Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:33][CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1.ClCCl>[O:31]1[C:27]2([CH2:32][CH2:33][N:24]([C:21]3[CH:20]=[CH:19][C:18]([N:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[NH:8][CH2:9][CH2:10]4)=[CH:23][CH:22]=3)[CH2:25][CH2:26]2)[O:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cc2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc2c(c1)NCCN2c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 99.9 %

Procedure:
0.27 g of 4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in 3 ml of a 4N solution of hydrochloric acid in dioxane. The mixture is stirred at ambient temperature for 28 h. The reaction mixture is diluted with dichloromethane and then a saturated aqueous sodium hydrogencarbonate solution is added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under vacuum. 0.21 g of 1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1CCCC1.[CH3:16][C:17]([CH3:19])=[O:18]>>[CH3:16][C:17]1([CH3:19])[CH2:2][C:3](=[O:4])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:18]1
Reactant: CC(C)=O
Reactant: O=C(CO)c1ccccc1
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
The reaction of 2-hydroxyacetophenone with acetone in the presence of pyrrolidine analogously to Synthesis 886, 1978 gives 2,2-dimethyl-4-chromanone of melting point 80°-85° C. 2,2-Dimethyl-4-hydroxy-chroman (oil) is obtained from 2,2-dimethyl-4-chromanone by reduction using sodium borohydride in ethanol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:8]([O:26][CH3:27])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-])=O)[C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:8]([O:26][CH3:27])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([NH2:23])[C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3c([N+](=O)[O-])cccc3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2cc3c(N)cccc3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
The above nitro compound (200 mg, 0.42 mmol) was suspended in about 10 mL EtOAc and 10% Pd/C (50 mg) in 2 mL EtOAc was added. Hydrogen gas was introduced into the flask from an H2-filled balloon attached to a needle inserted through a septum. The black suspension was stirred 12 h at room temperature. After stirring 12, the black suspension was filtered through diatomaceous earth and the filter cake was washed several times with EtOAc. The combined filtrates were dried (MgSO4), filtered and the solvent was removed to afford 4-amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide as a pale yellow solid (170 mg, 90%).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].[C:19](C1NC=CN=1)(C1NC=CN=1)=[S:20]>C(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:19]=[S:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)c1ccccc1Oc1ccccc1N
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ccccc1N=C=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 135a (14.48 mg, 0.0600 mmol) in anhydrous DCM (1.0 ml) was added dropwise to a cold solution of thiocarbonyl diimidazole (21.39 mg, 0.1200 mmol) in anhydrous DCM (0.50 ml). The reaction was stirred at 0° C. for 1 h and then warmed to rt with stirring for 2 h. The mixture was concentrated down to afford crude 135b which was taken directly onto the next step without purification.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C=O)C>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]([CH:3]([N:2]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[CH:34][C:24]=3[NH:23][C:20](=[O:22])[CH3:21])[C:27]2=[O:28])[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH3:19]
Reactant: CCOc1cc(C(N)CC(O)CC)ccc1OC
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC(O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 77.2 %

Procedure:
A stirred mixture of 5-amino-5-(3-ethoxy-4-methoxyphenyl)pentan-3-ol hydrochloride (1.15 g, 3.97 mmol), 3-acetamidophthalic anhydride (0.82 g, 3.97 mmol) and triethylamine (0.4 g, 3.97 mmol) in DMF (20 mL) was heated at 80-90° C. for 6 hours. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (80 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.35 g, 77%); 1H NMR (CDCl3) δ 9.52 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.09-7.07 (m, 2H), 6.83-6.80 (m, 1H), 5.61-5.55 (J=3.9, 11.9 Hz, 1H), 4.11 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.47 (m, 1H), 2.97-2.86 (m, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 1H), 1.78 (b, 1H), 1.62-1.52 (m, 2H), 1.45 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) δ 170.39, 169.23, 168.11, 148.94, 148.14, 137.32, 135.83, 131.81, 131.19, 124.72, 120.30, 117.94, 115.31, 112.87, 111.09, 70.01, 64.36, 55.86, 51.29, 37.92, 30.46, 24.92, 14.73, 9.90.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:16]Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:16])[CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncc(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0° C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0° C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4), and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:3]=1[C:4]#[N:5]>CO.O1CCOCC1.[Fe]>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1c(N)cccc1Br
Temperature: 25 °C
Yield: 87.6 %

