Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:22]=[CH:21]2.[OH:33][CH2:34][C:35]([CH2:37]O)=[O:36]>CC(C)=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([O:31][CH2:37][C:35](=[O:36])[CH2:34][OH:33])=[O:30])[CH:22]=[CH:21]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=C(CO)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)OCC(=O)CO)ccc2c1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (2.84 g, 13.8 mmol) in acetone (40 mL) was added, drop-wise, to a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.14 g, 13.6 mmol), 1,3-dihydroxy-acetone (3.11 g, 34.5 mmol) and N,N-dimethylaminopyridine (DMAP, 1.4 g, 11.5 mmol) in acetone (100 mL) and stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea was removed by filtration. The filtrate was concentrated and the residue was dissolved in CH2Cl2 (150 mL), washed with 3N HCl (150 mL), water (150 mL×3), brine, and dried over Na2SO4, filtered and concentrated. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (1:2, Rf=0.13) to obtained a mixture of the title compound and its dimer. The reaction mixture was treated with ethyl ether and the dimer was removed by filtration. The filtrate was concentrated and dried under vacuum to give the title compound as a sticky oil (1.59 g). The resulted material was use in the next step without further purification. Mass spectrum (API-TIS) m/z 303 (MH)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:15]=O)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.C[O:18][C:19](=O)[CH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]2[CH:30]=1.N1CCCCC1>C1C=CC=CC=1.C(#N)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([CH:30]=[C:21]([C:20]3[C:19](=[O:18])[O:14][C:11]4[C:10]([CH:15]=3)=[CH:9][C:8]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][F:1])[C:13]=3[CH:12]=4)[N:22]=2)[CH:25]=1
Reactant: COC(=O)Cc1cn2cc(Cl)ccc2n1
Reactant: O=Cc1cc2c(cc1O)N(CCF)CCC2
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC#N
Product: O=c1oc2cc3c(cc2cc1-c1cn2cc(Cl)ccc2n1)CCCN3CCF
Yield: 67.4 %

Procedure:
200 mg (0.896 mmol) 1-(2-Fluoro-ethyl)-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbaldehyde and 201 mg (1 eq.) (6-chloro-imidazo[1,2-a]pyridin-2-yl)-acetic acid methyl ester in 6 mL benzene and 3 mL acetonitrile are treated with 0.177 mL (2 eq.) piperidine and refluxed for 18 h. The reaction mixture is allowed to reach room temperature and the precipitate filtered, washed with acetonitrile and dried under high vacuum to yield 240 mg (67%) of desired product as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21].[CH2:22]([O:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][C:35]=1[Cl:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=3[O:20][CH3:21])=[CH:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=2)[CH:33]=[CH:34][C:35]=1[Cl:36])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(-c2c(OC)cccc2OC)c(Br)c1
Reactant: CC1(C)OB(c2ccc(Cl)c(OCc3ccccc3)c2)OC1(C)C
Product: COC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Yield: 45.1 %

Procedure:
According to the method described in example 10.2, starting from 2.79 g (7.94 mmol) of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate and 3.28 g (9.53 mmol) of 2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, we obtain 1.75 g of methyl 3″-(benzyloxy)-4″-chloro-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate in the form of oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:15]1([CH:14]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)[C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2ccc(Br)cc2)C2CCCCC2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C2CCCCC2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 524.3 [M−H]−.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([Cl:19])[N:7]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.C(O)C>[Cl:19][C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1nc(Cl)ccc1Nc1cncnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1nc(Cl)ccc1Nc1cncnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 6-chloro-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (98 mg, 0.35 mmol) in THF (1 ml) and ethanol (0.5 ml) was cooled to 0° C. and treated with 1M LiOH (0.7 ml, 0.7 mmol). The ice bath was removed and the reaction mixture was stirred at rt. for 2 h. 1M HCl (0.7 ml, 0.7 mmol) was added and stirring was continued until a precipitate was forming. The reaction mixture was sucked off and the product was obtained upon drying of the precipitate as yellow solid (60 mg, 67%).
Reaction SMILES: O1CCOC1C1C=C(NC(=O)C2C=C(C)C=NC=2)C=CC=1.[F:22][C:23]([F:34])([F:33])[C:24]1[N:29]=[C:28]([C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=1.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:44])=[C:40]([CH2:42][OH:43])[CH:41]=1>>[F:44][C:39]1[CH:38]=[CH:37][C:36]([NH:35][C:30]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[N:29]=2)=[O:31])=[CH:41][C:40]=1[CH:42]=[O:43]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Agent: Cc1cncc(C(=O)Nc2cccc(C3OCCO3)c2)c1
Product: O=Cc1cc(NC(=O)c2cccc(C(F)(F)F)n2)ccc1F

