Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:10]=[CH:11][CH:12]=1.[C:14](OCC)(=[O:16])C>>[O:13]1[C:3]2[C:4]3[CH:9]=[CH:8][N:7]=[CH:6][C:5]=3[CH2:10][CH2:11][CH2:12][C:2]=2[NH:1][C:14]1=[O:16]
Reactant: CCOC(C)=O
Reactant: Nc1cccc2cnccc2c1=O
Product: O=c1[nH]c2c(o1)-c1ccncc1CCC2
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
N,N'-carbonyldiimidazole (4.86 g, 0.030 mole) was added portionwise to a stirred, aqueous solution of 6-aminocyclohepta[1,2-c]pyridin-5-one (4.20g, 0.0169 mole) maintained at 2° C. After stirring for 30 minutes, ethyl acetate (~300 ml) was added and the mixture stirred until it reached room temperature. The organic phase was extracted with water (150 ml), washed with brine, and dried (MgSO4). The light brown solid isolated after solvent removal was heated (180° C.) for 35 minutes, cooled to room temperature, then quenched with water (200 ml). The aqueous mixture was stirred for about 12 hours and the brown residue collected by filtration, after washing with ethyl acetate (50 ml), then methylene chloride (50 ml), was recrystallized from aqueous ethanol (50%, ~50 ml) to give 0.29 g of the desired product, m.p. >285° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(Nc2ccccn2)nc1
Reaction time: 17 h
Yield: 58 %

Procedure:
2-Bromo-5-methylpyridine (300 mg, 1.74 mmol), 2-aminopyridine (180 mg, 1.91 mmol), potassium tert-butoxide (293 mg, 2.61 mmol), (±)-BINAP (4.3 mg, 0.07 mmol) and Pd2(dba)3 (4 mg, 0.05 mmol) were stirred in toluene (4 mL) at 90° C. under Ar(g). After 17 h stirring, the reaction was diluted with CH2Cl2 (5 mL), and silica was added. The solvent was removed under reduced pressure and the resulting dry loaded material purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:2) to furnish I as a yellow solid (187 mg, 58%).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].O1CCCC1.O.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][N:28]=[C:27]([O:30][CH2:31][CH:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33][OH:34])[C:26]=2[CH:43]=1>O1CCCC1.C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][N:28]=[C:27]([O:30][CH2:31][CH:32]([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:33][O:34][S:2](=[O:3])(=[O:4])[NH2:5])[C:26]=2[CH:43]=1
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)COS(N)(=O)=O

Procedure:
To a solution of 0.378 ml of chlorosulfonyl isocyanate in 5 ml of tetrahydrofuran is dropwise added 0.78 ml of a tetrahydrofuran-water mixture (9:1 v/v) at -10° C. over five minutes, and the temperature is gradually elevated to 15° C. To this mixture are dropwise added at the same temperature 0.61 ml of triethylamine and a solution of 1.0 g of 5-chloro-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 10 ml of tetrahydrofuran over ten minutes, after which they are subjected to reaction at room temperature for two hours. Water and ethyl acetate are added to the reaction mixture, they are shaken and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a silica gel column chromatography [eluant:toluene:ethyl acetate=5:1], to obtain 1.0 g of oily 5-chloro-3-(2-tert-butoxycarbonylamino-3-sulfamoyloxypropoxy)-1,2-benzoisoxazole.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1

Procedure:
To a mixture of 3-Amino-2-carboethoxyindole (572 mg) and triethylamine (400 mg) in methylene chloride (100 mL) was added benzoyl chloride (450 mg). After 30 min at room temperature the reaction mixture was washed with 0.1N HCl, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with ether to afford 3-Benzamido-2-carboethoxyindole as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH:14]([CH:20]([CH3:22])[CH3:21])[C:15](OCC)=[O:16]>>[CH:20]([CH:14]1[S:11][C:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:12][C:15]1=[O:16])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: NC(=S)NCCN1CCOCC1
Product: CC(C)C1SC(NCCN2CCOCC2)=NC1=O

