Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:22]1([CH3:40])[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH:23]=1.[C:41]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([CH3:53])[C:50](O)=[O:51])=[CH:45][C:44]=1[F:54])#[N:42].C(N(CC)CC)C>>[C:41]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([CH3:53])[C:50]([NH:35][CH2:34][C:33]2[C:28]([C:24]3[CH:23]=[C:22]([CH3:40])[CH:27]=[CH:26][CH:25]=3)=[N:29][C:30]([C:36]([F:37])([F:39])[F:38])=[CH:31][CH:32]=2)=[O:51])=[CH:45][C:44]=1[F:54])#[N:42]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(C#N)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (1.5 equiv), 1-hydroxybenzotriazole (1.5 equiv), and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (1 equiv) are added to a solution of 2-(4-cyano-3-fluorophenyl)propanoic acid (5 equiv) drop-wise triethylamine (2.5 equiv). The reaction mixture is stirred overnight at room temperature. The reaction is quenched with water and extracted with ethyl acetate. The extracted organic layer is dried over magnesium sulfate. After evaporate solvent, purified by column chromatographic purification (ethylacetate:hexane) afforded 2-(4-cyano-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(CNCCc2ccccc2)c1
Temperature: 0 °C
Yield: 82 %

Procedure:
2-Chloro-5-nitro-benzaldehyde (5 g, 27 mmol) and 2-phenylethylamine (4.1 g, 33.75 mmol) were dissolved in methanol, cooled to 0° C., and sodium cyanoborohydride (2.1 g, 33.75 mmol) was added. The reaction was adjusted to pH 6 with acetic acid and warmed to room temperature for 6 h. The reaction mixture was quenched with ice and diluted with water. The pH was adjusted to 11 with sodium hydroxide and the mixture was extracted with methylene chloride. The organic extracts were washed with water and brine and dried briefly over sodium sulfate. Filtration of the mixture and concentration of the filtrate in vacuo yielded the title compound (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[C-:18]#[N:19].[Na+]>CN(C)C=O.O>[C:18]([CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([OH:10])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)#[N:19]
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (6.7 g) in dimethylformamide (198 ml) at 60° C. was added dropwise over 25 minutes a solution of sodium cyanide (2.84 g) in water (49 ml). Heating at 60° C. was continued for five hours. The reaction mixture was then cooled, poured into water (900 ml), and extracted with ethyl acetate (3×150 ml). The combined organic extracts were washed with saturated aqueous brine, dried (Na2SO4 ) and evaporated to dryness to give a pale yellow solid (6.1 g) which was triturated with ethyl ether. The residual solid was recrystallized from ethyl ether/methanol to give the title compound, 4.13 g (56%), m.p. 217°-219° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([I:14])[N:10]=[C:9]2[CH3:15])[N:5]=[CH:4][N:3]=1.[OH-:16].[K+]>C(O)(C)(C)C>[I:14][C:11]1[N:10]=[C:9]([CH3:15])[N:8]([C:6]2[N:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[C:12]=1[CH3:13]
Reactant: [OH-]
Reactant: Cc1nc(I)c(C)n1-c1cc(F)ncn1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(I)c(C)n1-c1cc(=O)[nH]cn1

Procedure:
The title compound, light yellow crystalline solid, MS: m/e=316.9 (M+H+), was prepared in accordance with the general method of example 1a by treatment of 4-fluoro-6-(4-iodo-2,5-dimethyl-imidazol-1-yl)-pyrimidine with 50% KOH in tert-butanol.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[Se:15][C:14]=1[C:22]([NH2:24])=[O:23].CN(C=O)C.[OH-].[Na+]>>[C:18]([C:16]1[Se:15][C:14]([C:22]([NH2:24])=[O:23])=[C:13]([NH:12][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1ncnc2ncccc12
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ncnc3ncccc23)c(C(N)=O)[se]1

Procedure:
The reaction of 4-chloropyridino[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a yellow color solid, mp 222-224° C. IR (KBr) vmax 3310, 3180, 2961, 1616, 1572, 1383, 1332, 1316, 1280, 1245, 1226, 1090 cm−1; 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 9.10 (1H, dd, J=4.4, 1.6 Hz), 8.96 (1H, s), 8.81 (1H, s), 8.55 (1H, dd, J=8.4, 1.6 Hz), 7.54 (1H, dd, J=8.4, 4.4 Hz), 6.50 (2H, br s), 1.48 (9H, s); 13C NMR (100 MHz, CDCl3+DMSO-d6): 168.6, 168.3, 158.6, 157.9, 156.5, 155.8, 146.1, 131.3, 121.9, 121.1, 111.7, 110.3, 36.8, 32.2; LC-MS (negative ion mode): m/z 372, 374 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.Br[CH2:23][CH2:24][N:25]=[C:26]=[O:27].[H-].[Na+].Cl>ClCCl>[O:27]=[C:26]1[NH:25][CH2:24][CH2:23][N:1]1[CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Reactant: O=C=NCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CN1CCNC1=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice-cooled solution of 302 mg (0.99 mmol) of the compound from Example 101A in 10 ml of dichloromethane was admixed dropwise with 99 μl (1.09 mmol) of 2-bromoethyl isocyanate. After 10 minutes, the ice bath was removed and the mixture was stirred for a further 5 min. All of the volatile components were removed on a rotary evaporator. The residue was taken up in 5 ml of anhydrous THF and admixed, with ice cooling, with 44 mg of sodium hydride (60% in mineral oil, 1.09 mmol). After 2 h, 1 ml of 1M hydrochloric acid was added and the reaction mixture was freed from the solvent on a rotary evaporator. The aqueous residue was dissolved in DMSO and purified by preparative HPLC [Method 23]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 210 mg (38% of theory) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[S:15]1[CH:16]=[CH:17][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])=[CH:14]1
Reactant: Brc1ccsc1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccccc1-c1ccsc1
Temperature: 150 °C
Yield: 56 %

