Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([CH3:13])[CH3:12])[C:6]#[CH:7])(=[O:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:4][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([CH3:13])[CH3:12])[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: C#CC(C)(CCC(C)=C(C)C)OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CCC(C)(CCC(C)=C(C)C)OC(C)=O
Temperature: 45 °C

Procedure:
409.0 g of 3,6,7-trimethyl-6-octen-1-in-3-yl acetate and 20.0 g of Lindlar catalyst (5% Pd+3.5% Pb on CaCO3) are put in an autoclave and heated under nitrogen to a temperature of 45° C. Nitrogen is exchanged by hydrogen (H2) and the reaction mixture put at an absolute pressure of 2 bar. After the calculated amount of hydrogen has been consumed the reaction mixture is filtered and distilled (2 mbar, 130° C.) to obtain 3,6,7-trimethyl-6-octen-3-yl acetate (=compound of formula (Ib)).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
To a solution of 252 (1 g, 1.63 mmol) in DCM (50 mL) was added TFA (15 mL) and the reaction mixture was stirred for 1.5 h then concentrated, diluted with water and 4M NaOH to pH 11 and extracted with DCM/MeOH. The extract was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 253 (800 mg, 1.56 mmol, 96% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.75 (d, J=0.8 Hz, 1H), 7.72 (dd, J=2.4 and 13.6 Hz, 1H), 7.66 (s, 1H), 7.36 (t, J=8.8 Hz, 1H), 7.21-7.16 (m, 1H), 6.57 (d, J=2.85 Hz, 1H), 6.54 (d, J=5.6 Hz, 1H), J=6.4 Hz, 2H), 3.36 (t, J=5.6 Hz, 2H), 3.22 (s, 3H), 2.89 (t, J=6.4 Hz, 2H), 2.67 (t, J=5.6. Hz, 2H), 2.58-2.53 (m, 1H), 0.68-0.61 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 511.56 (M+H).
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[C:7]=1[S:26]([CH3:28])=[O:27].I[CH:30]([CH3:32])[CH3:31]>C(O)C>[CH:30]([O:25][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)([CH3:32])[CH3:31]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CC(C)I
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A suspension of sodium ethoxide (0.34 g) in ethanol was added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in ethanol. 2-Iodopropane (1 ml) was then added and the mixture stirred overnight at 20° C. and evaporated. The residue (in dichloromethane) was water-washed, dried (magnesium sulfate), concentrated and purified by chromatography on silica gel to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(isopropyl)oxime (0.35 g), m.p. 128-130° C. Compound 24. By proceeding in a similar manner the following compounds were also prepared: 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(ethoxycarbonylmethyl)oxime, Compound 25, m.p.127-128° C.; and 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(carbamoylmethyl)oxime, Compound 26, m.p.165-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:20][C:15]4[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1CBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12Cc1ccccc1C2

Procedure:
A mixture of 6-bromo-indan-1-one (1.05 g, 5 mmol), 1,2-bis(bromomethyl)benzene (1.31 g, 5 mmol) in THF (50 mL) was added NaH (240 mg, 10 mmol) at room temperature, the mixture was refluxed for 2 hours. The mixture was quenched with water, concentrated, then extracted with DCM, washed with brine, dried over Na2SO4, concentrated to 6-bromo-1′,3′-dihydro-2,2′-spirobi[inden]-1(3H)-one (1.8 g, 33%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH3:21][C:22]1([C:37](Cl)=[O:38])[CH2:26][C:25]2[C:27]([CH3:36])=[C:28]([N+:33]([O-:35])=[O:34])[C:29]([CH3:32])=[C:30]([CH3:31])[C:24]=2[O:23]1>CN(C=O)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:37]([C:22]1([CH3:21])[CH2:26][CH:25]2[CH:27]([CH3:36])[C:28]([N+:33]([O-:35])=[O:34])=[C:29]([CH3:32])[C:30]([CH3:31])=[C:24]2[O:23]1)=[O:38]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C(=O)Cl)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C2OC(C)(C(=O)N3CCc4c([nH]c5ccccc45)C3)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid, 20 ml of methylene chloride and 0.27 g of thionyl chloride were added, followed by heating at reflux for 2 hours. After returning the temperature to room temperature, the solvent was distilled off to obtain 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride. To 0.33 g of 2,3,4,9-tetrahydro-1H-beta-carboline, 0.23 g of triethylamine and 15 ml of DMF, a solution prepared by dissolving 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride in DMF was added, followed by stirring overnight at room temperature. The mixture was poured into ice-water and a crystal was collected by filtration. The crystal was dissolved in chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 0.54 g of the objective product.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:16]([OH:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>O=[Mn]=O>[CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16](=[O:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(NC(=O)C2CCCCC2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Mn]=O
Agent: c1cc[nH+]cc1
Product: CC(C)(C)OC(=O)NCCC(=O)c1cccc(NC(=O)C2CCCCC2)c1

