Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH2:5][N:6]=1.C(N(CC)CC)C.Cl.[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])[CH3:17]>ClCCl>[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:6]1[CH2:5][CH2:4][N:3]=[C:2]1[CH3:1])=[O:24])[CH3:17]
Reactant: CN(C)CCCCCC(=O)Cl
Reactant: CC1=NCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=NCCN1C(=O)CCCCCN(C)C
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Dichloromethane (400 mL), 2-methyl-2-imidazoline (56.38 g, 0.637 mol), and triethylamine (283.51 g, 2.802 mol) are placed in a 2000 mL three-necked round bottomed flask equipped with a reflux condenser, internal thermometer, mechanical stirrer, addition funnel, and argon inlet. The solution is brought to reflux and 15 min later a solution of 6-(N,N-Dimethylamino)hexanoyl chloride-hydrochloride (150 g, 0.700 mol), prepared as described in example II, dissolved in dichloromethane (300 mL) is added dropwise over 45 min. The mixture is refluxed for an additional 2 h before being cooled to room temperature. The salts are filtered and washed with methylene chloride. The combined flitrates are washed with 5% NaHCO3 solution (3×300 mL) and water (300 mL), After drying over MgSO4 and filtration, the organic layer is concentrated first by rotary evaporation at 50° C. and then by Kugelrohr distillation at 60°-70° C. (0.2 mm Hg) to give 95.20 g (66%) of an oil which solidifies on standing.
Reaction SMILES: O=P(Cl)(Cl)Cl.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+].CN([CH:21]=[O:22])C>>[CH:21]([C:10]1[S:6][C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: c1csc(-c2cccs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
250 ml of DMF in 1 liter flask was added 50.2 ml of POCl3 and stirred for 1 hour at 0° C. to form a complex. 83 g of 2,2'-bithiophene was dissolved in 200 ml of DMF and then added into the complex. After the solution was stirred at 10° C. for 0.5 hour, then the temperature was raised to 40° C. and stirred for 20 hours. The orange viscous product was poured into 3 l beaker and crushed ice cubes were added and stirred for 0.5 hour and then neutralized with 600 ml of 10% aqueous NaOH solution. After the solution was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and the crude product was purified by column chromatography. 90 g of product was thus obtained and the melting point thereof was 56°-57° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=O)[CH3:2].[F:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:13]=1[NH2:14]>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH:21]([CH3:22])[CH3:23])=[CH:15][C:13]=1[N:14]1[C:7](=[O:10])[C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[C:4]1=[O:6]
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: CCC1=C(C)C(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: CCC1=C(C)C(=O)N(c2cc(OC(C)C)c(Cl)cc2F)C1=O
Reaction time: 5 h

Procedure:
5 g of 2-ethyl-3-methylmaleic anhydride, 7.3 g of 2-fluoro-4-chloro-5-isopropoxyaniline and 0.61 g of 4-dimethylaminopyridine are combined in 100 ml of xylene in a distillation apparatus and the solvent is slowly distilled off. After 5 hours, the reaction is complete. The xylene still present is removed under a water-jet vacuum. The dark residue is taken up in ethyl acetate and extracted with 2M hydrochloric acid, water, 10% sodium bicarbonate solution and lastly with saturated sodium chloride solution. After drying over sodium sulphate, the ethyl acetate is distilled off in a rotary evaporator and the residue is chromatographed over a column of silica gel with hexane:ethyl acetate 1:1. After evaporating the solvent, 5 g of the title compound are obtained in the form of a red oil having a refractive index of nD22 =1.5351.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18](Cl)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1
Reactant: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Yield: 14 %

Procedure:
To a stirred solution of 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.23 mmol), prepared as described in Example 355 in toluene (2 mL) in a round bottomed flask was added Pd(PPh3)4 (16 mg, 0.014 mmol) under bubbling argon. Phenyl boronic acid (36 mg, 0.3 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (97 mg, 0.91 mmol) pre-dissolved in water (0.25 mL) was added to the suspension. Argon was bubbled through this suspension for 10 min before the flask was placed in an oil bath preheated at 120° C. The reaction was stirred at reflux for 6 days. The reaction was then allowed to cool to RT. After this time, the reaction mixture was poured into water (10 mL). The resultant solution was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL) followed by saturated aqueous NaCl (2×5 mL). The organic layer was dried (MgSO4), filtered and concentrated to obtain crude product. This crude product was purified by reverse phase HPLC to give the title compound, 2-(4-(isoxazol-5-yl)benzyl)-7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (15.5 mg, 14%) as pale yellow solid. HPLC: 3.68 min; MS, M+H=480; 1H NMR (CDCl3), ppm: 8.31 (1H, d, J=2.0 Hz), 8.22 (1H, s), 7.77 (2H, d, J=10.0 Hz), 7.51 (2H, d, J=10.0 Hz), 7.26-7.42 (7H, m), 7.09 (2H, d, J=10.0 Hz), 6.54 (1H, d, J=5.0 Hz), 5.29 (2H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: IC1CCOCC1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCOCC3)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8) and 4-iodotetrahydro-2H-pyran (Maybridge) by General Procedure N.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][N:8]1[C:12](=[O:13])[C:11](=[O:14])[NH:10][C:9]1=[S:15]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:10]1[C:11](=[O:14])[C:12](=[O:13])[N:8]([CH3:7])[C:9]1=[S:15]
Reactant: CN1C(=O)C(=O)NC1=S
Reactant: BrCCCCBr
Product: CN1C(=O)C(=O)N(CCCCBr)C1=S

Procedure:
By the procedure of Example 1(i), 1,4-dibromobutane is reacted with 1-methyl-2-thioxo-4,5-imidazolidinedione to yield 1-(4-bromobutyl)-3-methyl-2-thioxo-4,5-imidazolidinedione which, on reaction with thiourea by the procedure of Example 1(ii) gives S-[4-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))butyl]isothiourea hydrobromide, m.p. 113°-114°. Hydrolysis of the latter compound and working up of the product by the general procedure of Example 1(iii) and conversion to the sulphate with ion-exchange resin (Amberlite IRA 400, sulphate form) gave the title product as a hygroscopic amorphous solid, m.p. 63°-65°.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][OH:5].[N+:6]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2OC2C=CC=CC=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7].Cl>C1(O)C=CC=CC=1.CCOCC>[ClH:1].[N+:6]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2[NH:2][CH2:3][CH2:4][OH:5])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Oc3ccccc3)c12
Reactant: NCCO
Agent: Cl
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1cccc2nc3ccccc3c(NCCO)c12
Temperature: 80 °C
Yield: 91 %

Procedure:
This compound is synthesized generally using the methods described in EP 38579. Specifically, 2 g of 2-amino-ethanol hydrochloride is added to 6.4 g of 1-nitro-9-phenoxyacridine dissolved in 20 g of freshly distilled phenol. The mixture is heated for 40 minutes at a temperature of 80° C. and then cooled, diluted with ether. It is then poured into dry ether that was acidified with an ethereal solution of hydrogen chloride. The orange colored precipitate of 1-nitro-9-(2-hydroxyethylamino)-acridine hydrochloride, obtained in this way is filtered and crystallized from dry ethanol. The melting point of the compounds obtained was 170° C., with decomposition. Yield 91%. Elementary analysis for the formula: C15H14N3O3Cl:calculated:56.47%; C, 4.42%; H, 13.17%; N. determined: 56.44%; C, 4.40%; H, 13.03%; N.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[O:10][C:9]([C:19]2[N:24]=[CH:23][N:22]3[CH:25]=[CH:26][CH:27]=[C:21]3[CH:20]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[CH:15]=2)[O:10][C:9]([C:19]2[N:24]=[CH:23][N:22]3[CH:25]=[CH:26][CH:27]=[C:21]3[CH:20]=2)=[CH:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C=O)cc12
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CNCc3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 4-tert-Butoxyimino-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carbaldehyde (example 144B) (50 mg; 0.14 mmol) in dichloromethane (5 ml), was added molecular sieves and 4-Fluoro-benzylamine (19 mg; 0.15 mmol). After 2 hours at room temperature, sodium triacetoxyborohydride (29 mg, 0.14 mmol) and acetique acid (2 ml), were added. After stirring at room temperature for 18 hours, the reaction mixture was quenched with a saturated solution of sodium hydrogenocarbonate and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-100%) to afford the title compound (20 mg, 30%) as a green solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[C:11]#[CH:12]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:13][CH2:10][C:11]#[CH:12])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT overnight during which time solid precipitated out. 600 mL hexane was added and the mixture was vigorously stirred for a few hours. The solid was collected by filtration and washed with hexane to give 5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%) which was used directly without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0 (chlorine pattern).