Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:18][CH3:19])[CH3:17]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][NH:5][CH2:4][C:3]1([CH2:18][CH3:19])[CH3:17]
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1N
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCC(C)(CC)C1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 4-amino-1-benzyl-3,5-diethyl-3-methylpiperidine (2.1 g, 8.07 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (4 atm.) at 45° C. for 4 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,5-diethyl-3-methyl-piperidine as an oil.
Reaction SMILES: [Cl-:1].[C:2]([O:5][C:6]1[C:7]([CH3:22])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH3:21])([C:18](O)=[O:19])[CH2:10][CH2:9]2)(=[O:4])[CH3:3]>ClC1C=CC=CC=1>[C:2]([O:5][C:6]1[C:7]([CH3:22])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH3:21])([C:18]([Cl:1])=[O:19])[CH2:10][CH2:9]2)(=[O:4])[CH3:3]
Reactant: [Cl-]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Solvent: Clc1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2

Procedure:
To a mixture of 1.34 g. of dimethylchloroformimium chloride and 12 ml of chlorobenzene were added 2.92 g of (± )-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The resulting solution was heated at 110° under N2 for 40 min and stripped of solvent to give (±) 6-acetoxy-2,5,7,8 tetramethylchroman-2-carboxylic acid chloride as a light yellow, very viscous gum. To a mixture of 2.89 mmoles of this material in 4 ml of acetone was added 0.43 ml of triethylamine and 90 mg of 10% palladium on carbon catalyst. The mixture was hydrogenated at atmospheric pressure and room temperature. Uptake ceased after 1.0 hr. The suspension was filtered and the filtrate was stripped of solvent, taken up in ether, washed with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl, and brine, dried over sodium sulfate and stripped of solvent. The residue was chromatographed on silica gel with 8:2 parts by volume benzene-ethyl acetate and then crystallized from 30°-60° petroleum ether to give (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde as a white solid, m.p. 92.5°-96°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:2].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:16]=[O:18])=[C:8]([Cl:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(N=C=O)c(Cl)c1

Procedure:
In analogy to the procedure described in example 9.1, (4-amino-3-chloro-phenyl)-acetic acid ethyl ester was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 48 h to give the title compound as brown solid which was used in the next step without further purification. MS: m/e=257.0 [M+NH4+].
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13](C)C)=[C:8]([O:16]COCC)[C:7]=1C)C.Cl.O>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][C:8]=1[OH:16]
Reactant: CCOCOc1ccc(OC(C)C)c(OCOCC)c1C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(O)cc1O
Yield: 127.9 %

Procedure:
A solution of 5c (157 mg, 0.53 mmol) in MeOH (4.40 mL) at room temperature was treated dropwise with 3 M HCl (1.40 mL, 4.21 mmol), then heated to reflux for one hour. Water (5 mL) was added and the solution was extracted with EtOAc (3×10 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 6c as a red amorphous solid (95 mg, 99%): 1H NMR (CDCl3, 500 MHz) δ 6.54 (d, J=8.7 Hz, 1H), 6.21 (d, J=8.7 Hz, 1H), 5.78 (s, 1H), 4.37-4.32 (m, 1H), 2.09 (s, 3H), 1.25 (d, J=6.1 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 147.7, 144.9, 137.5, 110.8, 109.8, 104.0, 71.7, 21.3 (2C); IR (film) νmax 3526, 2974, 2924, 2853, 1717, 1607, 1475, 1238, 1113, 1067, 928, 887, 791 cm−1.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])N.[C:6]1([NH2:16])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>CN1CCCC1=O.ClC1C=CC=CC=1Cl>[NH2:16][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([S:1]([OH:3])(=[O:5])=[O:4])=[CH:8][CH:7]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: NS(=O)(=O)O
Solvent: CN1CCCC1=O
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(S(=O)(=O)O)c2c1CCCC2
Temperature: 150 °C
Reaction time: 7 h
Yield: 48.6 %

