Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1.[H-].[Na+]>CN1CCCC1=O>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([N:32]2[CH:36]=[N:35][CH:34]=[N:33]2)=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: c1nc[nH]n1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-n2cncn2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 20, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 1H-[1,2,4]triazole and sodium hydride in 1-methyl-pyrrolidin-2-one at reflux to give the title compound as colorless solid. MS: 485.3 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[N:17]=[N:18][N:19]([CH3:21])[N:20]=2)[C:10]2[CH:37]=[C:38]3[C:43](=[CH:44][C:9]1=2)[CH2:42][CH2:41][CH2:40][CH2:39]3)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:36][C:33]([F:34])([F:35])[C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=1)[CH2:22][N:15]([C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1)[C@H:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:44]=[C:43]3[C:38](=[CH:37][C:10]1=2)[CH2:39][CH2:40][CH2:41][CH2:42]3
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)CCCC4)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)CCCC4)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepine-1-carboxylic acid tert-butyl ester (0.67 mmol) in dichloromethane (18 mL) add trifluoroacetic acid (2 mL). After stirring at room temperature for 1 h, quench with concentrated sodium carbonate (10 mL) and dilute with dichloromethane (20 mL) and water (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (5-30%) to afford the title compound as a colorless foam. MS (ES+): 525 (M+H).
Reaction SMILES: [Br:1][CH:2](Br)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].C(OP([O-])OCC)C.C(N(CC)CC)C>O1CCCC1>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(N2CCCCC2)cc1)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(N2CCCCC2)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
2,2-Dibromo-1-[4-(1-piperidinyl)phenyl]ethanone (3 g, 8.3 mmol) (from Step A above) was dissolved in tetrahydrofuran (15 mL), and cooled to 0° C. To the resulting solution were added dropwise diethylphosphite (1.13 mL, 8.7 mmol) and triethylamine (1.21 mL, 8.7 mmol) in tetrahydrofuran (7 mL) at 0° C. with stirring. The mixture was slowly warmed to room temperature and stirred for 6 h. The reaction mixture was concentrated in vacuo and poured into ice/water. The precipitate was collected by filtration, washed with water and dried in vacuo to provide 2-bromo-1-[4-(1-piperidinyl)phenyl]ethanone (2.3 g, 100% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].[OH:35][CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>CN(C)C=O>[CH3:28][O:27][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:38]1[CH2:39][CH2:40][CH2:41][CH:36]([OH:35])[CH2:37]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([CH3:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][N:20]=2
Reactant: OC1CCCNC1
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCN1CCCC(O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (compound 398) (42 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (44 mg) and 3-hydroxypiperidine (32 mg) were added to the solution, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (29 mg, yield 56%).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Br:20][C:21]1[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1>C(Cl)Cl>[Br:20][C:21]1[CH:26]=[N:25][C:24]([N:27]=[S:2]([CH3:4])[CH3:1])=[CH:23][N:22]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CS(C)=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(C)=Nc1cnc(Br)cn1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of DMSO (11 g, 138 mmol) in 100 mL of DCM was added Tf2O (42 g, 149 mmol) at −70° C. The resulting mixture was stirred at −70° C. for 15 minutes then a solution of 5-bromopyrazin-2-amine (20 g, 115 mmol, in 100 mL of DCM and 50 mL of DMSO) was added dropwise. The mixture was stirred at −60° C. for 3 hours and diluted with 500 mL of DCM and washed with water. The water layer was basified to pH=1 with aq. Na2CO3 and extracted with DCM twice. The combined DCM layer was washed with brine, dried over Na2SO4 and evaporated to afford title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:23](=[O:24])[C:11]2[CH:12]=[N:13][C:14]3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:23](=[O:24])[C:11]2[CH:12]=[N:13][C:14]3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[N:9]1[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1[nH]c2c(cnc3c([N+](=O)[O-])cccc32)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(cnc3c([N+](=O)[O-])cccc32)c(=O)n1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
To a mixture of 2-tert-butoxycarbonyl-2,3-dihydro-6-nitro-1H-pyrazolo[4,3-c]quinolin-3-one (450 mg) and potassium carbonate (565 mg) in dimethylformamide was added methyl iodide (580 mg), and the mixture was stirred for 2 hours at 60° C. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane-ethyl acetate) to give 2-tert-butoxycarbonyl-2,3-dihydro-1-methyl-6-nitro-1H-pyrazolo[4,3-c]quinolin-3-one (114 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:22]=2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[O:24])[CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:21]=1[NH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NS(C)(=O)=O)CC2)cc1OC
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) were added to a solution of 2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (134 mg) in chloroform (2 mL). The mixture was stirred for an hour at ambient temperature. Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) were added to the reaction mixture. After stirring for an hour at ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The separated organic layer was washed with an saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were suspended in hot ethanol and cooled with stirring. The resultant was collected by filtration and washed with ethanol to give N-(3,4-dimethoxybenzyl)-2-[trans-4-(methanesulfonylamino)cyclohexylamino]-5-nitrobenzamide (142 mg) as yellow crystals.
Reaction SMILES: [C:1]([NH:11][C:12]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45]>CN(C)C=O>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][NH:40][C:17]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:19]
Reactant: NCCCCO
Reactant: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1(C(=O)NCCCCO)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred suspension of 12.9 g (0.010 mole) of 1-amino-1-cyclopentane carboxylic acid in 500 ml of methylene chloride is added 25 ml (0.10 mole) of N,O-bis(trimethylsilyl)acetamide. The mixture is stoppered and stirred at room temperature for 3 days, whereupon complete solution is obtained. 17 g (0.10 mole) of benzylchloroformate is added and the mixture stirred for an additional 1 hour. It is then washed with 300 ml each 2N HCl, water and saturated brine and dried over sodium sulfate. Filtration, evaporation and trituration with hexane gives 24 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, mp. 93°-5° C. 5.3 g (0.020 mole) of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid is dissolved in 100 ml dimethylformamide and 3.1 g (0.020 mole) of 1-hydroxybenzotriazole hydrate and 2.5 g (0.020 mole) of 1,3-diisopropylcarbodiimide are added. The mixture is stirred at room temperature for three hours and 1.8 g (0.020 mole) of 4-amino-1-butanol is added. Stirring at room temperature is continued for 24 hours. The solvent is removed in vacuo and replaced with 500 ml of methylene chloride. The mixture is washed with 2N HCl, saturated sodium bicarbonate solution and water and dried over sodium sulfate. Filtration and evaporation gives 6.7 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, 4-hydroxybutylamide, m.p 117°-8° C.
Reaction SMILES: S1[C:5]([CH2:6][C:7]#N)=[CH:4][CH:3]=[C:2]1[CH2:9][C:10]#N.[S:12]1[C:16](C=O)=[CH:15][CH:14]=[C:13]1C=O>>[CH2:10]([C:15]1[CH:14]=[CH:13][S:12][CH:16]=1)[CH2:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:9][CH2:2][CH2:3][CH3:4]
Reactant: N#CCc1ccc(CC#N)s1
Reactant: O=Cc1ccc(C=O)s1
Product: CCCCCCCCCCCCc1ccsc1

