Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:22])[C:18]([O:20]C)=[O:19]>CN(C)C=O>[C:18]([CH:17]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:22])([OH:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(C(C)C(=O)O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of thymine (0.317 mole) and potassium carbonate (0.634 mole) in dimethylformamide (900 ml) is added methyl bromopropionate (0.634 mole) and the mixture is stirred vigorously overnight under an atmosphere of nitrogen. The mixture is filtered, washed with ether and evaporated to dryness in vacuo. The solid residue is treated with water (300 ml) and 4N hydrochloric acid (12 ml), stirred for 20 minutes at 0° C filtered and washed with water (2×100 ml). The precipitate is treated with water and 2N sodium hydroxide (60 ml), and is boiled for 10 minutes. The mixture is cooled at 0° C., filtered and the title compound is precipitated by the addition of 4N hydrochloric acid (70 ml) to afford, after filtration, the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of 4-bromophenol (20.0 g, 116 mmol) dissolved in DMF (100 ml) were added successively benzyl bromide (13.7 ml, 116 mmol), potassium carbonate (47.9 g, 347 mmol) and sodium iodide (1.7 g, 11.6 mmol), and the mixture was stirred for 4 hr at room temperature. Insoluble material was filtered off and water (500 ml) was added to the obtained filtrate. The precipitate was collected by filtration and the obtained precipitate was dissolved in diethyl ether (300 ml). The mixture was washed with water (100 ml) and saturated brine (100 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was washed with cold hexane and dried to give the title compound (26.2 g, 86%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][NH:5][C:6](=[O:8])[CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14](B(O)O)[NH:15]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:2]1[C:3](=[O:9])[NH:4][NH:5][C:6](=[O:8])[CH:7]=1)[NH:15]2
Reactant: OB(O)c1cc2c(F)cccc2[nH]1
Reactant: O=c1cc(Br)c(=O)[nH][nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2cc3c(F)cccc3[nH]2)c(=O)[nH][nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 40.8 %

Procedure:
To a degassed solution of 4-bromo-1,2-dihydropyridazine-3,6-dione (100 mg, 0.5 mmol), (4-fluoro-1H-indol-2-yl)boronic acid (131 mg, 0.7 mmol) and K3PO4 (279 mg, 1.1 mmol) in DMF (2 mL) and H2O (0.2 mL) was added Pd(dppf)Cl2 (5 mg) under N2. The mixture was stirred at 80° C. for 12 h. After the solvent was removed, the residue was purified by prep-TLC (DCM:EtOAc=10:1) to give the product of 4-(4-fluoro-1H-indol-2-yl)-1,2-dihydropyridazine-3,6-dione (50 mg, yield: 39%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.95 (br. s, 1H), 7.47˜7.68 (m, 3H), 7.35 (d, J=8.0 Hz, 1H), 7.11˜7.19 (m, 1H), 6.81 (dd, J=8.0, 10.4 Hz, 1H). MS (M+H)+: 246.
Reaction SMILES: C([O:3][C:4]([C:6]([O:9][N:10]=[C:11]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[C:12]([OH:14])=[O:13])([CH3:8])[CH3:7])=O)C.ClCCl.[NH3:23]>>[NH2:23][C:4]([C:6]([O:9][N:10]=[C:11]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[C:12]([OH:14])=[O:13])([CH3:8])[CH3:7])=[O:3]
Reactant: N
Reactant: CCOC(=O)C(C)(C)ON=C(C(=O)O)c1ccco1
Solvent: ClCCl
Product: CC(C)(ON=C(C(=O)O)c1ccco1)C(N)=O
Reaction time: 22 h
Yield: 77 %

Procedure:
2-(2-Ethoxycarbonylprop-2-yloxyimino)-2-(fur-2-yl) acetic acid (syn isomer) (2.0 g) was dissolved in concentrated aqueous ammonia (50 ml) and the solution stood at room temperature for 22 hours. Most of the ammonia was removed by evaporation and the solution was then acidified with concentrated hydrochloric acid and extracted with ether. The ether extracts were washed with brine and dried and the solvent was removed to give a white solid. Trituration with dichloromethane gave the title compound (1.37 g, 77%), m.p. 160°-162°; λ max (EtOH) 271nm (ε 15,100).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6]
Reactant: OCCc1ccccc1Br
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: OCCc1ccccc1-c1cccs1

