Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(N)cc(OC)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc(OC)c1

Procedure:
To a stirred solution of 3,5-dimethoxybenzenamine (16c, 4g, 26.1 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.3g, 28.7 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound N-(3,5-dimethoxyphenyl)-4-nitrobenzamide (18c). To a stirred solution of amide (18c, 5g, 16.5 mmol) taken in toluene add lawessons reagent (4.6 g, 11.5 mmol) and refluxed at 110° C. for 6h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound N-(3,5-dimethoxyphenyl)-4-nitrobenzothioamide (19c). Treating the thioamide product (19c, 3g, 9.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,7-dimethoxy-2-(4-nitrophenyl)benzo[d]thiazole (20c) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20c. Reduction of the nitro compound (20c, 500 mg, 1.5 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21c). The compound 4-(5,7-dimethoxybenzo[d]thiazol-2-yl)benzenamine (21c, 200 mg, 0.698 mmol) on reaction with 3,4-dimethoxybenzaldehyde (22e, 116 mg, 0.698 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction by using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 6e as a light yellow solid (69%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(C(C)C)CC)(C)C>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][NH:4][C:3]1[C:2]([CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cccc([N+](=O)[O-])c1N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1c(C)cccc1[N+](=O)[O-]

Procedure:
A mixture of 2-methyl-6-nitroaniline (XIV, 2.00 g), ethyl bromoacetate (III, 3.5 ml) and diisopropylethylamine (3.5 ml) is heated at reflux (140°) for 8 hr. The resultant solution is allowed to cool to 20°-25°. After dilution with aqueous sodium bicarbonate, extraction several times with ethyl acetate, drying with magnesium sulfate and concentration the residue is resubmitted to the above reaction conditions for an additional 16 hr. After workup, purification by flash chromatography eluting with a gradient of hexane/ethyl acetate (10/1→5/1), pooling and concentrating the appropriate fractions, the title compound is obtained, mp 49°-52°; IR (mineral oil) 3365, 2953, 2925, 1731, 1536, 1475, 1461, 1374, 1344, 1236, 1207, 1104 and 1022 cm-1 ; NMR (CDCl3) 7.88, 7.33, 6.8-7.0, 6.86, 4.17, 3.94, 2.39 and 1.23 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14](I)=[C:13]([C:16]#[N:17])[C:12]([CH3:18])=[N:11]1.[Li]CCCC.CON(C)[C:27](=[O:36])[CH:28]([CH3:35])[CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32]>CCOCC>[CH3:32][O:31][CH:30]([O:33][CH3:34])[CH2:29][CH:28]([CH3:35])[C:27]([C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[N:11]=[C:12]([CH3:18])[C:13]=1[C:16]#[N:17])=[O:36]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2I)c(F)c1
Reactant: COC(CC(C)C(=O)N(C)OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(-n2nc(C)c(C#N)c2C(=O)C(C)CC(OC)OC)c(F)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To 1-(2-fluoro-4-methoxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (66 mg, 0.18 mmol) in Et2O (1.5 mL) at −78° C. was added n-BuLi (2.5 M solution in hexane, 0.1 mL, 0.24 mmol). After stirring for 15 min, N,4,4-trimethoxy-N,2-dimethylbutanamide was added in Et2O (1.5 mL). The reaction was stirred at −78° C. for 15 hours while warming to −40° C. The reaction was quenched with water and extracted using a mixture of Et2O and DCM. Drying using a phase separator followed by concentration and purification using silica gel (heptane-EtOAc, 1:0 to 0:1) afforded 5-(4,4-dimethoxy-2-methylbutanoyl)-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (33 mg, 48%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=[C:21]([O:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=4)=[CH:12][CH:11]=3)[CH:31]=[C:25]12
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22](=[O:29])[N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:43][C:44]#[N:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:43][C:44]#[N:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22](=[O:29])[N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17]1=[O:31])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](N(CC#N)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide (0.015 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.042 ml), followed by bromoacetonitrile (0.019 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was then cooled to −78° C. and further lithium bis(trimethylsilyl) amide (0.042 ml) added. After reaching room temperature, the reaction mixture was stirred for a further 18 h and then quenched by the addition of methanol (1 ml). The resultant solution was concentrated under reduced pressure and the residue partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified by mass directed preparative h.p.l.c to give the title compound (0.007 g) as a colourless gum.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:8][O:9][N+:10]=2[O-:11])[N:5]=[CH:6][N:7]=1.[H-].[Li+].Cl[CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17]>C1COCC1>[CH3:19][N:18]([C:16]([CH2:15][N:7]1[C:2](=[O:1])[C:3]2=[N+:10]([O-:11])[O:9][N:8]=[C:4]2[N:5]=[CH:6]1)=[O:17])[CH3:20]
Reactant: [O-][n+]1onc2ncnc(O)c21
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1cnc2no[n+]([O-])c2c1=O
Reaction time: 2 h