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7]([O:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OC1CCCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
Twelve grams (0.055 mole) fo crude 3-nitro-4-chlorobenzoyl chloride were dissolved in 200 ml. of benzene. Eight milliliters of pyridine were added to the reaction mixture. Six milliliters of cyclohexanol were dissolved in 50 ml. of benzene and the solution was added dropwise to the acid chloride-pyridine mixture. The reaction mixture was refluxed for 4 hours and filtered. The benzene filtrate was washed successively with dilute acid, dilute base and water. The washed benzene solution was dried and evaporated in vacuo to yield 12.5 g (88 percent) of cyclohexyl 3-nitro-4-chlorobenzoate, mp 57°-58° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:18].[CH2:19]([C:26]1[CH:37]=[CH:36][C:29]2[CH:30]=[C:31](B(O)O)[O:32][C:28]=2[CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([C:26]1[CH:37]=[CH:36][C:29]2[CH:30]=[C:31]([C:2]3[CH:17]=[CH:16][C:5]([CH2:6][N:7]4[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]4)=[CH:4][C:3]=3[F:18])[O:32][C:28]=2[CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reactant: OB(O)c1cc2ccc(Cc3ccccc3)cc2o1
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4ccc(Cc5ccccc5)cc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B2 and general procedure F using ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (0.150 g, 0.474 mmol) and 6-benzylbenzofuran-2-ylboronic acid (0.155 g, 0.617 mmol) to give ethyl 1-((4-(6-benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 443.2; Observed: 444.1 (M++1).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].O>CS(C)=O>[CH2:25]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
1-(8,9-Oxidononyl)-3,7-dimethylxanthine was synthesized as follows: A mixture of theobromine (17.64 g, 98 mmol) and sodium hydride (2.35 g, 98 mmol) in dimethylsulfoxide (250 ml) was stirred for 15 minutes. 9-Bromo-1-nonene (20.0 g, 98 mmol) was added and stirring continued for 3 days. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (4×200 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (2×150 ml), dried over sodium sulfate, and the solvents evaporated under vacuum. The residue was crystallized (dichloromethane-ether) to give 1-(8-nonenyl)-3,7-dimethylxanthine (24.34 g, 99% yield) as white crystals.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)=[C:2]=[O:3].[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(N=C=O)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: OCc1ccccc1
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The starting material is prepared as follows: The mixture of 0.5 g of N-(4-isocyanato-o-tolyl)-4-chlorophthalimide and 5ml of benzyl alcohol is heated to 120° under nitrogen for 6 hours and evaporated, to yield the N-(4-benzyloxycarbonylamino-o-tolyl)-4-chlorophthalimide.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:30]=[N:31][N:32]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:28])[CH2:23][C:24](=[O:27])[CH2:25][Cl:26])[C:19](=[O:29])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1.[N:33]([O-])=[O:34].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]2[N:4]([N:30]=[N:31][N:32]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:28])[C:23](=[N:33][OH:34])[C:24](=[O:27])[CH2:25][Cl:26])[C:19](=[O:29])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1
