Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C=O.[NH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(O)C>O>[S:1]1[CH:5]=[CH:4][CH2:3][C:2]1=[N:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: O=Cc1cccs1
Reactant: CCOP(=O)(CN)OCC
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CN=C1CC=CS1)OCC

Procedure:
11.2 g. (0.1 mol) Thien-2-aldehyde are added to 16.7 g. (0.1 mol) diethyl aminomethylphosphonate in 200 ml. absolute ethanol and the mixture is heated under reflux for 30 minutes. The water formed during the reaction is removed by azeotropic distillation. After complete evaporation of the solvent, 28 g. (about 100%) of a yellow oil are collected, which is pure according to LC, TLC and GC.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)[O-]
Reactant: CCCCCN1CCC=C(c2csc(N)n2)C1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCN1CCC=C(c2csc(NC(C)=O)n2)C1

Procedure:
Seven grams of the 4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolamine obtained in Example 6 was dissolved in 100 ml of acetic anhydride with 10 g of anhydrous sodium acetate. The solution was heated at reflux under a nitrogen atmosphere for three hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 150 ml dichloromethane and 150 ml 10% sodium bicarbonate solution. The organic layer was concentrated in vacuo and the residue was chromatographed on silica gel using 2% ammonium hydroxide in ethyl acetate as the eluent. The title compound was obtained as 4.10 g of a beige solid, mp 117°-120° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[NH:33][N:32]=[C:31]([CH2:34][C:35](O)=[O:36])[N:30]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:35](=[O:36])[CH2:34][C:31]1[N:30]=[C:29]([CH3:28])[NH:33][N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c(C)n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A solution of 3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2, Compound 90) (100 mg, 0.273 mmol), in CH2Cl2:DMF (1:1, 3 mL), then treated with (5-methyl-1H[1,2,4]triazol-3-yl)-acetic acid (50.0 mg, 0.355 mmol), followed by the addition of diisopropylethylamine μL, 0.819 mmol) and HATU (135 mg, 0.355 mmol). (100 The reaction stirred at room temperature for 8 h. The solution was washed with a saturated aqueous solution of NaHCO3 (10 mL) followed by brine (10 mL). The organic portion was dried over MgSO4, filtered and evaporated to an oil which was purified by silica gel flash chromatography with 5% then 10% MeOH/EtOAc as eluant to afford product as a colorless solid (86 mg, 65%). 1H NMR (CDCl3) 1.50-1.65 (m, 4H), 1.70-2.00 (m, 6H), 2.42 (s, 3H), 2.46 (s, 2H), 2.61-2.99 (m, 2H), 3.21-3.51 (m, 3H), 3.72-3.99 (m, 4H), 4.62-4.79 (m, 1H), 6.38-6.60 (m, 2H), 6.70-6.82 (m, 1H), 7.20-7.39 (m, 5H). 13C NMR 44.8 (CH2), 53.5 (CH2), 54.8 (CH), 55.3 (CH2), 56.6 (CH2), 63.2 (CH2), 105.4 (CH), 127.1 (CH), 128.2 (CH), 129.0 (CH), 130.0 (CH), 138.0, 139.8 (CH). LC/MS (Method B) 3.32 min, [M+1]+ 490.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:31]=[C:32]([CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:38]2[CH:37]=[C:32]([CH:31]=[C:30]([OH:29])[CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 120 °C
Yield: 42.8 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.16 mmol) and methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (64 mg, 0.23 mmol) were dissolved in 10 mL dioxane in a microwave vessel. A solution of sodium carbonate (2 M, 365 μl, 0.73 mmol) was added and the mixture was submitted to three vacuum-argon cycles. 2′-(Dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (5 mg, 0.01 mmol) was added and the mixture was submitted to three more vacuum-argon cycles. The reaction mixture was then heated at 120° C. under microwave conditions for 5 h. Further 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (5 mg, 0.01 mmol) and sodium carbonate (2 M, 365 μl, 0.73 mmol) were added and the reaction mixture heated at 120° C. under microwave conditions 2 h more. The reaction mixture was cooled at room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1® Purification System to obtain 35 mg (42% yield) of the title compound. Purity 100%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4.[H-].[Na+].Cl[C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]=1>CN(C)C=O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:27]1[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[C:29]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:28]=1)[C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.5 g (70.4 mmol) of 7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are dissolved in 400 ml of dimethylformamide under a protective-gas atmosphere, and 3.1 g of 60% NaH in mineral oil (78 mol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (22.6 g, 84.5 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is recrystallised from toluene. Yield: 40 g (67 mmol), 95% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:17]2[C:16]([CH3:19])=[N:15][N:14]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[CH:10][C:11]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][OH:26])=[N:12][C:13]=23)=[CH:30][CH:29]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(C)nn3c(-c4ccc(F)c(F)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(S)-(1-(7-(3,4-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (74 mg), 4-methylphenylboronic acid (27 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (7 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight under argon atmosphere at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure, concentrated and purified by column chromatography to yield the target compound (41 mg).
Reaction SMILES: [Br:1]C1C=C(C(F)(F)F)C=CC=1N1CCOC2C=C(S(Cl)(=O)=O)C=CC1=2.Cl[C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]1[CH2:42][CH2:41][O:40][C:39]2[CH:43]=[C:44]([S:47]([O:50][C:51]3[C:56]([F:57])=[C:55]([F:58])[C:54]([F:59])=[C:53]([F:60])[C:52]=3[F:61])(=[O:49])=[O:48])[CH:45]=[CH:46][C:38]1=2>>[Br:1][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]1[CH2:42][CH2:41][O:40][C:39]2[CH:43]=[C:44]([S:47]([O:50][C:51]3[C:56]([F:57])=[C:55]([F:58])[C:54]([F:59])=[C:53]([F:60])[C:52]=3[F:61])(=[O:49])=[O:48])[CH:45]=[CH:46][C:38]1=2
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br