Procedure:
To a stirring mixture of 2-bromophenethyl alcohol (0.72 mL, 5.31 mmol) and tetrakis (triphenylphosphine) palladium (0) (620 mg, 10 mol %) in 1,2-dimethoxyethane (45 mL) was added thiophene-2-boronic acid (2.0391 g, 0.0159 mol) and 1 N aqueous NaHCO3 (15 mL). The resultant reaction mixture was heated at reflux for 66 h under argon atmosphere. The dark reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×75 mL). The organic solution was dried over Na2SO4, filtered and concentrated. The dark residue was purified by flash chromatography on silica gel (30% EtOAc in hexane) to yield 2-(2-thienyl)phenethyl alcohol as a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([N:23]1[CH2:37][C:26]2=[C:27]3[N:32]([N:33]=[C:25]2[CH2:24]1)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]3)=[O:22])=O)(C)(C)C.Cl>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][CH2:13][C@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC[C@H]1CCCN1C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC[C@H]1CCCN1)C3
Yield: 41.4 %

Procedure:
A solution of (R)-2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg; 0.17 mmol; 1 eq.) and 2M HCl (3 mL; 6 mmol; 35 eq.) in DCM (5 mL) was stirred at room temperature for 18 hours then concentrated to dryness. 1M NaOH was added and extracted several times with DCM. The combined organics were dried over magnesium sulfate and concentrated in vacuo. Crystallization from MTBE afforded the title compound (30 mg, 41%) as a yellow solid. 1H NMR (DMSO) δ 7.46-7.39 (m, 1H), 7.31-7.27 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.05-7.00 (m, 1H), 4.82-4.54 (m, 2H), 3.91-3.89 (m, 2H), 3.35-3.25 (m, 1H), 2.84 (s, 1.5H), 2.80 (s, 1.5H), 2.61-2.58 (m, 5H), 1.73-1.30 (m, 4H). HPLC (max plot) 97.1%, Rt 2.65 min. UPLC/MS: (MS+) 426.2 ([M+H]+).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12]>C1COCC1>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12]
Reactant: O=Cc1ccc2c(n1)NCCC2
Solvent: C1CCOC1
Product: OCc1ccc2c(n1)NCCC2
Temperature: 5 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde 1 (0.5 g) and lithhiumborohydride (3.0 mL, 2.0 M) in THF (5.0 ML) was stirred at 5° C. for 1 h. The reaction mixture was then allowed to warm to room temperature over a period of another hour, quenched with acetic acid (2.0 mL) and concentrated under reduced pressure. The residue was partitioned between 1N NaOH (20.0 mL)and EtOAc (25 mL). The organic phase was washed with brine (2×0 mL), dried (Na2SO4), and concentrated to dryness. The resulting residue was purified by silica gel flash chromatography using EtOAc containing 10% methanol to give 0.3 g of the title compound as a pale yellow solid: 1H-NMR δ (CD3OD) 7.18 (d, 1H, J=7.6 Hz), 6.58 (d, 1H, J=7.6 Hz), 4.40 (s, 2H), 3.34 (m, 2H), 2.69 (t, 2H, J=6.0 Hz), 1.85 (t, 2H, J=6.0 Hz); ES-MS, m/z =165 (MH+).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(O)(=O)C.O.CO>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 56.3 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.6 g.), acetic acid (0.4 ml.), 10% palladium carbon (2.24 g.), water (4 ml.), methanol (23 ml.) and tetrahydrofuran (56 ml.) was treated in a similar manner to that of Example 21-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.5 g.).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl
Reactant: C#CCCO
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 459 (0.26 mmol) and but-3-yn-1-ol (0.29 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.9, 163.6 (d), 147.6, 146.3, 141.8 (d), 140.7, 138.3, 135.4, 134.8, 133.8, 132.6, 130.9 (d), 128.7, 122.4, 120.9, 120.0, 117.1, 116.1 (d), 113.7, 110.5 (d), 107.6 (d), 61.6, 28.7, 20.0
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[N:19][N:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2.CI.O>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[N:19][N:20]([CH3:22])[CH3:21])[CH:14]([CH3:1])[CH2:13]2
Reactant: CN(C)N=C1CCc2cc(Cl)ccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC1Cc2cc(Cl)ccc2C1=NN(C)C
Temperature: -40 °C
Reaction time: 3 h