Procedure:
The title compound is prepared according to the reaction 4.01a described above using 6-(trifluoromethyl)picolinoyl chloride and (5-amino-2-fluorophenyl)methanol, followed by the oxidation of the alcohol intermediate 6-trifluoromethyl-pyridine-2-carboxylic acid (4-fluoro-3-hydroxymethyl-phenyl)-amide: LC-MS A: tR=0.80 min; [M+H]+=315.06.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][CH2:12][CH2:13]O>S(=O)(=O)(O)O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][CH2:12][Cl:11])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(OCCCl)c1cccc(O)c1
Yield: 95.2 %

Procedure:
A solution of 3-hydroxybenzoic acid (15.0 g, 0.11 mol) in 2-chloroethanol (70 mL, 1.0 mol) and 1 mL of concentrated sulfuric acid was refluxed for overnight. TLC analysis (silica gel/20% ethyl acetate/hexane) showed clean conversion to a new material. The excess chloroethanol was removed by evaporation to obtain a brown solution which was dissolved in ethyl acetate and washed with water. The organic layer was dried with MgSO4 and concentrated to obtain 21.0 g of the product as a white solid: mp 50° C.; 1H NMR (CDCl3) δ3.81 (t, 2H, J=5.9 MHz), 4.57 (t, 2H, J=5.9 MHz), 4.77 (s, 1H), 7.06-7.66 (m, 4H); 13C NMR (CDCl3) δ41.52, 64.75, 116.43, 120.77, 121.98, 129.80, 130.71, 156.04, 166.57; MS m/e (rel intensity) 200 (26), 138 (59), 121 (100), 93 ( 31), 65 (21), 39 (12); Exact mass: calcd 200.0240, found 200.0242. ##STR27##
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH:29]3[CH3:33])=[CH:20][CH:19]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)F)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[CH3:33])=[CH:22][CH:23]=3)[O:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCCN1CCCOc1ccc(C(=O)NC2(CO)CCN(Cc3ccccc3)CC2)cc1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1CCCN1CCCOc1ccc(C2=NC3(CCN(Cc4ccccc4)CC3)CO2)cc1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
A solution of N-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]-4-[3-(2-methylpyrrolidin-1-yl)propoxy]benzamide ax62 (0.46 g, 0.98 mmol) in dichloromethane (10 ml) is cooled at 0° C. and diethylaminosulfur trifluoride (180 μl, 1.47 mmol) is added. After stirring at 20° C. for 1.5 hours, the reaction mixture is cooled to 0° C. and another portion of diethylaminosulfur trifluoride (40 μl, 0.33 mmol) is added. This is repeated once more with another portion of 20 μl. Potassium carbonate (0.203 g, 1.47 mmol) is then added to the mixture, which is stirred at room temperature for 30 minutes. The mixture is then washed with a saturated solution of sodium bicarbonate, and the aqueous layer is extracted again with dichloromethane. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.453 g of an orange oil, which is purified by chromatography over silicagel (dichloromethane/methanol/ammonia 94:5.4:0.6) to give 0.17 g of 8-benzyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-3-oxa-1,8-diazaspiro[4.5]dec-1-ene 30.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:2]1[CH:14]=[CH:13][CH:12]=[C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH:3]=1)[CH3:28]
Reactant: Ic1cccc(CN2CCOCC2)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cccc(CN2CCOCC2)c1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
To a solution of 4-(3-iodo-benzyl)-morpholine (3.44 g, 11.4 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (1.7 mL, 12.5 mmol), ethyl acrylate (4.1 mL, 45.4 mmol), tri-o-tolylphosphine (346 mg, 1.14 mmol) and palladium (II) acetate (127 mg, 0.57 mmol). The mixture was heated at 80° C. overnight. After concentration, the mixture was chromatographed on silica gel to afford Intermediate 172(a) as a colorless oil (2.37 g, 9.1 mmol) in 80% yield.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])[O:10][C:9]=2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(F)ccc1-c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Reactant: CCOC(=O)CCNC
Product: Cc1cc(F)ccc1-c1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Yield: 99 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({cyclohexyl[5-(4-fluoro-2-methylphenyl)-2-methyl-3-furyl]methyl}amino)benzoic acid (464 mg) as well as ethyl 3-(methylamino)propanoate (171 mg) to give the title compound (552 mg, 99%) as an amorphous compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1I.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Clc1cccc(Cl)c1I
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1c(Cl)cccc1Cl
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 1,3-dichloro-2-iodobenzene 0.23 g, cesium carbonate 0.22 g, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.5 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg were added, and it was stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(2,6-dichloroanilino)-4-phenethylbenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Product: Nc1c(C(=O)NC2CCC2)nnc2c(-c3ccc(Cl)cc3)cccc12
Yield: 70.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 4-chlorophenyl boronic acid (176 mg) were reacted to afford the title compound (112 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.31 (d, 1H), 8.43 (d, 1H), 7.86 (m, 1H), 7.79 (m, 1H), 7.73 (m, 2H), 7.54 (m, 2H), 4.52 (m, 1H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=353 (M+H).
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].Br[CH2:15][CH2:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])(=[O:22])[O:19][CH2:20][CH3:21]>>[CH3:5][N:4]1[C:6]2[N:7]=[CH:8][N:9]([CH3:10])[C:11]=2[C:12](=[O:13])[N:1]([CH2:15][CH2:16][CH2:17][P:18](=[O:22])([O:23][CH2:24][CH3:25])[O:19][CH2:20][CH3:21])[C:2]1=[O:3]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCOP(=O)(CCCn1c(=O)c2c(ncn2C)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.067 mol of theobromine and 0.08 mol of diethyl 3-bromopropanephosphonate analogously to Example 32.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][C:8]1[N:17]2[N:18]=[C:19]([NH2:21])[N:20]=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][C:8]1[N:17]2[N:18]=[C:19]([NH2:21])[N:20]=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: Nc1nc2c3ccccc3nc(Cc3cccc([N+](=O)[O-])c3)n2n1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cccc(Cc2nc3ccccc3c3nc(N)nn23)c1
Reaction time: 5 h
Yield: 68.9 %