Procedure:
A hot suspension of 20 g of sulphamic acid in 40 ml of N-methylpyrrolidone is added to a solution of 10 g of 5,6,7,8-tetrahydronaphthylamine in 100 ml of 1,2-dichlorobenzene. The mixture is heated with stirring for 7 hours at 150° C. The product is filtered off and washed with dichlorobenzene and then with toluene. The precipitate is resuspended in 70 ml of water and neutralized to pH 7 with 5.5 ml of 30% sodium hydroxide. The insoluble matter is filtered off and the aqueous phase is extracted with ether. The aqueous phase is adjusted to pH 5 by adding HCl, at 5° C.; the mixture is filtered, and the residue is washed with water and dried to obtain 7.5 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][CH2:11][C:12](Cl)=[O:13].O>ClCCl>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:13]
Reactant: Nc1ccccc1C=O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-Aminobenzaldehyde (650 mg) was dissolved in dichloromethane (20 ml) to prepare a solution. Chloroacetyl chloride (728 mg) was added to the solution, and the mixture was stirred at room temperature overnight. Water was added thereto, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and 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 column chromatography using chloroform to give 2-chloro-N-(2-formylphenyl)-acetamide (1.05 g, yield 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([CH:22]=[CH:23][NH:24]5)=[CH:20][CH:19]=4)[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=3)[CH:3]=2)=[O:43])=[CH:45][CH:46]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4cc[nH]c4c3)n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5cc[nH]c5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(1H-indol-6-yl)-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure 4-tert-butyl-N-{3-[8-(1H-indol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@H:68]([C:83](OCC#N)=[O:84])[CH2:69][CH2:70][C@@H:71]1[S:75][CH2:74][N:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[CH2:72]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]>C(#N)C>[NH2:58][C:55]1[CH:56]=[CH:57][N:52]([C@@H:26]2[O:25][C@H:24]([CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]3[C@@H:39]([O:40][C:83](=[O:84])[C@@H:68]([NH:67][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:66])[CH2:69][CH2:70][C@@H:71]4[S:75][CH2:74][N:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[CH2:72]4)[C@@H:38]([OH:41])[C@H:37]([N:42]4[CH:50]=[N:49][C:48]5[C:43]4=[N:44][CH:45]=[N:46][C:47]=5[NH2:51])[O:36]3)([OH:32])=[O:31])[CH2:27]2)[C:53](=[O:59])[N:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 25 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (44.0 mg, 0.069 mmol) and (S)-tert-butyl 5-((S)-3-((tert-butoxycarbonyl)amino)-4-(cyanomethoxy)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk3) (89 mg, 0.207 mmol) in acetonitrile (0.3 mL) was added to buffer A (12.5 mL), and the mixture was stirred at room temperature for 1.25 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (5S)-tert-butyl 5-((3S)-4-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)Oxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk4) (17.4 mg, 25%).
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][NH:17][C:18]([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]3[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:21]2[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=2[Cl:49])=[O:19])[CH:10]=1)(C)(C)C.ClC(Cl)C.FC(F)(F)C(O)=O>>[Cl:49][C:43]1[CH:44]=[C:45]([Cl:48])[CH:46]=[CH:47][C:42]=1[CH:21]1[CH:20]([C:18]([NH:17][O:16][CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:50])=[O:5])=[O:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)COc1cccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(OCC(=O)O)c2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A mixture of 730 mg of tert-butyl(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetate, 5 ml of dichloroethane, and 5 ml of trifluoroacetic acid was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was recrystallized from ethyl acetate to obtain 184 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid as a colorless crystal.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:41](=[O:42])[CH2:40][Cl:39])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Temperature: 4 °C
Reaction time: 25 h
Yield: 95.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (1.1 g, 2.5 mmol; prepared as described in Example 31-starting materials) was dissolved in a mixture methylene chloride (20 ml) and diisopropylethylamine (1.0 ml) under a nitrogen atmosphere. The solution was cooled in an ice/water bath to 4° C. and chloroacetyl chloride (0.2 ml, 2.63 mmole) was added. The reaction mixture was stirred cold for two 25 hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (1.14 g, 94.9%); Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccc(C)nc1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(C)nc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.3 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.37 g, 0.007 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (4.30 g, 0.033 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (2.00 g, 0.007 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (410 mg, 15%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:21]1([CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][NH:11][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][N:3]=3)[CH2:15][CH2:16]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1noc2ccccc12
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(CN2CCC(CCNc3noc4ccccc34)CC2)cc1
Yield: 15.5 %

Procedure:
The procedure described in Example 21 was followed with 3-chloro-1,2-benzisoxazole (0.682 g, 4.44 mmol), 4-aminoethyl-1-phenylmethyl piperidine (0.970 g, 4.44 mmol), and K2CO3 (0.614 g, 4.44 mmol) in DMSO (30 mL). After purification, the title compound (0.231 g, 15%) was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][CH:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][CH:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1
Reactant: ClC1=NC(Cl)NC2=C1CCCC2
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: ClC1N=C(Nc2cc(C3CC3)n[nH]2)C2=C(CCCC2)N1
Temperature: 120 °C