Procedure:
33.1 ml of a 2M solution of lithium diisopropylamide in THF/heptane/ethylbenzene are added dropwise to 300 ml of dry tetrahydrofuran (THF) under argon. At −70° C., 12 g of N′-(5-chloroindan-1-ylidene)-N,N-dimethylhydrazine, dissolved in 100 ml of dry THF, are added dropwise to this solution. After the reaction mixture has been stirred at −70° C. for 1 h and at −40° C. for a further 3 h, 3.882 ml of methyl iodide are added dropwise and the mixture is stirred further overnight. 200 ml of water are added dropwise to the reaction mixture which has warmed to room temperature; the THF is removed in vacuo, and the residue is extracted with ethyl acetate. The ethyl acetate extract is treated with active carbon, dried over sodium sulfate, filtered, concentrated in vacuo and chromatographed on silica gel with ethyl acetate/heptane ½. N′-(5-chloro-2-methylindan-1-ylidene)-N,N-dimethylhydrazine is obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)O)c1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI, PREPARATION 3, 1.4 g, 4.1 mmol) in THF/water/methanol (4/2/2, 8 mL) is added to lithium hydroxide monohydrate (0.17 g, 4.05 mmol). The mixture is stirred at 20 degrees -25 degrees C. for 1 hour and then solvent is removed under reduced pressure. The residue is dissolved in water (50 mL) and hydrochloric acid (1 N) is added to adjust the pH to about 3. The aqueous mixture is extracted with ethyl acetate and the organic phase is separated and dried over magnesium sulfate to give the title compound. Analytical calculated for C14H18BrNO3: C, 51.23; H, 5.53; N, 4.27; Br, 24.35. Found: C, 51.37; H, 5.56; N, 4.28.
Reaction SMILES: [Cl:1][C:2]1[C:28]([S:29][CH3:30])=[CH:27][C:5]2[N:6]([C@@H:9]3[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C(SC)=CC2N=CN([C@@H]3OC[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@H]3OC(=O)C)C=2C=1.[Br:61]N1C(=O)CCC1=O>O1CCCC1>[Br:61][C:7]1[N:6]([C@@H:9]2[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([S:29][CH3:30])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CSc1cc2c(cc1Cl)ncn2[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: CSc1cc2ncn([C@@H]3OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2cc1Cl
Solvent: C1CCOC1
Product: CSc1cc2c(cc1Cl)nc(Br)n2[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared according to General Procedure IV using 5-chloro-6-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole and 6-chloro-5-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole as a mixture of regioisomers (0.36 g, 0.79 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 1.68 g (9.4 mmol) of N-bromosuccinimide that was added over 2 h. The product from work-up by General Procedure IV was purified on a silica gel column with dichloromethane and a step gradient from 0-0.5% methanol. This provided 0.18 g (0.34 mmol) of the title compounds as a mix of regioisomers. The regioisomers were separated by SFC on a semi-preparative Chiralcel OD lot No. S017OD00CJ-HC001 eluting with a mobile phase of 90% carbon dioxide and 10% methanol at a flow rate of 2.0 ml/min and a pressure of 3000 psi at a temperature of 40° C. with signal detection at 254 nm. 2-Bromo-5-chloro-6-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole eluted first (RT=5.78 min) and 0.047 g was obtained after evaporation of the solvent. 1H NMR (DMSO-d6) δ7.79 (s, 1H), 7.68 (s, 1H), 6.03-6.00 (d, 1H), 5.78-5.74 (m, 2H), 5.57 (m, 1H), 4.23-4.17 (m, 1H), 4.09-4.01 (t, 1H), 2.64 (s, 3H), 2.26 (s, 3H), 2.04 (s, 3H), 1.80 (s, 3H). 2-Bromo-6-chloro-5-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole eluted from the chiral column last (RT=7.22 min) and 0.057 g was obtained after evaporation of the solvent. 1H NMR (DMSO-d6) δ8.27 (s, 1H), 7.51 (s, 1H), 5.98-5.95 (d, 1H), 5.78-5.72 (m, 3H), 4.17-4.16 (m, 1H) 4.06-3.98 (t, 1H), 2.26 (3, 3H), 2.04 (s, 3H), 1.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=[CH:9][N:8]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([NH:14][CH2:13][C:12]2[C:7]([NH:6][CH2:5][C:4]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=3[O:2][CH3:1])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:23][CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(CNc2ncccc2CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncccc2CNC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a stirred solution of N-(2,4-Dimethoxybenzyl)-3-(aminomethyl)pyridin-2-amine (2.04 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.41 g, 2.04 mmol) in DCE (8 ml) and AcOH (115 μL, 2.04 mmol) was added NaBH(OAc)3 (0.43 g, 2.04 mmol) and the reaction stirred at RT until judged complete by LCMS. The reaction mixture was diluted with DCM and sat. aq. Na2CO3, the layers were separated and the organic layer was dried (Na2SO3) and evaporated to dryness. Purification by column chromatography (MeOH/DCM) gave the desired product (0.64 g, 69%). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=457; tR=2.19.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Reactant: C1CNCCN1
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1N1CCNCC1
Reaction time: 4 h