Procedure:
Oxidation of tert-butyl 3-(3-(cyclohexanecarboxamido)phenyl)-3-hydroxypropylcarbamate (37) following the method used in Example 12 except PCC was used in lieu of MnO2 gave tert-butyl 3-(3-(cyclohexanecarboxamido)phenyl)-3-oxopropylcarbamate as a white solid. Yield (0.36 g, 91%); 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.15-8.18 (m, 1H), 7.82 (dd, J=1.2, 8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 6.79 (br.t, 1H), 3.24 (q, J=6.0 Hz, 2H), 3.08 (t, J=6.4 Hz, 2H), 2.25-2.35 (m, 1H), 1.69-1.82 (m, 4H), 1.58-1.66 (m, 1H), 1.33 (s, 9H), 1.10-1.44 (m, 5H).
Reaction SMILES: Cl.NC(C([O-])=O)C(OC)=O.[NH2:11][CH:12]([C:18]([O-:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=N>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]2[NH:21][C:18](=[O:20])[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:23]=2[CH:24]=1
Reactant: Cc1ccc(N)c(C(=N)c2ccccc2)c1
Reactant: CCOC(=O)C(N)C(=O)[O-]
Agent: COC(=O)C(N)C(=O)[O-]
Agent: Cl
Product: CCOC(=O)C1N=C(c2ccccc2)c2cc(C)ccc2NC1=O