Procedure:
Synthesis was performed from N-(2-morpholin-4-ylethyl)thiourea and ethyl 2-bromo-3-methylbutanoate according to Method C.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:5][OH:6].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]([CH2:5][OH:6])[C:3]([OH:14])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred solution of 2-(4-Chloro-phenyl)-3-hydroxy-propionic acid methyl ester (Preparation 243, 500 mg, 2.33 mmol) in THF (7 mL) was added a solution of lithium hydroxide monohydrate (244 mg, 5.82 mmol) in water (2 mL) dropwise at 0° C. and the resulting mixture stirred at room temperature for 1 hour. The reaction mixture was acidified (pH˜3) with 2N hydrochloric acid and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and evaporated in vacuo to afford the title compound as a white solid in 90% yield, 420 mg.
Reaction SMILES: Cl.[C:2]1([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([OH:19])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]O>>[C:2]1([C:8]23[CH2:9][CH2:10][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:14][CH2:15]2)[CH2:12][CH2:13]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CC12CCC(c3ccccc3)(CC1)CC2
Agent: Cl
Product: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Reaction time: 4 h

Procedure:
A freshly prepared solution of hydrogen chloride in methanol (˜3 M; ˜2 mL, ˜6 mmol) was added to a solution of (4-Phenylbicyclo[2.2.2]oct-1-yl)acetic acid (0.3 g) in methanol (3 mL) under a calcium chloride guard tube and the mixture stirred for 4 h. The solvent was evaporated to leave the title compound as an off white solid (0.25 g; 78%).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C@H:28]([OH:31])[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>ClCCl.C1COCC1.O>[OH:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C@H:28]([O:31][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@H](O)CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H]2C(C)(C)[C@H](OS(C)(=O)=O)CC[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To a solution of the above Compound (36) (42 mg, 0.084 mmol) in 5 ml of dry dichloromethane were added 34 μl (0.244 mmol) of triethylamine and 14 μl (0.181 mmol) of methanesulfonyl chloride under ice-cooling, and the mixture stirred for 15 min at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil. This oil was dissolved in 2 ml of dry THF. To the solution was added 0.11 ml (0.11 mmol) of 1M tetrabutylammonium fluoride/THF solution under ice-cooling, and the mixture stirred for 20 min at the same temperature. After addition of ice-water, the reaction mixture was extracted with ethyl acetate. The extract was washed with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=15:1) to give 38 mg (98%) of Compound (13b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:27][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:29])[CH2:15][CH2:14]3)[N:10]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc(C3CCNCC3)n(-c3ncccn3)n2)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 9 HCl salt (72.4 mg, 0.17 mmol) in DMF (1.0 ml) was added 2-bromoacetophenone (83.0 mg, 0.42 mmol), followed by the portionwise addition of potassium carbonate (138.0 mg, 1.00 mmol). After stirring at ambient temperature overnight, the reaction mixture was quenched with a saturated solution of ammonium chloride, extracted with EtOAc, and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica gel cartridge using a gradient of 0-50% ethyl acetate in hexanes, followed by a gradient of 0-10% methanol in dichloromethane to give the title compound as a yellow oil, which solidified on standing. LC-MS (m/z): 443.10 [M+H]+. 1H NMR (CDCl3, 500 MHz): δ 8.92 (d, J=4.8 Hz, 2H), 8.25-8.27 (in, 2H), 8.10 (d, J=8.1 Hz, 2H), 7.60-7.62 (m, 1H), 7.50 (t, J=7.6 Hz, 2H), 7.37 (t, J=4.8 Hz, 1H), 7.15 (t, J=8.6 Hz, 2H), 3.88 (s, 2H), 3.80-3.86 (in, 1H), 3.13-3.15 (br, 2H), 2.41-2.45 (br, 2H), 2.07-2.27 (br, 4H).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1([F:17])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][OH:16])=[CH:14][C:8]=2[O:7]1>[O-2].[O-2].[Mn+4].O1CCCC1>[F:17][C:6]1([F:5])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH:15]=[O:16])=[CH:14][C:8]=2[O:7]1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 20 mL of chloroform containing 930 mg of (2,2-difluorobenzo[1,3]dioxol-5-yl)methanol and 20 mL of a tetrahydrofuran solution, 2.20 g of manganese dioxide was added, and the mixture was stirred at room temperature for 3 days. The insoluble material filtered off, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate:hexane 1:2] to obtain 687 mg of a yellow oily substance, 2,2-difluorobenzo[1,3]dioxol-5-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].I[CH3:29].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[N:16]([CH3:29])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reaction time: 0.17 h