Procedure:
Heterocycles can also be easily included in the copolymer chain. The literature records the preparation of an insoluble cyano-substituted alternating polymer derived from thiophene-2,5-diacetonitrile and thiophene-2,5-dicarboxaldehyde (Kossmehl, G. Ber. Bunsenges. Phys. Chem., 1979, 83, 417) and copolymers based on the thiophene-2,5-dicarboxaldehyde and 2,5-dimethoxyterephthaldehyde (H. Horhold, Z. Chem., 1972, 12). The bischloromethylation of 3-dodecylthiophene gave the unstable product (17), which was immediately treated with cyanide to give the bisnitrile (18). Alternatively, the bis-aldehyde (19) can be synthesized from (17) in 3 steps in an analogous fashion to before. Condensation of (18) with (7) gave a purple polymer (onset of absorbance of 670 nm).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2nc(N3CCCCC3)ccc2c1
Temperature: 25 °C

Procedure:
The product (208 mg, 1.0 mmol) from Step B and piperidine (0.5 mL, 5 mmol) were mixed in absolute ethanol (3 mL) and then heated at reflux for 4 h. The reaction mixture was cooled to r.t., and the solvent removed under vacuum. The solids were taken up in EtOAc (125 mL). The mixture was transferred to a separatory funnel and washed with water (3×15 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum to afford the product as a yellow solid, MS: m/z 258 (MH+) which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:11][NH:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[F:29]>N1C=CC=CC=1>[CH2:23]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([F:29])=[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:11]3)[CH:22]=2)[C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19]1)[CH3:24]
Reactant: c1cc(C2CNCCN2)cs1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccsc4)C3)cc21
Yield: 27.5 %