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (530 mg, 1.89 mM) was treated with piperazine using essentially the conditions of Example 4, except that the reaction conditions were 140° for 4 hours, and work-up did not include an acid wash. Crude product was chromatographed on a 50 g silica Mega Bond Elut® column, eluting with a mixture of dichloromethane/methanol/ammonia 90:10:1. Relevant fractions were combined to give the desired product (601 mg). MS (ESP): 347 (MH+) for C17H11FN4O3
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>CCOCC.O>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([N:9]1[CH2:10][CH:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:12]2)[CH2:8]1)=[O:30]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(c1cccc(F)c1)N1CC2CC2(c2ccccc2)C1

Procedure:
A 6.4 g. portion of 1-phenyl-3-azabicyclo[3.1.0]-hexane is added to 60 ml. of benzene. A 4.2 g. portion of sodium carbonate in 40 ml. of water is added with stirring. A 6.3 g. portion of m-fluorobenzoyl chloride is added and the mixture is stirred overnight. The oil present in the aqueous layer is extracted with chloroform, washed successively with water, dilute hydrochloric acid and water, dried over magnesium sulfate, filtered and evaporated giving an oil. This oil is dissolved in ether. A small amount of petroleum ether is added and the product is recovered as a white solid, mp 68°-69.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.Br.CC1C([C:22]2[NH:23][CH2:24][CH2:25][N:26]=2)=C(C)NN=1.C(N(CC)CC)C>CN(C=O)C>[NH:26]1[CH2:25][CH2:24][N:23]=[C:22]1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: Cc1n[nH]c(C)c1C1=NCCN1
Reactant: NCCCOc1ccc2cc[nH]c2c1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cc2ccc(OCCCNC3=NCCN3)cc2[nH]1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
500 mg (2.6 mmol) of 6-(3-aminopropoxy)indole 23 [prepared in accordance with Example 9.1] are dissolved in 10 ml of DMF together with 0.97 g (3.9 mmol) of 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidazole hydrobromide and 1.7 ml (11.9 mmol) of triethylamine, and the solution is stirred at 60° C. for 12 hours. After the solution has been evaporated, the crude product is purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10][CH2:9]2)=[C:4]([O:30][C:31]([F:34])([F:33])[F:32])[CH:3]=1.[NH3:35].O.[ClH:37]>CCO.CCOC(C)=O.[Cu].Cl[Cu]>[ClH:37].[ClH:37].[ClH:37].[NH2:35][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10][CH2:9]2)=[C:4]([O:30][C:31]([F:34])([F:33])[F:32])[CH:3]=1
Reactant: N
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](NCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: Cl[Cu]
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCc3ccc(N)cc3OC(F)(F)F)CC2)nc2ccccc12

Procedure:
To a solution of cis-N2-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step A of example 28 (1.5 g, 2.79 mmol) in EtOH (25 mL) were added copper powder (443 mg, 6.93 mmol), CuCl (690 mg, 2.79 mmol), and 28% aqueous NH3 (25 mL). The reaction mixture was stirred at reflux for 3.5 hr. The mixture was poured into water, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give a colorless oil. To a solution of above oil in EtOAc (4 mL) was added 4 M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. A solution of the residue in Et2O (15 mL) was stirred at ambient tempareture for 1 hr. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-[4-(4-amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine trihydrochloride (104 mg, 6%) as a white solid.