Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: II
Reactant: C[C@H](CO)CN1C(=O)COc2ccccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CI)CN1C(=O)COc2ccccc21
Yield: 80 %

Procedure:
The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM26-23) (2.52 g, 11.4 mmol), triphenylphosphine (6.12 g, 23.3 mmol), imidazole (1.98 g, 29.1 mmol) and iodine (8.88 g, 35.0 mmol) in CHCl3 (30 mL) were reacted according to GP4 to give the title compound (108LM27-24) (3.02 g, 80%). 1H NMR (CDCl3) δ 7.07-7.00 (m, 4H), 4.65-4.55 (m, 2H), 3.94 (dd, J=1.7 Hz, J=6.7 Hz, CH2), 3.23-3.14 (m, 2H), 2.18-2.07 (m, 1H), 1.05 (d, J=6.1 Hz, CH3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1O)[OH:8])([CH3:4])([CH3:3])[CH3:2].BrCCBr.C(=O)([O-])[O-].[K+].[K+].[CH2:27](O)[CH2:28][OH:29]>O>[C:1]([C:5]1[C:6]2[O:29][CH:28]=[CH:27][O:8][C:7]=2[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: BrCCBr
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC=CO2
Temperature: 120 °C

Procedure:
3,5-Di-tert-butylhydroquinone (3.33 g, 15 mmol) was combined with 1,2-dibromoethane (5.6 g), potassium carbonate (4.35 g) and ethylene glycol (25 mL). The mixture was heated in a 120° C. oil bath under an Ar atmosphere for 12 h. Water was added to the reaction mixture to quench the reaction and then the organic compound was extracted by CH2Cl2. The resulting solution was concentrated to afford a crude oil. The crude oil was then chromatographed (silica, hexane/ethyl acetate=20:1) mixture to afford the title compound (Rf=0.5, 5:1 hexane/ethyl acetate). 1H NMR (500 MHz, CDCl3): δ 7.03 (d, J=2 Hz, 1H), 6.93 (d, J=2 Hz, 1H), 4.34 (s, 4H), 1.53 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]([O:18][CH3:19])=[C:8]([N:4]2[CH:5]=[N:6][C:2]([CH3:1])=[N:3]2)[CH:13]=1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1F
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])c(F)cc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 18.6 %

Procedure:
Step B (1): A mixture of 3-methyl-1H-1,2,4-triazole (2.20 g, 26.4 mmol), 1,5-difluoro-2-methoxy-4-nitrobenzene (5.00 g, 26.4 mmol), and potassium carbonate (3.65 g, 26.4 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 500 mL of water/10 mL brine solution. The aqueous mixture was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (50% EtOAc/hexane) to afford 1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.24 g, 18% yield). LC-MS (M+H)+=253.2. 1H NMR (500 MHz, chloroform-d) δ ppm 8.95 (s, 1 H) 8.00 (d, J=11.60 Hz, 1 H) 7.80 (d, J=6.10 Hz, 1 H) 4.09 (s, 3 H) 2.50 (s, 3 H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:55]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:54]=2[O:53][CH2:52][CH2:51]1>CN(C=O)C>[O:50]1[C:55]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH:66][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:54]=2[O:53][CH2:52][CH2:51]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
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: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)OCCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 76.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 79% yield: LCMS (ESI) m/z 430 (MH+).
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12](OCC)=O)=[O:10]>CO>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)C(C=O)Cc1cccnc1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Yield: 38 %

Procedure:
(a)(i) Sodium (1.15 g) was dissolved in methanol (50 ml), and nitroguanidine (4.7 g) was added to the cooled solution. The mixture was refluxed for 45 minutes, ethyl 2-formyl-3-(3-pyridyl)propionate (9.3 g) was added portionwise and the mixture was refluxed for 45 hours and evaporated to dryness. Water was added to the residue and the mixture was extracted with chloroform. The aqueous phase was adjusted to pH 5 with acetic acid, and the solid which was precipitated was filtered off, washed and dried to give 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 214.5°-216°, in 38% yield.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1)=O.Cl.[NH2:32][OH:33].C(O)C.[OH-].[K+]>N1C=CC=CC=1>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4](=[N:32][OH:33])[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(C(=O)c3ccc(F)cc3F)CC1)CCCC2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.2 %