Reactant: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC(=O)CCl)[C@H]3SC2)nn2nnnc12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NO)C(=O)CCl)[C@H]3SC2)nn2nnnc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-7-(4-chloro-3-oxobutyramido)-3-cephem-4-carboxylic acid (6.72 g; 0.0171 mole) in acetic acid (60 ml), a solution of sodium nitrite (1.65 g; 0.0239 mole) in water (6 ml) was added at 5°-10° C. After stirring for 3.5 hours at room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (4×200 ml). The combined extracts were washed with water, dried over NaSO4 and evaporated to a foam. Trituration of this product with diethyl ether afforded the title compound as a beige powder, 6.3 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[C:13]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=2[S:15](=[O:25])[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[C:13]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=3[S:15](=[O:25])[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(Oc3ccc(Br)cc3)c3ccc(OC)cc3S2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of 4-bromophenol (469 mg, 2.71 mmol) in DMF (3 mL) was added sodium hydride (60% suspension in oil, 108 mg, 2.71 mmol), the resulting mixture was allowed to stir for 10 min at room temperature. To the solution was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (900 mg, 2.46 mmol) as a solid. The reaction was heated to 80° C. for 18 h. Upon completing the reaction was cooled to room temperature, quenched with water and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product. The crude material was purified by column chromatography (SiO2, 0-60% EtOAc/Heptane) to afford 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (980 mg, 2.14 mmol, 87% yield) as a yellow solid.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[N+](=[CH2:18])=[N-]>C(OCC)C>[CH2:10]([C:9]1[CH:8]=[CH:7][C:6]([C@@H:4]([CH3:5])[C:2]([O:1][CH3:18])=[O:3])=[CH:15][CH:14]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: C=[N+]=[N-]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Solvent: CCOCC
Product: COC(=O)[C@H](C)c1ccc(CC(C)C)cc1

Procedure:
A solution of (R) (−)-ibuprofen (3.45 g) in ethyl ether, cooled to 5° C., is treated, dropwise, with a 0.6 M solution of diazomethane in ethyl ether, up to a persistent yellow colour. The solvent is removed—under vacuum; the residual oil is purified by flash chromatography to yield 3.3 g of methyl (R) (−) 2-(4′-isobutylphenyl)-propionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:6]=[N:7][C:8]=1[N+:9]([O-])=O>CO.[Pd]>[NH2:9][C:8]1[N:7]=[CH:6][C:5]([CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOP(=O)(Cc1cnc([N+](=O)[O-])c(OC)c1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1cnc(N)c(OC)c1)OCC
Yield: 91.9 %

Procedure:
Diethyl [(5-methoxy-6-nitropyridin-3-yl)methyl]phosphonate (Compound 308B, 102.6 mg) was hydrogenated in the presence of 10% Pd/C (20 mg) in MeOH (5 mL) under 1 atmosphere for 4 h. The catalyst was filtered off, the filtrate was concentrated, and the residue (85 mg, 92% yield) was used in the next step without purification. 1H NMR (CDCl3, 400 MHz): δ=1.27 (dt, J=2.0, 6.8 Hz, 6 H), 3.02 (d, J=20.8 Hz, 2 H), 3.84 (s, 3 H), 4.01-4.08 (m, 4 H), 4.74 (s, 2H), 6.98 (t, J=2.0 Hz, 1 H), 7.52 (t, J=2.0 Hz, 1 H). MS (ES+): m/z 275.10 [MH+]. HPLC: tR=0.77 min (UPLC TOF, polar—3 min).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=O.O1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:12]1([N:8]=[C:1]=[N:3][CH:7]2[CH2:6][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Solvent: ClCCl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
Malonitrile is alkylated (or dialkylated) by treatment with NaH in an appropriate solvent such as dimethylformamide or tetrahydrofuran at 0° to 25° C. to give compounds (51). Treatment of the substituted nitrile with (n-Bu)3SnN3 in refluxing dioxane for 24 hours gives, after acidic hydrolysis, the tetrazole (52), which is then alkylated with an alkyl halide (R4Br) in CH3CN employing Et3N as base to give a mixture of regioisomers (53) and (54). The regioisomers are then separated by flash chromatography and each nitrile is then reduced to the corresponding aldehydes (55) and (56) by treatment with Raney nickel in formic acid at 60° C. The resulting aldehydes are then treated with a stabilized ylide such as ethyl(triphenylphosphoranylidene)acetate in CH2Cl2 at room temperature to give (57) and (58) which are reduced catalytically using hydrogen gas, Pd/C as catalyst in methanol or ethanol at room temperature to give esters (59) and (60). These are then hydrolyzed to the corresponding acids (61) and (62) by treatment with alcoholic (MeOH/EtOH) alkali metal hydroxide (NaOH or KOH) at reflux. The acids are then coupled with an appropriate amine employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl2 at 0° C. to give amides (63) and (64).