Procedure:
2,4-Dichloro-1,2,5,6,7,8-hexahydro-quinazoline (1 g, 4.93 mmol) and 3-amino-5-cyclopropylpyrazole (0.606 g, 4.93 mmol) in ethanol (8 ml) was treated with triethylamine (1.24 ml, 8.87 mmol) and the mixture heated at 120° C. for 3 days, cooled and filtered to give (0.72 g, 51%) as a colourless solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:23][CH:24]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cscn2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
To a solution of tert-butyl thiazol-4-ylcarbamate (13.0 g, 64.9 mmol) in DMF (150 mL) was added Cs2CO3 (42.3 g, 130 mmol) and 1-(chloromethyl)-4-methoxybenzene (12.1 g, 78.0 mmol, Spectrochem). The reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was allowed to cool to room temperature and water (500 mL) was added. The aqueous layer was extracted with diethyl ether (2×500 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100-200 mesh and 0-20% ethyl acetate in hexanes) to obtain tert-butyl 4-methoxybenzyl(thiazol-4-yl)carbamate (15.0 g, 80%) as an off-white solid. MS (ESI, positive ion) m/z=321 (M+1)+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)C(C)C)(C)C>C1COCC1>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Reaction time: 15 h
Yield: 58.6 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (260 mg, 1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in THF (3 mL) at rt, was added dropwise a solution of phenyl chloroformate (170 mg, 1.1 mmol) in THF (2 mL) and the reaction mixture was stirred for a further 15 h. N,N-Diisopropylethylamine (129 mg, 1 mmol) was added to the reaction mixture and stirring continued for an additional 4 h. The reaction mixture was filtrated, the filtrate concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and washed with brine, then concentrated under reduced pressure to give a solid which was recrystallized from diethyl ether to afford crude phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg) which was used without further purification. LC-MS (ESI) m/z 342 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:26](=[O:25])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12][CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)cc2c(=O)o1

Procedure:
To the mixture of 15 g of 2-amino-5-(4-benzylpiperazin-1-yl)benzoic acid in 90 mL of dioxane, under stirring and external cold water cooling 12.7 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 120 mL of ether. The product is stirred for 5 minutes in the mixture of 100 mL of methanol and 10 mL of triethylamine, it is filtered off and washed with 50 mL of methanol. After drying 17 g of the title product is obtained, m.p.: 235° C.
Reaction SMILES: C(SC=C)=C.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.O=O.C(S[C:31]1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([OH:50])[CH:45]=2)[C:34]2([CH:41]3[CH2:42][CH:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)[O:33][O:32]1)C.[O:51]1[CH2:54][CH2:53][O:52]1>C(Cl)Cl>[OH:51][CH2:54][CH2:53][O:52][C:31]1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([OH:50])[CH:45]=2)[C:34]2([CH:41]3[CH2:40][CH:39]4[CH2:38][CH:37]([CH2:36][CH:35]2[CH2:43]4)[CH2:42]3)[O:33][O:32]1
Reactant: CCSC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Reactant: C1COO1
Agent: C=CSC=C
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: O=O
Solvent: ClCCl
Product: OCCOC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Temperature: -78 °C

Procedure:
The vinyl sulfide of Example 1(b) (0.099 g) was irradiated for 11.5 min in 15 mL of CH2Cl2 containing a few crystals (<1 mg) of methylene blue with continuous oxygen bubbling at -78° C. using a 1000 W Na lamp. TLC indicated that the vinyl sulfide was consumed. N-Chlorosuccinimide (0.044 g) was added and the mixture maintained at -78° C. for 15 minutes. Ethylene glycol (37 uL) was added and the solution warmed to room temperature. Progress of the reaction was monitored by the appearance of a new material by TLC (20% ethyl acetate in hexane) which emitted blue light when the plate was heated and by observing the color of chemiluminescence from an aliquot of the reaction solution reacted with 0.1 M TBAF in DMSO. The yellow emission of dioxetane 1 was gradually replaced by the blue emission of dioxetane 10 over a period of an hour. The solution was concentrated to dryness and the residue extracted with ether. The ether was evaporated and the resulting residue chromatographed on a silica prep. TLC plate with 40% ethyl acetate in hexane. The major band contained 18 mg of dioxetane 10.