Procedure:
To a solution of 7.0 g (0.0143 mole) of 3-[2-[4-(2,4-difluoro-benzoyl)-piperidino]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 70 ml of pyridine, 5.4 g (0.0777 mole) of hydroxylamine hydrochloride and 100 ml of ethanol 1.6 g (0.0286 mole) of potassium hydroxide are added. The reaction mixture is heated to boiling for 10 hours, cooled to room temperature and the solvent is removed in vacuo. To the residue 100 ml of water are added and the mixture is extracted with 100 ml of dichloromethane. The organic phase is washed twice with 50 ml of water each, dried over anhydrous magnesium sulfate and evaporated. The residual crude product is recrystallized from ethyl acetate. Thus 4.2 g of 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one are obtained. Yield 65.1%. According to HPLC analysis the purity of the product is 97.2%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22].C(N(CC)CC)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.C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3)c2)ccc1O
Temperature: 50 °C
Yield: 77.2 %

Procedure:
A mixture of Intermediate 1 (2.5 g), ethynylbenzene (800 mg), copper (I) iodide (124 mg), bis(triphenylphosphine)palladium (II) dichloride (1.37 g), triethylamine (19.0 g) and acetonitrile (20 ml) is heated with stirring at 50° C. under argon atmosphere. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (1.8 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=1>C(OCCO)C>[OH:30][C:28]1[CH:29]=[C:24]([NH:23][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:25]=[CH:26][C:27]=1[O:31][CH3:32]
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: COc1ccc(N)cc1O
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3c(OC)cccc23)cc1O
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 200.0 mg (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 140.6 mg (1.0 mmol) of 5-amino-2-methoxy-phenol in 10 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 261.6 mg (89.0%) of the product as a deep yellow solid, m.p. 138-140° C. (dec.), mass spectrum (electrospray, m/e): M+H 321.9.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH:30][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH3:29])=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C(C)(C)C)cc1
Yield: 55 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-tert-butyl-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 55% of theory; LC (method 5): tR=1.22 min; Mass spectrum (ESI+): m/z=404 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH2:6]([C:8]([CH2:10][CH3:11])=[O:9])[CH3:7]>>[CH3:1][Si:2]([CH3:5])([CH3:4])[O:9][C:8]([CH2:10][CH3:11])=[CH:6][CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CCC(=O)CC
Product: CC=C(CC)O[Si](C)(C)C

Procedure:
From reaction between diethylketone and trimethylchlorosilane to form 3-trimethylsilyloxy-2-pentene (1.2.4.17). This product was reacted with 1-fluoropyridinium triflate (1.2.4.5) to obtain 2-fluoro-3-pentanone (1.2.4.9). After bromination with pyridinium bromide followed by reduction using diborane 2-fluoro-4-bromopentane-3-ol (1.2.4.18) was obtained. Reaction of this product with sodium methylate yielded the title compound (1.2.4.16). This compound was made also by reacting 2-(1-bromoethyl)-3-methyl oxirane (1.2.4.13) with HF/Py (70%) followed by treatment of the resulting 2-bromo-4-fluoropentan-3-ol (1.2.4.18) with K2CO3 /MeOH.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]([CH:12]=O)[C:10]#[N:11])[CH:6]=[CH:5][N:4]=1.[NH2:14][NH2:15].O.Cl>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:12]=[N:14][NH:15][C:10]=2[NH2:11])[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C(C#N)C=O)n1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1nccc(-c2cn[nH]c2N)n1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A suspension of 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile (5) (100 g, 0.52 mol), NH2NH2—H2O (85%, 31.2 g, 0.62 mol) and conc. HCl (60 mL) in ethanol (1 L) was stirred at reflux for 5 h. After cooled to room temperature, the mixture was concentrated in vacuum, and the residue was washed with ether (200 mL×3) and suspended in H2O (200 mL). The mixture was basified with saturated aq. Na2CO3 to pH 9 and the precipitate was collected. The solid was washed with H2O (100 mL×3) and ether (200 mL×3), then dried in vacuum to give 4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-5-amine (6) (56.8 g, 51.8%) as a yellow solid. 1H NMR (400 MHz, CD3CN): δ 8.295 (d, 1H), 7.826 (s, 1H), 7.101 (d, 2H), 5.800 (d, 1H), 2.586 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([OH:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[BH4-].[Na+]>CO>[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:17]([OH:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)c(O)c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
1.83 g (13 mmol) of 2-(4-fluoro-phenyl) ethyl amine were added to 2.32 g (13 mmol) of 4-tert-butyl-2-hydroxy benzaldehyde dissolved in 130 ml methanol. The reaction mixture was stirred at rt over night under nitrogen. 492 mg (13 mmol) of sodium borohydride were added in portions and the reaction mixture was stirred for 2 h at rt. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with water and with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel; DCM, then DCM/methanol 19:1) to yield 3.26 g (83%) of 5-tert-butyl-2-{[2-(4-fluoro-phenyl)-ethylamino]-methyl}-phenol as a yellow viscous oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.24 (t, 2H), 7.09 (t, 2H), 6.95 (d, 1H), 6.71 (d, 1H), 6.68 (s, 1H), 3.76 (s, 2H), 1.23 (s, 9H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1)[CH2:2]2.[CH2:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:20][CH3:21])[CH:27]=3)[CH:15]=[CH:16][CH:17]=1)[CH2:2]2
Reactant: CCc1cccc(B(O)O)c1
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Product: CCc1cccc(-c2cccc(NC(=O)OC3CN4CCC3CC4)c2)c1
Yield: 56 %

