Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C@H:8]([NH2:30])[CH2:9][C@@H:10]1[C@@H:14]([OH:15])[C@@H:13]([O:16]CC#C)[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[NH2:29])[O:11]1)[C:3]([OH:5])=[O:4].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-]=[N+]=[N-].C(#N)C.O.C(O)(C(F)(F)F)=O>O.CN(C=O)C.S([O-])([O-])(=O)=O.[Cu+2].CO.O.CC(O)=O>[CH:23]1[N:24]=[C:25]([NH2:29])[C:26]2[N:27]=[CH:28][N:20]([C@@H:12]3[O:11][C@H:10]([CH2:9][C@@H:8]([NH2:30])[CH2:7][CH2:6][C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[C@@H:14]([OH:15])[C@H:13]3[OH:16])[C:21]=2[N:22]=1
Reactant: C#CCO[C@@H]1[C@H](O)[C@@H](C[C@@H](N)CC[C@H](N)C(=O)O)O[C@H]1n1cnc2c(N)ncnc21
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C[C@@H](N)CC[C@H](N)C(=O)O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a mixture consisting of Compound 7 (˜671 μg, 0.0016 mmol) in water (100 μL) with sodium ascorbate (1 mg, 0.005 mmol) in water (200 μL) was added copper(II) sulfate (500 μg, 0.0031 mmol) in water (100 μL) and CAL Fluor® Red 610 azide (Biosearch Technologies, Inc. Lot #MVR1716, 1.4 mg, 0.0016 mmol) in DMF (400 μL). The reaction mixture was stirred at room temperature overnight. HPLC (Gemini C18, 110 {acute over (Å)}, 5μ, 250×4.6 mm, 1 mL/min, 5/95/0.05→90/10/0.05 ACN/H2O/TFA) showed mainly one product (13.2 min, 21%) and starting fluorophore azide (19.6 min, 60%). Prep HPLC (Gemini C18, 110 {acute over (Å)}, 10μ, 250×21.2 mm, 20 mL/min, 15/85/0.05→90/10/0.05 ACN/H2O/TFA) was done to purify the product which eluted from the column at around 9 min. The product solution was concentrated to remove the ACN and then lyophilized to afford the title detection analyte compound (248 μg as quantified by UV (MeOH, extinction coefficient 91,000), 13% yield) as a dark purple solid; LC/MS (Gemini C18, 3μ, 2.0×50 mm, 400 μL/min, A: 90/10/0.01 H2O/MeOH/HOAc, B 90/10/0.01 MeOH/H2O/HOAc 0-6 min 0-100% B, 6-9 hold at 100% B, 9.1-15 min re-equilibrate at 0% B) consistent with that expected for pure title detection analyte compound (5.2 min, ESI+ m/z=1162/2=581).
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]([CH:16]([OH: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: CC12CCC(C1)C1(C)Oc3ccc(C(=O)COc4ccc(C(=O)OCc5ccccc5)cc4)cc3C21C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC12CCC(C1)C1(C)Oc3ccc(C(O)COc4ccc(C(=O)O)cc4)cc3C21C

Procedure:
4.41 g (8.9 mmol) of the benzyl ester obtained in Step (a) of Example 12 in 90 ml of dioxane were hydrogenated in the presence of 660 mg of palladium (10%) on charcoal at a hydrogen pressure of 7 bars at room temperature for 3 hours. After filtration of the reaction medium through Celite, evaporation and chromatography on silica in the eluent CH2Cl2 /methanol (9:1), 1.60 g (63%) of the expected compound, melting at 123.20° C., was isolated.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccccc2c(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
The title compound (1.2 g, 60%) was prepared from 2-methyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 6.25 mmol) and 4-[2-bromoethoxy]nitrobenzene (1.69 g, 6.9 mmol) and K2CO3 (1.73 g, 12.5 mmol) as a base by a similar procedure to that described in preparation 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C(N(CC)CC)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C=CC(C)=O)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
To a methylene chloride (100 mL) solution of 1-(4'-hydroxy-3'-methoxyphenyl)-1-butene-3-one (10.0 g, 52 mmol) is added triethyl amine (5.8 g, 57.2 mmol) and t-butylchlorodimethyl silane (15.7 g, 104 mmol). The reaction is stirred at room temperature for 12 hours under an argon atmosphere. The mixture is washed with water (3×100 mL) and brine (100 mL). The organic layer is dried over MgSO4 and evaporated. Flash chromatography (ethyl ether/hexane 1:1) affords 12.8 g (80%) of the desired 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-butene-3-one, mp=65°-68° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:31][C:32]#[N:33])[CH2:24][C:23]([CH2:28][C:29]#[N:30])([CH2:25][C:26]#[N:27])[CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.FC(F)(F)C(O)=O.C(N)CN>CO>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C:21]3([CH2:31][C:32]#[N:33])[CH2:22][C:23]([CH2:25][C:26]#[N:27])([CH2:28][C:29]#[N:30])[CH2:24]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CC#N)(CC#N)C4)c3)ncnc21
Solvent: CO
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(CC#N)CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1