Procedure:
Perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate was prepared from INTERMEDIATE C according to the procedure used to prepare INTERMEDIATE F. MS (ESI, positive) m/z: 625.8 (M+Na).
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[CH3:30][OH:31]>[Pd]>[CH3:30][O:31][C:8]1([CH2:13][C:14]2[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:7][C:6]2[C:10](=[CH:11][CH:3]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:5]=2)[C:9]1=[O:12]
Reactant: CO
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ncccc1C(F)(F)F)C2=O
Agent: [Pd]
Product: COC1(Cc2ncccc2C(F)(F)F)Cc2cc(N3CCOCC3)ccc2C1=O
Reaction time: 6 h

Procedure:
Compound 67 (80 mg, 0.197 mmol) was dissolved in methanol 15 mL, Pd/C 50 mg added, and the reaction stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude. The crude was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 26% ethyl acetate in hexane as half white coloured solid compound 68. 1HNMR (400 MHz, CDCl3) δ ppm 8.64 (d, 1H), 7.91 (d, 1H), 7.22 (d, 2H), 6.83 (s, 1H), 3.89 (m, 7H), 3.65 (dd, 1H), 3.44 (m, 1H), 3.16 (m, 6H), 2.72 (dd, 1H); MS (ESI) m/z 407.0 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C(N(CC)CC)C.[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25]>ClCCl>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:27]([O:26][CH2:24][CH3:25])=[O:28])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 48 h

Procedure:
To trans-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (1.09 g) and triethylamine (0.77 ml) in dichloromethane (20 ml), cooled in an ice bath, was added ethylchloroformate (0.67 ml). The mixture was allowed to attain room temperature and stirred for 2 days. The reaction mixture was washed with water and dried over anhydrous magnesium sulphate. Filtration and evaporation and chromatography (chromatotron, gradient elution: 10-30% Ethyl acetate-pentate) gave one fraction (456 mg) which was recrystallised from ethyl acetate-pentane to give the compound of this example (319 mg); mp 147°-148° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[O:12]1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:12][C@H:13]([CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[C@@H:14]([OH:17])[C@H:15]2[OH:16])=[CH:26][CH:25]=1
Reactant: NCCc1ccncc1
Reactant: O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1n1cnc2c(NCCc3ccncc3)ncnc21
Yield: 30.7 %

Procedure:
(2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-trifluoromethoxymethyl-tetrahydro-furan-3,4-diol (42 mg), 2-pyridin-4-yl-ethylamine (58 mg), and diisopropylethylamine (0.124 ml) were heated at 80° C. in isopropanol (5 ml) in a reactivial for 17 h. The solution was evaporated under a stream of nitrogen and purified by autoprep HPLC to afford the title compound as a colourless solid (16 mg).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([S:17](=[O:22])(=[O:21])[N:18]([CH3:20])[CH3:19])=[CH:16][C:4]=2[CH2:3]1.[N:23]1([CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][O:33][C:32]2=[O:36])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[CH3:19][N:18]([CH3:20])[S:17]([C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:26]3[CH2:27][CH2:28][N:23]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][O:33][C:32]4=[O:36])[CH2:24][CH2:25]3)[CH2:3][C:4]=2[CH:16]=1)(=[O:22])=[O:21]
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2

Procedure:
11.9 g of 10-chloro-10,11-dihydro-2-dimethylsulphamoyldibenzo[b,f]thiepin in 250 ml of chloroform are treated with 20 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and the mixture is heated under reflux for 24 hours. Then the mixture is evaporated under reduced pressure and the residue taken up in ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is dissolved in benzene and filtered through a column filled with 100 g of aluminium oxide (activity stage II). The eluate is evaporated and, for the purpose of further purification, chromatographed on 75 g of silicagel (0.2-0.5 mm), elution being effected with a 1:1 mixture of chloroform saturated with concentrated ammonia/carbon tetrachloride. The purified product is recrystallised from ethyl acetate/petroleum ether. There is obtained 3-[2-[4-{10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]thiepin-10-yl}-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 164°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[C:16]([OH:18])=O)=[O:4].Cl.CN.C1C=CC2N(O)N=[N:28][C:26]=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:26][NH:28][C:16]([C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][O:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:18]
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccccc2)noc1C(=O)OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.3 %