Procedure:
4.6 g (30 mmol) of 7-hydroxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide and 0.28 g (35 mmol) of lithium hydride are heated at 50° C. for 30 minutes in 65 ml of THF. A solution of 4.6 g (38 mmol) of 2-chloro-N,N-dimethylacetamide in 10 ml of THF is then added dropwise and the mixture is heated under reflux for 4 hours. The solvent is completely stripped off in a rotary evaporator and the residue is stirred with 30 ml of water for 2 hours. The precipitate is filtered off with suction and recrystallised from THF, and 2.4 g (33%) of 6-(N,N-dimethylaminocarbonylmethyl)[1,2,5]oxadiazolo[3,4-d]pyrimidine-7(6H)-one-1-oxide are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23]O)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:23][CH2:22][C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][CH:19]=2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: Cc1cccc(CCO)c1
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc(C)c2)c1
Yield: 86.9 %

Procedure:
3-Hydroxy-4-nitro-benzoic acid methyl ester (1.00 g, 5.07 mmol) and 2-(3-methylphenyl)-ethanol (0.829 g, 6.09 mmol) were reacted in analogy to step 1 of example 1 to give 1.39 g of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1)(=[O:3])[CH3:2].[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(I)c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(=O)Oc1cccc(C#CCCO)c1
Temperature: 25 °C

Procedure:
A solution of 3-iodophenyl acetate (5.6 g) (J. Org. Chem. 1983, 48,1542-4) in acetonitrile (100 mL) was treated with (Ph3P)2PdCl2 (673 mg) and Cul (368 mg) and stirred at room temperature. 3-Butyn-1-ol (1.78 g) was added and the reaction mixture stirred for a further 20 h and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from cyclohexane to DCM) to give the title compound. LCMS RT=2.54 min
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[F:7][C:8]([F:33])([F:32])[S:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:20]=[CH:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[C:16](=[C:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:15]=2[CH:31]=1)=[O:10]>CO.C(Cl)(Cl)Cl>[OH:3][CH:1]([N:28]1[CH2:29][CH2:30][C:25](=[C:16]2[C:15]3[CH:31]=[C:11]([S:9]([C:8]([F:33])([F:7])[F:32])=[O:10])[CH:12]=[CH:13][C:14]=3[CH:20]=[CH:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]2=3)[CH2:26][CH2:27]1)[CH3:2]
Reactant: O=S(c1ccc2c(c1)C(=C1CCNCC1)c1ccccc1C=C2)C(F)(F)F
Reactant: C1CO1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)N1CCC(=C2c3ccccc3C=Cc3ccc(S(=O)C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.244 g. of ethylene oxide in 30 ml. of methanol at dry-ice temperature is added to an ice cold solution of 2.25 g. of 4-(3-trifluoromethylsulfinyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 15 ml. of chloroform and 75 ml. of methanol. The solution is stirred at ambient temperature overnight. A second quantity (0.25 g.) of ethylene oxide is added as before and the mixture is again stirred overnight. The mixture is concentrated to dryness and the residue is coevaporated in vacuo several times with acetonitrile. The product is recrystallized several times from acetonitrile to give 1-hydroxyethyl-4-(3-trifluoromethylsulfinyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:30][N:31]([CH3:34])[CH:32]=[O:33]>>[CH:30]([N:31]1[CH2:34][CH2:5][N:4]([CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:21])[CH2:3][C:32]1=[O:33])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1N(CCBr)CCC1(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: O=C1CN(CCN2CCC(c3ccccc3)(c3ccccc3)C2=O)CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from the Example 28A (0.182 g, 0.6 mmol) in N,N-dimethylformamide (5 mL) was added 1-(2-bromoethyl)-3,3-diphenylpyrrolidin-2-one (Example 64B, 0.2 g, 0.6 mmol), potassium carbonate (0.25 g, 1.8 mmol), and a catalytic amount of potassium iodide. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and partitioned in H2O/dichloromethane. The organic layer was separated, dried over MgSO4, and concentrated. The obtained residue was chromatographed eluting with 5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (m, 10H), 7.20 (m, 11H), 3.50 (t, J=6.10 Hz, 2H), 3.38 (t, J=6.44 Hz, 2H), 3.33 (m, 2H), 3.00 (m, 2H), 2.71 (m, 4H), 2.58 (t, J=6.27 Hz, 2H), MS (ESI+) m/z 530 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Na].Cl[CH2:11][C:12]1[N:16]=[C:15]([CH2:17]Cl)[O:14][N:13]=1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:11][C:12]1[N:16]=[C:15]([CH2:17][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])[O:14][N:13]=1
Reactant: ClCc1noc(CCl)n1
Reactant: Nc1ccccc1S
Agent: [Na]
Solvent: CCO
Product: Nc1ccccc1SCc1noc(CSc2ccccc2N)n1