Procedure:
To a solution of 5-(3-nitro-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine (0.10 g, 0.31 mmol), prepared as described in Example 2, in N,N-dimethylformamide (10 mL), 10% Pd/C (50% w/w, 0.05 g) was added. The mixture was reacted in Parr Apparatus at 40 p.s.i. for 5 h. The suspension was filtered through Celite®. After washing the filter with methanol, the solution was evaporated to dryness. The crude was twice crystallized from ethyl acetate to provide the title product (0.062 g, 67% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CCO>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH2:5][CH2:6]1
Reactant: Clc1ncccn1
Reactant: O=C1Cc2cc(C3CCNCC3)ccc2N1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(C3CCN(c4ncccn4)CC3)ccc2N1
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
To a solution of 5-(piperidin-4-yl)indolin-2-one (39.8 mg, 0.184 mmol) in EtOH 3 ml) were added 2-chloropyrimidine (33.7 mg, 0.294 mmol) and iPr2NEt (0.095 ml, 0.551 mmol). After stirring at 80° C. for 6 h, the reaction mixture was concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to give 5-(1-(pyrimidin-2-yl)piperidin-4-yl)indolin-2-one (47.9 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])=[CH:4][CH:3]=1.Cl[C:20](Cl)(Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:15]([CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)=[O:7])[CH3:16]
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: CCCCC(CC)COC(=O)c1ccc(N)cc1
Product: CCCCC(CC)COC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC(CC)CCCC)cc2)c2ccccc2)cc1