Procedure:
This compound is obtained by the procedure described in Example 22, the hydrochloride of methyl aminomalonate and compound 4356 CB being replaced by the equivalent quantities of, respectively, the hydrochloride of ethyl aminomalonate and (2-amino-5-methylphenyl)-phenyl-methane-imine prepared according to Example 12.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c(Br)cc1F
Temperature: 28 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a stirred solution of 1-bromo-2,5-difluorobenzene (1.000 g, 5.181 mmol, Aldrich, used as received) in conc. H2SO4 (8.0 mL) at 0° C, KNO3 (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to 28° C. and stirred at 28° C. overnight. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous NaSO4, removed under vacuum, and the resulting white solid was dried further under vacuum to afford 1.102 g (89%) of the title compound as a white powder; m.p. 58-60° C.; 1H NMR (CDCl3: δ 7.591 (dd, 1H, J1=9.6 Hz, J2=5.4 Hz), 7.891 (t, 1H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[NH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4]([C:5]1[CH:10]=[CH:9][C:8]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:15])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCN
Solvent: CCO
Product: CCOC(=O)CCNc1ccc(C(=O)N(CC)CC)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 63.4 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.200 g, 0.833 mmol), ethyl 3-aminopropanoate (0.116 g, 0.757 mmol) in 80% aq. EtOH (5 mL) was heated at 90° C. overnight. After work-up, the crude product was purified by silica gel column chromatography (50% EtOAc/Hexanes to 100% EtOAc) to provide the title compound (0.162 g, 63%). 1H-NMR (CDCl3): δ 8.34 (br t, J=5.6 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.58 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.69 (q, J=6.4 Hz, 2H), 3.44 (br s, 4H), 2.72 (t, J=6.4 Hz, 2H), 1.30 (t, J=6.4 Hz, 3H), 1.22 (t, J=6.8 Hz, 6H). MS (ESI) (M+H)+=338.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: Clc1nc2ccccc2n2ccnc12
Product: CC(C)Nc1nc2ccccc2n2ccnc12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with isopropylamine according to a procedure that is similar to that followed in example 3 there is obtained 4-isopropylaminoimidazo[1,2-a]quinoxaline. m.p. (DSC)=102.7° C. (onset); IR (KBr): 3230, 2966, 1559 cm-1 ; 1H-NMR (DMSO-d6): δ8.55 (1H,s), 8.2÷7.95 (1H,m), 7.6÷7.4 (2H,m), 7.4÷7.2 (3H,m), 4.5 (1H,m), 1.25 (6H,d); UV (EtOH): λmax =227, 244, 285, 297, 318, 332 nm. Elementary analysis for C13H14N4 (m.w. 226.28): calcd. C 69.00, H 6.23, N 24.76%; found C 69.17, H 6.70, N 25.05%.
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:44])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of N-[4-[hydroxy(2-pyridyl)methyl]-phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (351.3 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.28 g) at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol-diethylether=1:1), and recrystallized from ethanol to give N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 167) (184 mg) as colorless crystals.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].IC.[C:21](=O)([O-])O.[K+]>CN(C=O)C>[CH3:21][O:17][C:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12]1)=[O:18]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of N-carbobenzyloxypyrrolidine-3-carboxylic acid (10.15 g, 40.72 mmol) and iodomethane (5.08 mL, 81.44 mmol) in N,N′-dimethylformamide (80 mL) was added powdered potassium hydrogen carbonate (8.15 g, 81.44 mmol) and the reaction mixture stirred at ambient temperature for 5 hours. The mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The residue was purified by flash chromatography on silica gel using 5-50% ethyl acetate in hexane to give the title compound (10.59 g, 99%). MS(DCI): m/z 264 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]2[CH3:55])=[CH:14][N:13]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=3)=[CH:16][C:15]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:52])=[O:53])[CH2:47][C@@H:46]3[CH3:55])=[CH:14][N:13]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Reactant: COc1cc(N)cnc1Cl
Product: COc1cc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cnc1Cl

Procedure:
The title compound was prepared from 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc.) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (preparation similar as reported in Example 316, Steps 1 to 2; from (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.)) via similar steps as previously described in Example 316 and isolated as a yellow solid. m/z (ESI, +ve ion) 534 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.99-12.52 (m, 1H) 8.76-9.96 (m, 1H) 8.15-8.63 (m, 3H) 6.57-8.07 (m, 2H) 4.09-5.06 (m, 2H) 3.94 (s, 3H) 3.59-3.86 (m, 2H) 2.86-3.35 (m, 7H) 2.46 (s, 3H) 0.96-1.58 (m, 4H).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN.O>C(O)C>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCC=C(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCC=C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 7.8 g (20. mmol) 2-(6,6-diphenyl-hex-5-enyl)-isoindol-1,3-dione and 2.0 g (40.0 mmol) hydrazine.hydrate in 80 ml ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.[CH3:23][N:24](C=O)C>O>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: O=c1[nH]cc2c(c1-c1ccc(Br)cc1)Nc1ccccc1S2
Solvent: O
Product: N#Cc1ccc(-c2c3c(c[nH]c2=O)Sc2ccccc2N3)cc1