Procedure:
A microwave vial (20 ml) was charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 3-bromo-thiophene (326 mg, 2.0 mmol), and 8 ml of acetonitrile. To this mixture was added 4 ml of aqueous sodium carbonate (1M), followed by 50 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide a crude material, which was purified by ISCO to give 211 mg of 2-thiophen-3-yl-benzaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:16])[C:14]#[CH:15])=[CH:9][CH:8]=1.I[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:29]/[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36])/[C:22](=[O:28])[NH:23]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([OH:16])[C:14]#[C:15][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2/[C:21](=[CH:29]/[C:30]2[NH:31][CH:32]=[CH:33][C:34]=2[O:35][CH3:36])/[C:22](=[O:28])[NH:23]3)=[CH:11][CH:12]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)c1ccc(OCCCN(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(OCCCN(C)C)cc3)c21

Procedure:
Using Method C above, 3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propyne (201 mg, 0.86 mmol) (from Example 22 above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (34 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, to yield rac-(Z)-1,3-dihydro-4-[3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 151 mg, 80%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:15]([NH:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@H](N)C(=O)NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)NCC(=O)O
Reaction time: 1.5 h

Procedure:
To a solution of L-valyl-glycine (1.0 g. 5.74 mmol) in 1 N NaOH (4.74 ml, 5.74 mmol) cooled to -5° C., 6.89 ml (689 mmol) of 1N NaOH and 968 1 (6.89 mmol) of benzoyl chloride were alternately stirred in for 30 minutes. After 90 minutes, the reaction mixture was diluted with water and washed with diethyl ether. The product was isolated by precipitation in the aqueous layer which was acidified to pH 1.5. The precipitate was then washed with diluted HCl, water, and ether. Recrystallization from water afforded 1.16 g (73% overall yield from 1): mp 190°-191° C.; Rf(D)=0.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]S(C)=O.CI>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H), 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methy iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCI solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (br t, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H, 4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1)#[N:2].[H][H]>[Ni].CO>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1F
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CN)cc1F

Procedure:
The catalyst (0.151 g Raney nickel), N-(4-cyano-2-fluoro-phenyl)-methane sulphonamide (1.15 g) and methanol (25 ml) were placed in a hydrogenator. The mixture was stirred over night under hydrogen at a pressure of 2 bar. 0.26 ml hydrogen was taken up. The reaction mixture was drawn off through the filtering material and the filter cake was washed with methanol. The solvent was removed under vacuum and the residue was dried. The desired product was obtained in the form of a solid (476 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[CH3:18][C:19](=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH:4]=[C:19]([CH3:18])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1Cl)OCC
Reactant: CC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=Cc1ccc(Cl)cc1Cl)C(C)(C)C
Yield: 61.7 %