Procedure:
A mixture of 1 g of 2-(3-thienyl)piperazine and 538 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 8 ml of pyridine was further reacted as described in Example 26 giving 220 mg of the desired product, mp 198°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)([Cl:15])=O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Solvent: ClCCCl
Product: O=C(Cl)Cc1ccc(F)c(F)c1
Yield: 100 %

Procedure:
To (3,4-difluoro-phenyl)-acetic acid (2.0 g) dissolved in 1,2-dichloroethane (5 mL) was added thionyl chloride (5 mL) and the mixture was refluxed for 16 hours under argon. The crude mixture was concentrated in vacuo to furnish 2.2 g (100%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3): 4.10 (s, 2H), 7.00 (m, 1H), 7.11 (m, 1H), 7.17 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[NH:11][C:10](=[O:17])[C:9]=1[NH:18][C:19](=O)[CH:20]([CH3:22])[CH3:21].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(Cl)C1C=CC=CC=1.Cl>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:11]2[C:10](=[O:17])[C:9]3[NH:18][C:19]([CH:20]([CH3:22])[CH3:21])=[N:7][C:8]=3[N:13]([CH2:14][CH3:15])[C:12]2=[O:16])=[CH:27][CH:26]=1
Reactant: CCn1c(N)c(NC(=O)C(C)C)c(=O)[nH]c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCc1ccccc1
Product: CCn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2[nH]c(C(C)C)nc21
Reaction time: 3 h
Yield: 33.9 %

Procedure:
3.17 g (28.2 mM) of potassium t-butoxide (t-BuOK) were added to a solution of 6.11 g (27.5 mM) of 6-amino-1-ethyl-5-isobutyrylamino-uracil. At 0° C., 4.90 g (30.4 mM) of 4-chlorobenzylchloride were added. After 3 hr at 0-5° C., further 1.22 g t-BuOK and 2.45 g of 4-chloro-benzylchloride were added. After further 3 hr another 2.45 g of benzylchloride are supplemented. After 3 days (1 day is sufficient) the solution was neutralized with 1N HCl and the solvents evaporated. The residue was suspended in water, the solid collected and washed. The crude intermediate amide was heated under reflux in 100 ml of 1N NaOH and 10 ml of 1-propanol. After 1 hr the mixture was neutralized to pH 7 and extracted with chloroform. Crystallization from dichloromethane (mainly evaporated)--methanol gave 2.99 g (31.3%) of the title xanthine, mp 194-5° C. The mother liquors gave 6.33 g of impure material which was separated on 15 g of silica gel elutions with dichloromethane and gave additional 0.78 g (8.2%) of the xanthine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:16][CH2:2][CH2:3][CH2:4][C:5]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCCc1nc2ccccn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: ClCCCc1nc2ccccn2n1
Temperature: 0 °C

Procedure:
To a solution of 34.5g of 2-(3-hydroxypropyl)-s-triazolo-[1,5-a]pyridine in 500 ml of chloroform is added dropwise 77g of phosphorous oxychloride at a temperature of from 5° to 15°C. After the addition is completed, the reaction mixture is heated on a water bath for 1 hr. and then added to 300 g of ice-water. The mixture is then treated with an aqueous sodium hydroxide solution. Then the organic layer is separated from the aqueous layer, dried over anhydrous sodium sulfate and concentrated to give the residue, which is chromatographed over alumina with benzene. Twenty-three grams of 2-(3-chloropropyl)-s-triazolo[1,5-a]pyridine are obtained as colorless needles after recrystallization from cyclohexane, melting point 56.5°-57°C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:29])[O:11][C:12]3[C:17]([C:18]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=[C:14]([O:27][CH3:28])[CH:13]=3)=[CH:5][CH:4]=1.Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C.CO.CCOC(C)=O>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10](=[O:29])[O:11][C:12]3[C:17]([C:18]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:22][CH:21]=2)=[CH:16][CH:15]=[C:14]([O:27][CH3:28])[CH:13]=3)=[CH:7][CH:8]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Yield: 64.1 %