Procedure:
N,N'-Bis[4-(2-ethylhexyl)oxycarbonylphenyl]benzamidine (3) was prepared from 2-ethylhexyl 4-aminobenzoate and α,α,α-trichlorotoluene; viscous, gold oil: 1H-NMR (CDCl3) 7.9-6.8 (m, 14H), 4.1 (d, 4H, J=4 Hz), 1.9-0.8 (m, 30H); IR (Neat) 3330, 1710, 1585; MS (m/e) 584 (M+), 336 (base).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1S([O-])(=O)=O.[Na+].[OH-:16].[Na+].O>C(C1C(CC2C=CC=CC=2)=C(C)C=CC=1)C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:16]
Reactant: O=S(=O)([O-])c1ccc2ccccc2c1
Reactant: [OH-]
Agent: Cc1cccc(Cc2ccccc2)c1Cc1ccccc1
Agent: [Na+]
Solvent: O
Product: Oc1ccc2ccccc2c1
Temperature: 300 °C
Yield: 92.5 %

Procedure:
Sodium naphthalene-2-sulfonate (230 g) was suspended in 795 g of dibenzyltoluene, and 176 g of a 50% aqueous solution of sodium hydroxide was added. The mixture was stirred under a nitrogen stream and heated to 300° C. to dehydrate it. The dehydrated mixture was stirred at 310° C. for 3 hours. After cooling, 1.2 liters of water was added to the reaction mixture to separate the reaction medium layer. The aqueous layer was decolorized with activated carbon and then precipitated with an acid to give 133.2 g (yield 92.5%) of 2-naphthol.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>C1(C)C=CC=CC=1>[C:1]1([O:7][C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Oc1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(O)/C=C/C(=O)Oc1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
A mixture of phenol (22.41 g), sodium (5.47 g) and toluene (500 ml) was heated for 4 hours while refluxing. The reaction mixture was cooled to 85° C., and maleic anhydride (23.35 g) was added. After stirring at 85° C. for 1 hour, the reaction mixture was poured over ice-water, and the aqueous layer was collected. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then treated with activated charcoal, after which the solvent was distilled off, to yield fumaric acid monophenyl ester (10.59 g, 23%), which was then recrystallized from ethyl acetate-hexane to yield colorless needles having a melting point of 127° to 128° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])=[O:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>CO.[Pd]>[NH2:1][C@@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])=[O:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 5 h
Yield: 86.5 %

Procedure:
After 5.5 g (7.6 mM) of Z-D-Glu(OtBu)-Gly-Arg-CHA was dissolved in 150 ml of MeOH, 1 g of palladium black was added to the solution followed by catalytic reduction at 30° C. for 5 hours. After the reaction, the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 5.5 ml of 5% HCl-MeOH and 20 ml of MeOH. The solution was precipitated again in ether. The precipitates were taken out by filtration and dried and then purified through TOYOPEARL HW40F column using MeOH as a developing solvent to give 3.6 g (75.8%) of H-D-Glu(OtBu)-Gly-Arg-CHA.2HCl.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1.[CH3:20][CH:21]([CH3:26])[CH:22]([OH:25])[C:23]#[CH:24].C(N(CC)CC)C>CC#N.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.[Cu]I>[OH:25][CH:22]([CH:21]([CH3:26])[CH3:20])[C:23]#[C:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1
Reactant: C#CC(O)C(C)C
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(O)C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Temperature: 50 °C
Yield: 75.4 %

Procedure:
In a 15-mL sealed tube flushed with nitrogen, tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (2.00 g, 7.0 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.58 g, 0.70 mmol), and copper (1) iodide (0.34 g, 1.8 mmol) were diluted in MeCN (70 mL). To the reaction mixture was first added 4-methylpent-1-yn-3-ol (3.7 ml, 35 mmol), followed by triethylamine (25 ml, 176 mmol). The reaction was then heated at 50° C. for 7.5 h. The crude material was dissolved in minimal DCM and purified via MPLC (twice)(eluting with 0-10% MeOH/NH4OH:DCM) to yield tert-butyl (6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (1.823 g, 75% yield) as a light brown solid.