Procedure:
Methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (F) (0.44 g) was added to a stirred suspension of oil-free sodium hydride (0.31 g) in dry tetrahydrofuran (10 ml), under an atmosphere of nitrogen. The dark-red solution was stirred for 10 minutes, and iodomethane (0.18 g) was added. The mixture was stirred for 30 minutes, and was poured into 1M hydrochloric acid (30 ml). The mixture obtained was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with brine (25 ml), then dried (MgSO4), and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (50 ml), eluting with 50:45:5 v/v/v hexane:dichloromethane:ethyl acetate, to give methyl 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)benzoate (F') (0.33 g, 72%) as a yellow oil, which was crystallized from dichloromethane/hexane to give a yellow solid, mp 144°-146° C.; NMR: 3.81(s, 3H, NCH3), 3.83(s, 3H, COOCH3), 3.92(s, 3H, OCH3), 4.11(s, 2H, CH2Ar), 7.27(d, 1H), 7.37(s, 1H, H2 -indole), 7.49 (m, 2H), 7.60(d, 1H), 8.01(dd, 1H, H6 -indole), 8.50(d, 1H, H4 -indole).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[C:17]1([C:23]2[S:24][CH:25]=[C:26]([CH:28]=O)[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[O:11]=[C:9]1[NH:8][C:7](=[O:12])[CH:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([OH:16])=[C:2]([N:1]=[CH:28][C:26]3[N:27]=[C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:24][CH:25]=3)[CH:3]=2)[S:10]1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: Nc1cc(CC2SC(=O)NC2=O)ccc1O
Solvent: CCO
Product: O=C1NC(=O)C(Cc2ccc(O)c(N=Cc3csc(-c4ccccc4)n3)c2)S1
Yield: 97.8 %

Procedure:
A mixture of 500 mg of 5-(3-amino-4-hydroxybenzyl)-2,4-dioxothiazolidine, 405 mg of 2-phenyl-4-formylthiazole and 30 ml of ethanol is refluxed for 20 minutes, and the solvent is distilled off. 840 mg of 4-(2,4-dioxothiazolidin-5-yl)methyl-2-[(phenylthiazol-4-yl)methylidene]aminophenol obtained as a crude product are dissolved in 40 ml of benzene, and 1.26 g of lead tetraacetate are added thereto. After the mixture is stirred at room temperature for 15 minutes, the solvent is distilled off. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1), whereby 400 mg of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(2-phenyl-1,3-thiazol-4-yl)benzoxazole are obtained. The Mass and IR data of this product are identical with those of the product obtained in Example 8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CC(O)=O.[CH:18]([NH2:21])([CH3:20])[CH3:19].[BH3-]C#N.[Na+]>CO>[CH:18]([NH:21][CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)([CH3:20])[CH3:19]
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
1-(Pyridin-4-yl)piperidin-4-one (1.5 g, 8.52 mmol, 1.0 eq.) was dissolved in MeOH (40 ml); AcOH (0.6 ml) and isopropylamine (1.39 ml, 17.04 mmol, 2.0 eq.) were added and the mixture was stirred for 3 hours at RT. NaCNBH3 (856 mg, 12.78 mmol, 1.5 eq.) was then added in portions at 0° C. and stirring was carried out for a further 14 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was taken up in water (100 ml) and extracted with DCM (150 ml). The org. phase was washed with sat. NaHCO3 solution (100 ml), dried over sodium sulfate, concentrated and purified by column chromatography (Alox, 2% MeOH in DCM). Yield: 64% (1.2 g, 5.47 mmol)
Reaction SMILES: C(Br)(Br)(Br)[Br:2].[OH-].[Na+].[C:8]([O:12][P:13]([O-:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])([CH3:10])[CH3:9].P([O-])([O-])[O-]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[P:13]([Br:2])(=[O:19])([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OP([O-])OC(C)(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(Br)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 172.1 %