Procedure:
2,2′,2″-1-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutane-1,3,3-triyltriacetonitrile (0.03 g, 0.00006 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min and then evaporated to dryness. The residue was mixed with ethylenediamine (0.2 mL, 0.003 mol) in MeOH (1 mL) at rt for 1 h. The reaction was evaporated to dryness and the residue was purified with prep. LCMS (pH=10) to give the desired product. LCMS calculated for C19H17N8(M+H)+: m/z=357. 1; Found: 357.4. 1H NMR (400 MHz, DMSO-d6): δ 12.06 (1H, br s), 8.79 (1H, s), 8.63 (1H, s), 8.38 (1H, s), 7.55 (1H, d, J=3.6 Hz), 7.01 (1H, d, J=3.6 Hz), 3.46 (2H, s), 3.03 (2H, s), 2.97 2H, d, J=15.2 Hz), 2.76 (2H, s), 2.57 (2H, d, J=15.2 Hz) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:31].[Na+].C(OC(=O)NC1CCN(CCN2C3C=C(OC)C=CC=3OCC2=O)C(=O)C1)(C)(C)C>O.[Ru](=O)=O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[C:12](=[O:31])[CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(C#N)cc32)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(C#N)cc32)C(=O)C1

Procedure:
tert-Butyl{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 59, 835 mg, 2.1 mmol) was reacted with sodium periodate (2.8 g, 13.1 mmol) and ruthenium (IV) oxide hydrate (30 mg, 0.21 mmol) as described for Intermediate 115 for 16 hours, except, chloroform was used for aqueous workup. The product was obtained as a colorless solid, 230 mg (27%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]([C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)[CH2:14][CH3:15]>>[CH2:13]([C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:14][CH3:15]
Reactant: CCC[C@@H]1COC(=O)N1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (3.2 mL) and (R)-4-propyloxazolidin-2-one (2.5 g) described in Preparation Example 29, the title compound (5.7 g) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:20]=[C:19]([F:21])[C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([NH2:22])=[CH:14][CH:15]=4)[C@@:10]4([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]4)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CCO.[Pd]>[F:21][C:19]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([NH2:22])=[CH:14][CH:15]=3)[C@@:10]3([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]3)[C:9]=2[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:20]=1
Reactant: [H][H]
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Agent: [Pd]
Solvent: CCO
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(C3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
The (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (0.231 g, 0.606 mmol) was taken up in EtOH (2 mL). Palladium (10%) on carbon (0.090 g, 0.084 mmol) was added. A 1-L balloon filled with hydrogen was emptied into the flask, venting through a needle. The vent was removed, and another 1-L balloon was attached. The reaction was stirred at RT overnight. The reaction was filtered through Celite, rinsing with 10% MeOH-DCM (60 mL). The filtrate was concentrated. The residue was purified through silica gel (35 mL) which had been deactivated with Et3N (3.5 mL), eluting with 4% to 8% MeOH-DCM containing 1% v/v Et3N, affording (S)-4′-fluoro-2′-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (48 mg, 0.123 mmol). MS m/z=384 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C@:5]1([CH2:11][NH:12]C(OC)=O)[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1.[ClH:18]>O1CCOCC1.O>[ClH:18].[NH2:12][CH2:11][C@@:5]1([CH2:4][C:3]([OH:17])=[O:2])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1
Reactant: COC(=O)C[C@]1(CNC(=O)OC)CC[C@@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CC[C@@](CN)(CC(=O)O)C1
Yield: 53 %