Procedure:
Using general procedure E, quinuclidin-3-yl3-bromophenylcarbamate, 3-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (78 mg, 56%). 1H NMR (500 MHz, CDCl3) δ 7.64 (br s, 1H), 7.43-7.27 (m, 6H), 7.24 (br s, 1H), 7.18 (d, J=8.0 Hz, 1H), 4.85 (m, 1H), 3.30 (m, 1H), 2.99-2.73 (m, 5H), 2.70 (q, J=7.5 Hz, 2H), 2.12 (m, 1H), 1.92-1.84 (m, 1H), 1.75-1.67 (m, 1H), 1.62-1.55 (m, 1H), 1.48-1.38 (m, 1H), 1.27 (t, J=7.5 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 153.5, 144.8, 142.4, 140.8, 138.4, 129.4, 128.8, 127.1, 126.8, 124.6, 122.3, 117.4, 72.1, 55.4, 47.4, 46.5, 29.0, 25.4, 24.5, 19.5, 15.7 ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time 1.66 min; (M+1) 351.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:22]2[C:23]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=3)=[CH:24][N:20]=[CH:21]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Cn2cncc2Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 1-trityl-4-(4-Cyanobenzyl)-imidazole (1.99 g, 4.64 mmol) in CH2Cl2 (9.3 mL), Hunigs base (1.62 mL, 9.28 mmol) and the product from step B (1.0 g 4.64 mmol) at −78° C. was added trifluoromethanesulfonic anhydride (0.78 mL, 4.64 mmol). After 45minutes the reaction was allowed to warm to room temperature. The solvent was evaporated and the residue was dissolved in methanol (50 ml) and heated at reflux for 1 hour, cooled and evaporated to dryness. The residue was partitioned between sat. aq. NaHCO3 solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: COc1cccc(C=O)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C
Yield: 75.5 %

Procedure:
α-Aminomethyl-3,4-dimethoxybenzyl alcohol hydrochloride (5.84 g, 25 mmol) was suspended in methanol (30 ml). 2,3-Dimethoxybenzaldehyde (5 g, 30 mmol) was added to the suspension and then triethylamine (3.83 ml, 27.5 mmol) was added dropwise thereto under stirring at room temperature. The resultant solution was heated under reflux for 30 minutes and then sodium borohydride (1.4 g, 37 mmol) was slowly added thereto under stirring under cooling with ice. After the completion of foaming, the solvent was distilled off under reduced pressure. Water was added to the residue, which was made acidic with 3N hydrochloric acid and washed with ether. The cistern was made basic with aqueous ammonia and then subjected to extraction with dichloromethane. The dichloromethane layer was washed with water and then a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant crystals were washed with isopropyl ether to obtain 6.56 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[OH-].[NH4+].[CH3:19]O>>[NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:19])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)c1ccc(N)cc1O
Temperature: 70 °C
Yield: 60 %

Procedure:
To a suspension of 9.18 g (0.06 mole) 4-aminosalicylic acid (7) (Aldrich A7,960-4) in 40 mL of dry methanol was added 8 mL of concentrated sulfuric acid slowly. The mixture was heated under reflux at 70 ° C. for 1.5 hours and then it was cooled in an ice-water bath. Enough concentrated ammonium hydroxide solution was added to adjust the pH to 9 and the precipitate was filtered, rinsed with water and dried to give 6.01 g (60%) of 9 as a solid, mp 118-120° (ref. 120-121°). Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3473 and 3379 (NH2), 1643 (C=O),1284, cm−1. 1H nmr (90 MHz, CDCI3):δ 10.96 (1H, s, OH), 7.6 (1H; d, 3JH5-H6=9 Hz; H-6), 6.20-6.08 (2H, cm, H-3 and H-5), 4.2 (2H; br s; NH2), 3.87 (3H, s, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][OH:34])[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:36]>[Ag]=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][O:34][CH3:36])[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C(CO)C2C1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COCC1C(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C