Procedure:
2-Aminobenzenethiol (5.0 g, 0.04 mol) was dissolved in a solution of sodium (0.92 g, 0.04 mol) in ethanol (50 ml) and 3,5-di(chloromethyl)-1,2,4-oxadiazole (3.3 g, 0.02 mol) was added. After filtration of the mixture, the filtrate was collected and the solvent removed to yield the crude product which on re-crystallisation from isopropanol gave 3,5,-di-(2-aminophenylthiomethyl)-1,2,4-oxadiazole, m.p. 68°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:36][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Nc1ccccc1N
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)c2cc1OC
Yield: 85.9 %

Procedure:
The title compound (40.0 mg, 86% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid (37.5 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.93 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 4.99 (s, 2H, benzene-NH2), 6.56 (d, J=5.2 Hz, 1H, Ar—H), 6.63 (t, J=7.6 Hz, 1H, Ar—H), 6.81 (d, J=7.6 Hz, 1H, Ar—H), 6.98 (t, J=7.2 Hz, 1H, Ar—H), 7.36 (d, J=7.6 Hz, 1H, Ar—H), 7.43 (s, 1H, Ar—H), 7.56-7.58 (m, 2H, Ar—H), 7.65 (t, J=7.6 Hz, 1H, Ar—H), 7.87-7.90 (m, 2H, Ar—H), 8.08 (d, J=8.0 Hz, 1H, Ar—H), 8.43 (d, J=9.2 Hz, 1H, Ar—H), 8.49 (d, J=5.2 Hz, 1H, Ar—H), 9.87 (s, 1H, benzene-NH). LC-MS (m/z) 466 (M+1).
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[N:10]([CH3:16])[N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:29]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH2:43][CH3:44])[C:33]1=[O:34])[CH2:30][CH3:31]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:13]([C:11]3[N:10]([CH3:16])[N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:40][C:39]=2[N:32]([CH2:29][CH2:30][CH3:31])[C:33]1=[O:34])[CH2:43][CH3:44]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCC(Oc1cc(C(=O)O)n(C)n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Cl:22])[C:12]=2[Cl:23])[N:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25].O>CS(C)=O>[N:1]([C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[C:13]([Cl:22])[C:12]=2[Cl:23])[N:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1cnn(-c2c(Cl)cc(C(F)(F)F)c(Cl)c2Cl)c1Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.2 %

Procedure:
1.0 g (0.015 mol) of sodium azide is added to 3.0 g (0.007 mol) of 5-bromo-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 50 ml of dimethylsulphoxide, the mixture is stirred at room temperature for 15 hours, poured into 150 ml of water and extracted several times with chloroform and ethyl acetate, the combined organic phases are dried over magnesium sulphate and concentrated in vacuo and the oily crude produc is purified by chromatography (silica gel; mobile phase: chloroform/acetone 9:1). 0.68 g (24% of theory) of 5-azido-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 84° C.-88° C. is obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccco4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes. 2-Furoyl chloride (0.4 g, 3.2 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (60 mL) and 2N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (20 mL) to give furan-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 58%) as a white solid: mp 219-221° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.30-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.39-4.49 (m, 3H), 4.53 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=5.0 and 13.1 Hz, 1H, CH), 6.62-6.63 9m, 1H), 7.14 (d, J=3.4 Hz, 1H), 7.47-7.65 (m, 3H, Ar), 7.84 (s, 1H), 8.00 (t, J=5.8 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.18, 38.72, 46.24, 51.58, 111.87, 113.69, 121.70, 128.32, 130.74, 131.61, 134.55, 140.11, 145.15, 147.61, 157.84, 168.05, 171.01, 172.85; Anal. calcd. for C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 61.91; H, 4.64; N, 11.38.
Reaction SMILES: [OH-:1].[Na+].C([O:7][C:8]([CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)[C:12]1=[O:33])=[O:9])(C)(C)C>C(O)C>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:13]2[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][C:8]([OH:7])=[O:9])[C:12]2=[O:33])[CH2:18][CH2:19]1)=[O:24])(=[O:1])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CN1CCCN(C2CCN(C(=O)OC(=O)c3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous 4N sodium hydroxide solution (10 mL) was added to a solution of benzyl 4-[3-(tert-butoxycarbonylmethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (1.7 g) obtained in Example 35a) in ethanol (20 mL), and the mixture was stirred at room temperature overnight. Ethanol was distilled off under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust pH to 3, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.5 g, quantitative) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][Br:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (94.0 Og 0.41 mol), carbon tetrabromide (198.7 g 0.6 mol) and dichloromethane (1500 ml) at 0° under nitrogen was treated portionwise, over 45 min, with triphenylphosphine (135.2 g 0.515 mol). The mixture was stirred for 1 h at 10° and 1 h at 25° and then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (Merck 9385), eluant cyclohexane: ethyl acetate (15:1, gradient to 10:1) to give the title compound as a clear liquid (81.8 g, 0.28 mol, 68%).