Procedure:
[(1S,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester (2.84 g, 11.7 mmol) was refluxed in a mixture of 1,4-dioxane (15 mL) and 6N Hydrochloric acid (30 mL) for 17 hours. The mixture was allowed to cool, diluted with water (200 mL), and washed with dichloromethane (2×100 mL). The aqueous layer was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/methanol (95:5) to give 1.28 g (53%) of ((1S,3R)-1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride;
Reaction SMILES: Br[Si](C)(C)C.C[O:7][P:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])/[C:30](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:31]\[O:32][CH3:33])[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])=[O:14])([O:10]C)=[O:9].C[Si](NC(OCC)=O)(C)C>ClCCl>[P:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])/[C:30](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:31]\[O:32][CH3:33])[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])=[O:14])([OH:9])([OH:10])=[O:7]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NP(=O)(OC)OC)CS[C@H]12)c1ccco1
Agent: CCOC(=O)N[Si](C)(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NP(=O)(O)O)CS[C@H]12)c1ccco1

Procedure:
Bromotrimethylsilane (0.61 g), in dichloromethane (3 ml) was added (at 0° under nitrogen) to a stirred solution of (6R,7R)-3-dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (0.53 g) and trimethylsilylurethane (0.965 g) in dry dichloromethane (5 ml). After 1.75 hours no starting cephalosporin remained as indicated by t.l.c.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1COCC1.CCCCCCC.[BH4-].[Na+]>O>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:27]=[CH:28][C:29]([CH2:30][OH:31])=[CH:32][CH:33]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COCCOCOc1ccc(C#Cc2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: COCCOCOc1ccc(C#Cc2ccc(CO)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
740 mg (1.6 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzaldehyde were introduced into 40 ml of a mixture of THF and methanol (50/50) in a round-bottomed flask. 32 mg (0.8 mmol) of sodium borohydride were introduced in small amounts at 5° C. and the temperature was permitted to increase to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[F:10].[C:11]1([P:17](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:4]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=1[P:17](=[O:18])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc(F)cc1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Into a 1L three neck round bottomed flask equipped with a mechanical stirrer, thermometer, nitrogen gas inlet, pressure equalizing addition funnel, and reflux condenser with drying tube was placed predried magnesium turnings (13.5 g, 0.55 mol) and dry tetrahydrofuran (THF, 50 mL). The mixture was cooled to ˜5° C. using an ice/water bath. A solution of 1-bromo-2,4-difluorobenzene (107.2 g, 0.55 mol, 20% molar excess) in THF (200 mL) was placed in the pressure equalizing addition funnel and added dropwise over a 1.5 hour period. The mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 3 hours and the flask was subsequently placed in the ice/water bath to cool the solution to ˜5° C. A solution of diphenylphosphinic chloride (107.9, 0.46 mol) in THF (100 mL) was added dropwise over a 1 hour period. The reaction mixture was allowed to warm to room temperature and was stirred under nitrogen for 15 hours. The resultant brown solution was poured into a mixture of concentrated ammonium chloride solution (700 mL) to give two layers. The organic layer was extracted successively with water, 5% aqueous sodium bicarbonate, and water and subsequently dried over magnesium sulfate. The THF was removed via rotoevaporation to give a dark red viscous liquid, 142.8 g, 98% crude yield. The viscous liquid was vacuum distilled (product distilled between 178-181° C.) and a yellow semi-solid was collected (118.6 g, 81% yield). The material was dissolved in 120 mL of hot toluene, treated which charcoal, and filtered while hot through Celite. To the toluene solution was added 120 mL of hexanes. The solution was allowed to cool, with stirring, overnight. A white crystalline material was collected via filtration (100.9 g, 69% yield). The solid exhibited a melting point of 111.1-112.3° C. as determined by differential scanning calorimetry (DSC) at 10° C./min. Anal. Calcd. for C18H13F2OP: C, 68.79%; H, 4.17%; F, 12.09%; P, 9.86%. Found: C, 68.38%; H, 4.26%; F, 11.17%; P, 10.28%. Mass spectroscopic analysis: M+413.2 [C20H13F6OP+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][N:8]2[CH2:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1n[nH]c2cc(F)ccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2cc(F)ccc12
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Ethyl 2-(6-fluoro-1H-indazol-3-yl)acetate (2.08 g, 9.36 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Cesium carbonate (9.15 g, 28.1 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (2.02 g, 9.35 mmol) was added, and reacted for 16 hours. Then the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 1.38 g, at a yield of 41.2%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:39][NH:40][CH2:41][CH2:42][CH2:43][CH3:44].O.OC1C2N=NNC=2C=CC=1>ClCCl.O>[CH3:39][N:40]([CH2:41][CH2:42][CH2:43][CH3:44])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CCCCNC
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCN(C)C(=O)CCCCCCCNC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
Combine 8-(t-butoxycarbonyl)amino-octanoic acid (1.28 g, 5 mmol), N-methylmorpholine (1.2 mL, 10 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride salt (0.95 g, 5.0 mmol), methyl-butyl amine hydrochloride salt (5.0 mmol), and 4-hydroxybenztriazole hydrate (0.05 g) in dichloromethane (20 mL). After 4 hours, add water and extract with ethyl acetate. Dry the organic layer over MgSO4 and evaporate in vacuo to give the title compound.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:32]([O:31][C:29](=[O:30])[NH:28][CH2:27][C@@H:11]([NH2:10])[CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:17][CH2:18]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@H](CN1CCC(Oc2ccc(F)cc2)CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H](N)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(R)-1-(tert-butoxycarbonylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-carbamic acid benzyl ester (0.88 g, 1.77 mmol) and ammonium formate (0.33 g, 5.31 mmol) in methanol is treated with 10% palladium on charcoal (0.3 g). The reaction mixture is stirred at ambient temperature for 1 hour under nitrogen and then is filtered and evaporated. The residue is dissolved in ethylacetate and washed with saturated brine. The ethylacetate phase is dried over MgSO4 and evaporated to afford {(R)-2-amino-3-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester. [MH]+ 368.1.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([N+:31]([O-])=O)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24]C1C=CC=CC=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N>CO>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([NH2:31])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
Sodium dithionite (2 g) was added to a solution of 3,4-Dibenzyloxy-1-nitro benzene (2.37 gm) in a mixture of methanol (30 ml)/aqueous ammonia (5 ml). After stirring for 12 hrs at room temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (75 ml) and water (75 ml). The ethyl acetate layer was washed with water (25 ml), brine solution (25 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography over silica gel eluting with ethyl acetate/hexane (1:1) provided 1.0 g of 1-Benzyloxy-2-methoxy-5-aminobenzene (Yield=47%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:22][C:23](=O)[CH2:24][CH3:25]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][CH2:23][CH2:24][CH2:25][CH2:22][CH2:23][CH2:24][CH2:25][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][CH3:7])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OC

