])[OH:17])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(B(O)O)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a suspension of methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.0 g) in acetone (70 ml) and water (70 ml) was added ammonium acetate (1.11 g) and sodium periodate (3.08 g), and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated and the residue was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give [3-methoxy-4-(methoxycarbonyl)phenyl]-boronic acid (1.4 g).
Reaction SMILES: C([C@@H](N[C@H](C(O)=O)C)CCC)(OCC)=O.CCC[C@H](N[C@H](C([N:30]1[C@H:38](C(O)=O)C[C@H:36]2[C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35]2)=O)C)C(OCC)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([C@@H]1C[C@H:63]2[C@H:58]([CH2:59][CH2:60][CH2:61][CH2:62]2)[NH:57]1)(O)=O.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C>[CH:58]1([N:57]=[C:38]=[N:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: O=C(O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Agent: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
Langlois et. al. in published PCT Appln. No. WO 01/58868 disclose a further method for preparation of the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting benzyl ester of (2S, 3aS,7aS)-2-carboxyperhydroindole, p-toluenesulfonate salt with (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine in the presence of 0.4 to 0.6 moles of 1-hydroxybenzotriazole; 1 to 1.2 moles of dicyclohexylcarbodiimide and I mole of triethylamine at 77° C. to give the dipeptide compound, which on debenzylation gives perindopril.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: Cn1ncc2c(NCCN3CCOCC3)nc(Cl)nc21
Product: Cn1ncc2c(NCCN3CCOCC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-morpholin-4-yl-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 155. NMR (CDCl3) 2.50 (m, 4H, 2×CH2), 2.70 (t, 2H, CH2, J=5.95 Hz), 3.71 (m, 4H, 2×CH2), 3.80 (m, 2H, CH2), 4.08 (s, 3H, CH3), 3.05 (sbr, H, NH), 7.44 (t, H, ArH, J=7.32 Hz), 7.54 (d, H, ArH, J=XXHz), 7.87 (s, H, ArH), 8.35 (m, H, ArH), 9.08 (s, H, NH). MS: (ESI+) MH+=379.17