Procedure:
2-Bromo-6-nitrobenzonitrile (5 g) was dissolved in a solution of methanol (100 mL) and dioxane (65 mL) and heated to reflux. Iron powder (4.6 g) was added portion wise over 20 minutes and the mixture was heated at reflux for 4 hours. The mixture was allowed to cool to room temperature, filtered and the filtrate was evaporated under vacuum. The residue was triturated with water and the solid was collected by filtration to give the title compound as a light brown solid (3.8 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[C:28](=[O:31])[NH:29][N:30]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:36])([F:37])[F:35])[C:28](=[O:31])[N:29]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:18])([F:17])[F:16])[CH:4]=3)[N:30]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccccc1-c1cc(CBr)ccn1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccnc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
145 mg (0.46 mmol) of the compound from Example 64A were dissolved in 3 ml of acetonitrile, and 141 mg (0.46 mmol) of the compound from Example 5A and 224 mg (0.69 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 16 h. After cooling to RT, the solid was filtered off and rinsed with a little acetonitrile. Under reduced pressure, the filtrate was reduced to a volume of about 2 ml, 0.1 ml of 1 N hydrochloric acid was added and the product was directly purified chromatographically [Method 19]. This gave 49 mg (20% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-])=O.CO.[H][H]>[Pd].CCCCCC>[NH2:1][C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6]
Reactant: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Product: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Temperature: 2.5 °C

Procedure:
2-nitro-2-(4-octylphenethyl)propane-1,3-diol (3 g) and methanol (60 mL) are charged into a hydrogenation vessel at 25-30° C. and stirred. 10% Pd/C (0.6 g) is charged into the vessel, a hydrogen pressure of 4-5 Kg/cm2 applied and the reaction mixture is maintained under the same conditions for about 5 hours. The reaction mixture is filtered through a hyflow bed and washed with methanol (10 mL). The obtained filtrate is concentrated under reduced pressure at a temperature below 36° C. to obtain 8 mL of concentrated reaction mass. n-Hexane (50 mL) is added, the reaction mixture is cooled to 0-5° C. and maintained at the same temperature for about 1 hour. The solid obtained is filtered, washed with n-hexane (10 mL) and dried under vacuum at 36° C. to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CS(C)=[O:14].[OH-].[Na+]>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:14])[CH:7]=1
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 60 °C
Reaction time: 22 h

Procedure:
192 g of 2,4-dichloronitrobenzene, 220 g of DMSO and 0.5 ml of the emulsifier specified in Example 1 are introduced into the reaction vessel. 160 g of 50% NaOH are added at 60° C. within 1 hour and the reaction mixture is stirred for 22 hours at 60° C. Subsequently 150 ml of water are added, the mixture is stirred until the temperature has cooled to 20° C. and the red sodium salt of 5-chloro-2-nitrophenol is suction-filtered and washed three times with 50 ml portions of water. The moist salt is added to 122 g of 30% HCl yielding 5-chloro-2-nitrophenol as an oil which is separated and dried in vacuo. The yield is 151.5 g of 5-chloro-2-nitrophenol (87% of the theory), m.p. 36.5° C. having a degree of purity of 100% according to gas chromatography.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[N:21]=1.O>C1COCC1>[F:19][C:20]1[N:21]=[C:22]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13])[CH:23]=[CH:24][CH:25]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COc1cccc(F)n1
Reaction time: 3.25 h
Yield: 78.1 %