Procedure:
29.7 g (0.1 mol) of diethyl 2,4-dichlorobenzylphosphonate, 10 g (0.1 mol) of pinacolone, 12 g (0.1 mol) of potassium t-butylate and 300 ml of absolute toluene are heated at the boiling point in a nitrogen atmosphere for 20 hours. The solution is cooled, washed with 2 80 ml portions of water, dried over sodium sulphate and freed from the solvent in vacuo. After the residue has been distilled, 15 g (69.7% of theory) of 1-(2,4-dichlorophenyl)-2,3,3-trimethylbut-1-ene of boiling point 85° C. under 0.13 mbar are obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])(=[O:32])=[O:31])[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CS(C)=O>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[S:30]([C:26]1[N:25]=[C:24]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(c1cccc(Cl)n1)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cccc(S(=O)(=O)c4ccccc4F)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.6 g, 2 mmol), 2-chloro-6-(2-fluorophenylsulfonyl)pyridine (0.400 g, 1 mmol), 2M sodium carbonate (1 mL, 2 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (8 mL). The flask was heated in a pre-heated (95° C.) heat bath while stirring under inert atmosphere overnight. The mixture was cooled, diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to provide N-(6-(6-(2-fluorophenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 428. Calculated exact mass for C20H14FN3O3S3: 427. 1H NMR (400 MHz, DMSO-d6): 8.49 (s, 1H), 8.20-8.36 (m, 2H), 8.08-8.19 (m, 2H), 7.95 (d, J=7.5 Hz, 1H), 7.79-7.88 (m, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.56 (m, 1H), 7.44 (m, 1H), 2.21 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[O:11]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12]1>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[N:4]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: OCC1CCOC1
Product: BrCc1cccc(COCC2CCOC2)n1
Yield: 37 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and (RS)-tetrahydrofuran-3-methanol by the alkylation method described for the final step of Example 32 to give the title compound (37%); NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 8.0 Hz), 7.37-7.33 (2H, m), 4.63 (2H, s), 4.53 (2H, s), 3.89-3.82 (2H, m), 3.77-3.72 (1H, m), 3.65-3.61 (1H, m), 3.56-3.46 (1H, m), 2.66-2.56 (1H, m), 2.09-1.99 (1H, m), 1.69-1.60 (1H, m); (M+H)+ 286, 288.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1.C[Si]([N:33]=[C:34]=[O:35])(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:34](=[O:35])[NH2:33])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C(N)=O)CC2)CCO1
Reaction time: 2.5 h
Yield: 90.5 %

Procedure:
To a solution of 4-amino-5-chloro-2-ethoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}-methyl]benzamide (Example 22) (1.0 g) in methylene chloride (15 ml) was added trimethylsilyl isocyanate (0.34 g) at room temperature, and the mixture was stirred for 2.5 hours. The solvent was removed in vacuo, and then to the residue was added water. The precipitated solid was filtered in vacuo, washed with aqueous ethanol and dried to give the titled compound (1.0 g) as a white solid. Melting point 201-207° C. (recrystallized from E/H)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH:18]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19]1>C(O)CO.C(OCC)(=O)C>[CH:18]1([CH2:21][CH2:22][NH:23][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)=[C:4]([NH2:17])[N:3]=2)[CH2:20][CH2:19]1
Reactant: NCCC1CC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Nc1nc(NCCC2CC2)nc2c1ncn2C1CCCCO1
Temperature: 120 °C
Yield: 100.2 %

Procedure:
To a suspension of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (3.49 g) in ethylene glycol (17 ml) at room temperature was added cyclopropylethylamine (4.69 g). The reaction mixture was heated to 120° C. with reflux condenser overnight, resulting in a yellow/brown solution. The reaction was allowed to cool, taken up in ethyl acetate (100 ml) and washed with water (2×100 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark brown gum (4.17 g)
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=[O:5])C.[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCOCC1>[C:21]([NH:20][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
t-Boc-Ala (4.16 gr, 22 mmol) was dissolved in 11 ml dioxane. N,N′-Dicyclohexylcarbodiimide (DCC) (11 mmol in 11 ml 1 M DMF) was then added and the reaction was carried out for 3 hours at 25° C. under stirring. Dicyclohexylurea (DCU) formed was removed by centrifugation. The symmetrical anhydride product thus obtained (t-Boc-Ala-anhydride) was reacted overnight under stirring with 2-aminofluorene (0.925 g, 11 mmol) in 30 ml dioxane-water (1:1, v:v) containing 11 mmol of NaHCO3. The white solid formed was collected and dried under P2O5 in vacuum for 24 hours. Intermediate a was obtained in 60% yield (1.31 g, 3.34 mmol). It migrated on TLC (dichloromethane) with Rt=0.17. Mass-spectroscopy revealed a mass of 352.45 Da (calculated mass=352.2 Da).
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16]C(=O)C)[C:14](=[O:20])[N:13]([CH2:21][CH2:22][NH:23][CH3:24])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].C(O)C>O>[BrH:1].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][NH:23][CH3:24])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CNCCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(C)cc2)Sc2ccccc21
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(C)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 0.8 g of (±)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin- 4(5H)-one hydrobromide, 10 ml of 5% aqueous sodium hydroxide solution and 5 ml of ethanol is stirred at room temperature for 1 hours. After the reaction is completed, the mixture is diluted with water and the aqueous mixture is extracted with chloroform. The extract is washed with aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is converted to its hydrobromide and recrystallized from ethanol, whereby 0.58 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide is obtained as prisms.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[N+:18]([O-])=O)[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[NH2:18])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(N)cc2N)CC1
Yield: 85.7 %

Procedure:
A 2 liter autoclave was charged with 148 g of N1 -methyl-N4 -(2,4-dinitrobenzoyl)piperazine, 1300 ml of methanol and 5 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated under 800 psi hydrogen pressure while maintaining the temperature below 100° C. with cooling. Hydrogen uptake ceased after 30 min. The mixture was cooled, filtered and the methanol removed under reduced pressure to give 101 g of N1 -methyl-N4 -(2,4-diaminobenzoyl)- piperazine, a light tan solid, mp 192° C.