Procedure:
To 10 parts of 4-(4-bromophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one suspended in 300 parts of DMF is added 4 parts of cuprous cyanide and the reaction mixture is refluxed for 2 to 12 hours. After cooling, water is added and the solution extracted with ethyl acetate. The combined extracts are washed with saturated NaCl solution and dried. Solvent removal gives a residue which upon recrystallization from aqueous DMF gives 4-(4-cyanophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, which melts above 290° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc([N+](=O)[O-])c2)cnn1-c1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of 5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.0 g, 24.52), Fe powder (3.84 g, 68 mmol) and ammonium chloride (3.84, 71.78 mmol) in ethanol (135 ml) and water (64 ml) was heated at reflux under nitrogen atmosphere. After 1 h, the reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo to give 5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5 g) as a solid.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)=[N:14][CH:15]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(OCc2ccc(Br)cc2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccc(C=O)cc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)-5-methyl-pyridine (5.40 g, 19.4 mmol) described in Manufacturing Example 44-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 8.73 mL, 23.3 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (2.99 mL, 38.8 mmol) was then added dropwise thereto, which was stirred for 10 minutes at −78° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:6→1:4) to obtain the title compound (2.93 g, 66.5%).
Reaction SMILES: [OH:1][P:2](=[O:27])([O:12][CH2:13][C@H:14]1[O:26][C@@H:17]([N:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[N:20][C:19]2=[O:25])[CH2:16][CH2:15]1)[O:3][P:4](=[O:11])([O:6][P:7](=[O:10])([OH:9])[OH:8])[OH:5]>O>[P:2]([O:12][CH2:13][C@H:14]1[O:26][C@@H:17]([N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:15][CH2:16][CH2:17][NH2:18])=[N:20][C:19]2=[O:25])[CH2:16][CH2:15]1)([O:3][P:4]([O:6][P:7]([OH:9])([OH:8])=[O:10])([OH:5])=[O:11])(=[O:1])[OH:27]
Reactant: Nc1ccn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Solvent: O
Product: NCCCNc1ccn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1

Procedure:
2',3'-dideoxycytidine-5'-triphosphate (20 umol) was dissolved in 1.0 ml of the 1,3-propanediamine/bisulfite reaction mixture and incubated at 37° C. for 60 hr. when HPLC indicated complete conversion of the starting material to one new major substance. The product was isolated by Sephadex chromatography and lyophilization in the manner described above to yield 16.0 umol (80%) of an amorphous solid and identified as N4 -(3-aminopropyl)-2'3'-dideoxycytidine-5-triphosphate AP-ddCTP. The structure of AP-ddCTP is depicted in FIG. 1 as B where N equals three. The solid was homogeneous by HPLC (RT=20.02 min, RT(ddCTP)=21.08) and characterized by UV lambda max (H2O)=272.5 nm.
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15](/[CH:18]=[C:19]4/[O:20][C:21]([C:23]5[C:28]/4=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:22])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:10][C@@H:11]1[C:45](=[O:46])[N:13]2[C:14]([C:29]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])=[C:15](/[CH:18]=[C:19]3/[O:20][C:21]([C:23]4[C:28]/3=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:22])[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C3/OC(=O)c4ccccc43)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C3/OC(=O)c4ccccc43)CS[C@H]12
Temperature: -20 °C
Reaction time: 0.42 h

Procedure:
Diphenylmethyl 7β-phenylacetamido-3-(E-phthalidylidenemethyl)ceph-3-em-4-carboxylate (1.3 g), dissolved in dichloromethane (10 mls) was cooled to -20° C. under argon. N-methylmorpholine (0.5ml) followed by a solution of phosphorous pentachloride (0.561 g) in dichloromethane (15 mls) were then added. After ca 30 mins, i.r. analysis showed no starting material. Dry methanol (10 mls) was added in one portion very rapidly, and the solution allowed to warm to room temperature over 30 mins. Water (20 mls) was added and the mixture vigorously stirred for 20-30 mins. After washing and drying the organic phase, the crude product was purified by flash chromatography, eluting with 70 and 80% ethyl acetate/hexane. The title compound was obtained as a pale yellow solid, (0.563 g, 53%), νmax (CH2Cl2) 1780(s), 1720, 1600(w,br), 1560 and 1210cm-1 ; δH (CDCl3) 3.56 (2H,ABq,J18.7Hz), 4.93 (1H,d,J5.1Hz), 5.10 (1H,d,J5.1Hz), 6.39(1H,s), 6.88 (1H,s), 7.21 (10H,m), 7.46-7.68 (3H,m), and 7.87 (1H,d,J7.6Hz); [mass spectrum: +ve ion (3-NOBA, Na+) M Na+, 532].