Procedure:
A 500 mL 3-neck flask equipped with dropping funnel and thermometer was charged with carbon tetrabromide (16.58 g, 50 mmol), benzyltriethylammonium chloride (1.14 g, 5.0 mmol) and dichloromethane (50 mL). A 20% w/w NaOH solution (50 mL) was added with vigorous stirring, followed by dropwise addition of a solution of di-tert-butylphosphite (20 g, 100 mmol) in dichloromethane (20 mL), the rate of addition was controlled to keep the temperature of reaction mixture not to exceed to 25° C. After addition of phosphite, the mixture was further stirred at room temperature for 3 h, diluted with dichloromethane (20 mL) and separated. The organic phase was washed with saturated sodium bisulfite, water, brine, dried (Na2SO4), filtered and concentrated at RT. After removing the solvent, the residue was further pumped in vacuo for 1 h to give di-tert-butyl phosphorobromidate as a colorless oil (23.5 g, 86%).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:6]=1[NH2:7].[CH3:17][CH:18]([NH2:20])[CH3:19]>>[OH:1][CH:2]([CH2:16][NH:20][CH:18]([CH3:19])[CH3:17])[CH2:3][O:4][C:5]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:6]=1[NH2:7]
Reactant: Cc1cc(OCC2CO2)c(N)c([N+](=O)[O-])c1
Reactant: CC(C)N
Product: Cc1cc(OCC(O)CNC(C)C)c(N)c([N+](=O)[O-])c1

Procedure:
The diamine used as intermediate is obtained by reacting the 2-(2,3-epoxypropoxy)-4-methyl-6-nitroaniline described in Example 1 with 2-propylamine to give 2-[2-hydroxy-3-(2-propylamino)-propoxy]-4-methyl-6-nitroaniline, which is then subjected to catalytic hydrogenation.
Reaction SMILES: S([O-])([O-])(=O)=O.N[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)[OH:16]>>[OH:16][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1
Reactant: Nc1ccc(C=O)cc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: O=Cc1ccc(O)cc1
Reaction time: 1 h

Procedure:
The procedure of Example 8 was followed except that the production of the sulphate of p-aminobenzaldehyde by reaction with sulphuric acid in 40% aqueous solution was effected at 40° C. for one hour, to obtain 2.0 g (0.016 mol) of p-hydroxybenzaldehyde. The yield thereof was 41%, based on the weight of p-aminobenzaldehyde used.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[CH:17]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCc3cccc(Cl)c3)nc(Cl)nc21

Procedure:
2-Chloro-6-[(3-chloro)benzylamino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine, 3-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:32][CH2:31][C:29]2[N:30]=[C:26]([CH:24]([CH3:25])[CH3:23])[S:27][CH:28]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN)cs1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CC(C)c1nc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 2-(1-methylethyl)-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 98%, 470.090 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(=O)([S:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH3:24])C.Cl>C(OCC)C>[CH2:10]([SH:9])[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH3:24]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCS
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
LiAlH4 (2.05 g, 54.1 mmol) was suspended in dry diethyl ether (100 mL) at 0° C. under inert atmosphere. To this suspension was added dropwise a solution of S-(3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraenyl ethanethioate (13.7 g, 49.2 mmol) in dry diethyl ether (50 mL) and the resulting grey mixture was stirred at 0° C. for ten minutes and then at ambient temperature for 30 minutes. The mixture was cooled to ˜5° C., added 1M HCl until pH=2 and filtrated through a short pad of celite. The pad was washed with water and diethyl ether, the phases were separated and the aqueous phase was extracted twice with diethyl ether (100 mL each). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 7.8 g (67% yield) of the title compound as oil.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:15][NH:14][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccccc2CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: ONC1CCc2ccccc2CC1
Reaction time: 8 h

Procedure:
To 6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (2.56 g, 16 mmol) and hydroxylamine hydrochloride (2.2 g, 32 mmol) in 27 mL of water is slowly added a solution of sodium carbonate (1.69 g, 16 mmol) in 14 mL of water. The mixture is stirred overnight. The solid is then filtered off, washed with water, and dried at 50° C. under reduced pressure to give 6,7,8,9-tetrahydro-N-hydroxy-5H-benzocyclohepten-7-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)C=O)[CH:5]=[CH:4][N:3]=1.Cl.O1CCOCC1.[CH3:23][O:24][CH:25](OC)[O:26][CH3:27]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:13]=[C:14]([CH:25]([O:26][CH3:27])[O:24][CH3:23])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: COC(OC)OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(OC)c1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 (3.69 g) was refluxed for two hours in trimethylorthoformate containing 10 mL of 4N HCl/dioxane. The solvent was removed by rotary evaporation to give product, which showed the expected M+H+ of 265 by LC-MS.