Procedure:
A solution of 3-(4-trifluoromethylphenyl)-4-(4-hydroxybenzyl)-7-methoxychromen-2-one (6.0 g, 14 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (3.3 g, 22.5 mmol), and K2CO3 (6.6 g, 47.8 mmol) in 30 mL of DMF was warmed at 120° C. for 2 hours. Solvent was removed under reduced pressure. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried and concentrated to provide a dark brown oil. Flash chromatography (CH2Cl2:EtOAc:MeOH:TEA) provided the desired product (4.7 grams, 64%). 1H NMR (300 MHz, DMSO-d6) δ 7.79 (d, 2H, J=8.1 Hz), 7.58 (d, 2H, J=8.1 Hz), 7.51 (d, 1H, J=9.0 Hz), 7.08 (d, 2H, J=8.9 Hz), 7.06 (d, 1H, J=2.5 Hz), 6.87 (dd, 1H, J=2.5, 9.0 Hz), 6.82 (d, 2H, J=8.9 Hz), 4.08 (t, 2H J=5.0 Hz), 3.96 (s, 2H), 3.84 (s, 3H), 3.17-3.12 (m, 2H), 2.94-2.88 (m, 4H), 1.8-1.78 (m, 4H). MS (ESI) m/z 524 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][OH:7].[OH-].[K+].Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>C(#N)C>[F:1][C:2]([F:10])([F:11])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][O:7][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CN(CC(F)(F)F)C(=O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CN(CC(F)(F)F)C(=O)COc1nc2ccccc2o1
Temperature: 20 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
17.1 g (0.1 mol) of N-(2,2,2-trifluoroethyl)-N-methyl-hydroxyacetic acid amide and 7 g of potassium hydroxide powder were initially introduced into 100 ml of acetonitrile at 20° C., and 15.3 g (0.1 mol) of 2-chlorobenzoxazole were added at a temperature between 20° and 40° C. The reaction mixture was stirred at 40° C. for one hour and at 20° C. for a further 15 hours and was concentrated and the concentrate was shaken with toluene and water. The organic phase was washed with dilute sodium hydroxide solution, washed until neutral, dried and filtered. The solvent was carefully distilled off from the filtrate under reduced pressure. 15 g (52% of theory) of N-(2,2,2-trifluoroethyl)-N-methyl-benzoxazol-2-yl-oxy-acetic acid amide of melting point 92° C. were obtained as the residue.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([C:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=3)[CH2:16][CH:15]=2)=[C:10]([CH3:30])[C:9]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=3)[CH2:16][CH2:15]2)=[C:10]([CH3:30])[C:9]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(N2CC=C(c3nnc(Cc4ccccc4)c(C)c3C)CC2)cn1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cnc(N2CCC(c3nnc(Cc4ccccc4)c(C)c3C)CC2)cn1
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of methyl 5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-5,6-dihydropyridin-1(2H)-yl)pyrazine-2-carboxylate (60 mg, 0.144 mmol) in 20 mL EtOH is added 10% Pd—C (77 mg, 72 mmol). The reaction mixture is stirred under hydrogen atmosphere for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford a yellow solid (60 mg, 100%).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:16])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].CCN(CC)CC.Br[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH2:32][CH3:33])[CH:26]=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([NH:4]/[C:5](=[CH:16]/[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH2:32][CH3:33])[CH:26]=1)/[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)OCc1ccccc1
Reactant: CCc1cc(Br)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(/C=C(/NC(C)=O)C(=O)OCc2ccccc2)ccc1N
Yield: 25.7 %

Procedure:
To benzyl 2-(acetylamino)acrylate (80.0 mmol) in acetonitrile (200 mL) was added Pd(OAc)2 (488 mg, 2.18 mmol), (o-Tol)3P (1.32 g, 4.35 mmol), Et3N (20 mL) followed by addition of 4-bromo-2-ethylaniline (14.5 g, 72.5 mmol). The reaction mixture was heated to reflux overnight, concentrated under reduce pressure, taken up in ethyl acetate, washed with aqueous NaHCO3, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was precipitated from ethyl acetate/hexane to provide the titled compound (6.3 g). The filtrate was precipitated a second time to provide and additional 5 g of the titled compound. MS (ESI(+)) m/e 339 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.40-7.20 (m, 8H), 6.59 (d, 1H), 5.52 (s, 2H), 5.16 (s, 2H), 2.42 (q, 2H), 1.98 (s, 3H), 1.13 (t, 3H).