Procedure:
A solution of 4-hydroxymethyl-5-[2-(3-trifluoromethylbenzoylamino)acetylamino]octahydrocyclopenta[c]-pyrrole-2-carboxylic acid tert-butyl ester in a small amount of DMF and a large excess of iodomethane is treated with silver oxide and stirred at room temperature until the reaction is complete. The reaction mixture is filtered through Celite and concentrated under vacuum yielding a residue. The residue is purified by flash column chromatography providing the title product.
Reaction SMILES: CC1C=CC(C([O:8][CH2:9][C@@H:10]2[CH:14]([O:15]C(C3C=CC(C)=CC=3)=O)[CH2:13][C@H:12]([N:25]3[C:29]4=[N:30][C:31]([NH2:36])=[N:32][C:33]([O:34][CH3:35])=[C:28]4[C:27]([I:37])=[N:26]3)[O:11]2)=O)=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[NH2:36][C:31]1[N:30]=[C:29]2[N:25]([C@@H:12]3[O:11][C@H:10]([CH2:9][OH:8])[CH:14]([OH:15])[CH2:13]3)[N:26]=[C:27]([I:37])[C:28]2=[C:33]([O:34][CH3:35])[N:32]=1
Reactant: COc1nc(N)nc2c1c(I)nn2[C@H]1CC(OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc(N)nc2c1c(I)nn2[C@H]1CC(O)[C@@H](CO)O1
Temperature: -10 °C

Procedure:
To a suspension of 15 (32.4 g, 50.40 mmol) in 600 mL of methanol was added 12.5 mL of 1M sodium methoxide in methanol. The reaction mixture was stirred at reflux for 18 h. and then cooled in a freezer (−10° C.). The crystals of 3 that formed were filtered and rinsed with ice-cold methanol: 10.95 g yield. Acetic acid (12.5 mL) was added to the filtrate and the volume was reduced to about 300 mL. The solution was allowed to sit in the freezer overnight and another crop of crystals (3.95 g) was collected. The filtrate was evaporated to dryness and the residual oil was triturated in ether. The solid that formed was filtered, dried and recrystallized from boiling water: 2.03 g. Total yield=16.93 g (83%); TLC (10% methanol in ethyl acetate), Rf=0.23; 1H NMR (DMSO-d6) δ 7.02 (2H, br s, 6-amino), 6.33 (1H, t, J=6.1 Hz), 5.24 (1H, d, J=4.4 Hz, 3′-OH), 4.73 (1H, t, J=5.6 Hz, 5′-OH), 4.36 (1H, m, 3′-H), 3.99 (3H, s, 4-methoxy), 3.75 (1H, m, 4′-H), 3.51–3.32 (2H, m, 5′-Hs), 2.79 and 2.17 (2H, 2×m, 2′-Hs). Anal. Calcd. For C11H141N5O4 0.3H2O; C, 32.02; H, 3.57; N, 16.98. Found C, 32.13; H, 3.35; N, 16.77.
Reaction SMILES: [CH3:1][C:2]12[CH2:37][CH:5]([C:6]3([CH3:36])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:35])[CH2:17][O:18][C:19]4[CH:34]=[CH:33][C:22]([C:23]([O:25]CC5C=CC=CC=5)=[O:24])=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]12[CH2:37][CH:5]([C:6]3([CH3:36])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:35])[CH2:17][O:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:33][CH:34]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: [H][H]
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(=O)COc4ccc(C(=O)OCc5ccccc5)cc4)cc3C21C
Agent: [Pd]
Solvent: C1COCCO1
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)COc4ccc(C(=O)O)cc4)cc3C21C
Yield: 73.5 %

Procedure:
4.41 g (8.8 mmol) of the benzyl ester obtained in step (a) in 70 ml of dioxane were hydrogenated in the presence of 132 mg of palladium (10%) on charcoal at 60° C. at a hydrogen pressure of 7 bars for 8 hours. After filtration of the reaction medium through Celite and evaporation, the residue was chromatographed on silica in the eluent CH2Cl2 /ethyl ether (95:5). After the product was converted into a paste in hexane, 2.63 g (73%) of the expected compound, melting at 187.5° C., were isolated.