Procedure:
A mixture of 28.5 g 3-methoxy-4-(hydroxy)benzoic acid methyl ester, 25.94 g Of finely powdered potassium carbonate, 0.070 g potassium iodide and 285 ml of 2-butanone is heated at reflux temperature for 41 hours. The reaction is cooled and filtered. The filtrate is concentrated in vacuo and recrystallized from hexane to give 40.8 g of the desired product as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].C1C2C(=CC=CC=2)C=CN=1>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cccc2cnccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: c1ccc2cnccc2c1
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The procedure described by Osborn AR, et al, J Chem Soc 1956:41191 was used. 5-Bromoisoquinoline (101 g, 0.485 mol) was dissolved in 300 mL concentrated H2SO4. KNO3 (58.85 g, 0.582 mol) was dissolved in 200 mL of concentrated H2SO4 and added dropwise to the isoquinoline/acid solution. After addition, the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice and the acid quenched carefully with the addition of NH4OH until the solution was strongly basic. The solids were dissolved in chloroform and filtered through a silica gel plug and eluted with chloroform. Evaporation, followed by trituration of the yellow solid with 5% ethyl acetate in hexane, gave the product (114.2 g, 93%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Br[CH2:12][C:13]#[N:14]>>[NH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]1
Reactant: CC(C)CN1CCNCC1
Reactant: N#CCBr
Product: CC(C)CN1CCN(CCN)CC1
Yield: 32.2 %

Procedure:
By using 1-isobutylpiperazine (2.84 g) and bromoacetonitrile(2.40 g), as in the case of Reference Example 28, 1.19 g (15%) of 4-(2-aminoethyl)-1-isobutylpiperazine was obtained.