Procedure:
A mixture of 5-(methoxycarbonyl)-3-phenylisoxazole-4-carboxylic acid (50 mg, 0.202 mmol), methylamine hydrochloride (19.12 mg, 0.283 mmol), HOBT (37.2 mg, 0.243 mmol), EDC (46.5 mg, 0.243 mmol) and diisopropylethylamine (0.141 mL, 0.809 mmol) in DMF was stirred at rt for 22 hr. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with saturated potassium bisulfate solution (30 ml), saturated sodium bicarbonate solution (30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to afford methyl 4-(methylcarbamoyl)-3-phenylisoxazole-5-carboxylate (38 mg, 0.146 mmol, 72.2% yield) as a tan solid. HPLC retention time=1.09 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=261.15. 1H NMR (400 MHz, chloroform-d) d ppm 2.97 (d, J=4.77 Hz, 3H) 4.04 (s, 3 H) 7.19 (brs, 1H) 7.42-7.51 (m, 3H) 7.66-7.73 (m, 2H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][O:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(OCc2ccc(COCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(OCc2ccc(COCCO)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of the product of Example 4 (528 mg, 1.09 mmol) dissolved in anhydrous THF (11 mL) was added a solution of TBAF (1.0 M solution in THF, 1.65 mL, 1.65 mmol) dropwise. After completion of addition the reaction was stirred at room temperature for 1 hour and then quenched with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4:1 hexanes:ethyl acetate) to provide the desired product (311 mg, 0.850 mmol) in 78% yield. 1H (CDCl3, 600 MHz): δ 7.70 (1H, s), 7.38 (4H, m), 5.30 (2H, s), 4.56 (2H, s), 3.76 (2H, t, J=4.9 Hz), 3.60 (2H, t, J=4.8 Hz), 2.00 (1H, br s), 1.61 (9H, br s); 13C(CDCl3159.0, 153.6, 150 MHz): δ 138.8, 134.4, 128.2, 127.2, 125.1, 118.3, 72.8, 71.6, 71.6, 66.4, 61.9, 27.8; HRMS calcd for C18H23ClN2O4: 367.141911, found 367.1419.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[CH:10]=[C:9]([C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5][C@H:4]1[O:18][CH3:19].[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][CH:29]=O)([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][CH2:29][NH:2][C@H:3]1[C@H:4]([O:18][CH3:19])[CH2:5][C:6]2[C:11](=[CH:10][C:9]([C:15](=[O:16])[NH2:17])=[CH:8][CH:7]=2)[C:12]1([CH3:14])[CH3:13])([CH3:23])([CH3:22])[CH3:21]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
trans-7-Amino-8,8-dimethyl-6-methoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid amide hydrochloride (0.75 g, 2.64 mmol), (3-oxo-propyl)-carbamic acid tert-butyl ester (0.55 g, 3.16 mmol), and N,N-diisopropylethylamine (1.38 mL, 7.92 mmol) were dissolved in dichloromethane (15 mL) at room temperature. Sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added and the reaction was stirred for 17 h at room temperature. Saturated sodium bicarbonate was added, and the reaction mixture was extracted with dichloromethane. The organic extract was dried with Na2SO4 and concentrated to give the title compound as the crude free base (1.07 g, 100% yield, 79% purity). (m/z): [M+H]+ calcd for C22H35N3O4, 406.3; found, 406.5.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=1.O.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(N)nc2)n1
Temperature: 90 °C
Yield: 94.8 %

Procedure:
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (363 mg, 1.19 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 DME:water:ethanol (7 mL). 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (496 mg, 2.25 mmol), 2M sodium carbonate solution (2 mL) and dichlorobis(triphenylphosphine) palladium (42 mg) were added to the solution and it was heated under reflux at 90° C. for 90 minutes under nitrogen atmosphere. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL), the organics dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired product as a yellow oil (410 mg) which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[O:33]=[C:28]1[NH:29][C:30](=[O:32])[C:31](=[CH:25][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:3]([CH2:1][CH3:2])[C:4](=[O:11])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:14]=3)=[CH:24][CH:23]=2)[S:27]1
Reactant: O=C1CSC(=O)N1
Reactant: CCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Product: CCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 85.4 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 300 mg (0.9 mmol) of N-ethyl-N-(4′-formyl-biphenyl-3-ylmethyl)benzamide with 100 mg (0.9 mmol) of 2,4-thiazolidine dione, 340 mg (88%) of the expected product are obtained.