Procedure:
NaH (7.0 g, 60% oil dispersion, 0.176 mol) was added portionwise over five minutes to a stirred slurry of 2-(hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (35.8 g, 0.161 mol) in 700 mL THF. After the resulting mixture was stirred for 3.25 hours, 2,6-difluoropyridine (15.4 g, 0.134 mol) was added neat over a 20 minute period, and the mixture was stirred overnight at room temperature. Water (250 mL) was added, THF was removed in vacuo, and the aqueous residue was extracted three times with 250 mL CH2Cl2. The combined extracts were washed with brine (250 mL), filtered through Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (5% CH3CN in CH2Cl2) to yield 2-[[[6-fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-benzeneacetamide (33.2 g, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:5]([OH:26])[CH:4]=1)#[N:2].Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:5]([O:26][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=2)[CH:4]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1ccc(OC)cc1F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Oc1ccc([N+](=O)[O-])cn1)c1ccc(OC)cc1F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (310 mg) and 2-chloro-5-nitropyridine (205 mg) in DMSO (2 ml) was added cesium carbonate (423 mg). The mixture was stirred at 50° C. for 5 h. The solvent was evaporated, the residue was dissolved in EtOAc and washed with water (2×) and brine (1×). The organic phase was dried, filtered and concentrated. The product was purified by flash chromatography (cyclohexane/EtOAc 9:1=>4:6) to give (RS)-N-[4-cyano-2-(5-nitro-pyridin-2-yloxy)-benzyl]-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Light yellow foam. MS 481.4 ([M+H]+)
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]=1Br.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:36]2[CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:37]=2)=[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: CS(=O)(=O)Nc1cc(B(O)O)cc(C(F)(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(C)(=O)=O)cc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)boronic acid (529 mg, 24% purity, 0.45 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 284 μl of a 2M aqueous solution of cesium carbonate in dioxane (3 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (0 to 80%, hexane-ethyl acetate) using SP1® Purification System to give 52 mg (38% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]([NH2:20])([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[CH3:12][C:13]([NH:20][S:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
6-Chloro-pyridine-3-sulfonyl chloride (148.0 g, 0.7 mol) was suspended in 1000 ml dry dichloromethane and added in portions over 45 minutes to a solution of 1,1,3,3-tetramethylbutylamine (465 ml 2.8 mol) and triethylamine (195 ml, 1.4 mol) in 2800 ml dry dichloromethane, keeping the temperature between −40° C. and −30° C. After addition the mixture was allowed to warm up to room temperature and stirred for an additional hour. The reaction mixture was washed three times with 1 M HCl (2000 ml each time) and twice with water (1000 ml each time). The organic layer was dried over sodium sulphate and evaporated to dryness. The residue was triturated with iso-hexane and filtered off and dried in vacuo at 40° C. to yield 90 g of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43](O)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30].[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1S(C)(=O)=O
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (105 mg, 0.59 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (118 mg, 1.18 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (150 mg, 61%) as a pale yellow foam: mp 104–107° C.; EI-HRMS m/e calcd for C19H24N2O5S3 (M+) 456.0847, found 456.0846.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([Cl:27])[CH:21]=[CH:20]2>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([Cl:27])[CH:21]=[CH:20]3)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: Clc1ccc2cc(CBr)ccc2n1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3nc(Cl)ccc3c2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 6-bromomethyl-2-chloro-quinoline in place of 7-bromomethyl-1-chloroisoquinoline. The crude product is purified by column chromatography eluting with a gradient of 2% MeOH/CH2Cl2 to 4% MeOH/CH2Cl2 to afford the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC[O:24][C:25]([CH:27]1[C:31](=O)[CH2:30][CH2:29][CH2:28]1)=O>>[O:24]=[C:25]1[N:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]2=[N:1][C:28]2[CH2:29][CH2:30][CH2:31][C:27]1=2
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Nc1ncccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(O)c1cccn2c(=O)c3c(nc12)CCC3
Reaction time: 0.38 h

Procedure:
A mixture of 5.0 g of 2-aminonicotinic acid, 0.4 g. p-toluenesulfonic acid, and 25 ml of ethyl cyclopentanone-2-carboxylate is stirred magnetically and immersed in an oil bath preheated to 125°. The temperature of the oil bath is gradually raised and reaches 170° in 23 minutes. A clear solution occurs in 55 minutes when the oil bath temperature reaches 178° and 4.0 ml of distillate is collected in a Dean-Stark trap. The product crystallizes from the cooled reaction mixture. The filtered, air-dried product weighs 6.2 g., m.p. 187°-192°. Recrystallization from 100 ml of toluene gives 4.91 g of product, m.p. 189°-193°.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:8][CH2:7]1.[NH2:19][NH2:20]>C(O)(C)C>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][NH:19][NH2:20])[CH2:7][CH2:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Agent: Cl
Solvent: CC(C)O
Product: NNCCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 75 °C
Yield: 94.4 %

Procedure:
1-(3-Chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride (20.0 g, 0.065 mol) is suspended in isopropanol (65 ml) and anhydrous hydrazine (31.7 g, 0.988 mol) is added. The reaction mixture is heated at 70-80° C. for 2.5 hours and cooled to room temperature. The upper layer is separated and concentrated under reduced pressure. The residue is dissolved in isopropanol (50 ml) and the upper layer is separated, dried (Na2SO4), and concentrated to yield 16.5 g (94.5% yield) of 1-(3-chlorophenyl)-4-(3-hydrazinopropyl)piperazine (85% pure) as a viscous oil. The product is used directly without further purification or stored at room temperature in toluene or isopropanol solution by adding 1% MgO.