Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]2.[CH3:15][O:16][C:17]([C@@H:19]1[O:21][CH2:20]1)=[O:18].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[CH3:15][O:16][C:17](=[O:18])[CH:19]([OH:21])[CH2:20][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: COC(=O)[C@H]1CO1
Reactant: CN1C(=O)CCc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)C(O)CNc1cc(F)c2c(c1)CCC(=O)N2C
Yield: 62 %

Procedure:
6-Amino-8-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (Step 3, 2.25 g, 0.0116 mol), methyl (2R)-glycidate (1.18 g, 0.0116 mol) and lithium trifluoromethanesulfonate (1.81 g, 0.0116 mol) in acetonitrile (10 ml) are heated at 90° C. overnight. The reaction is concentrated and the residue diluted with ethyl acetate, washed with water and saline, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (50% ethyl acetate/hexane) to give the title compound as a yellow solid (2.13 g, 62%); MS (m/z): [M+H]+=297.
Reaction SMILES: C([S:3]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:7]=1)(=O)=O)C.[C:26]([N:34]=[C:35]=S)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O>C1COCC1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:14]1[C:13]([C:8]2[N:7]=[C:6]3[S:3][C:35]([NH:34][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:12][C:11]3=[CH:10][CH:9]=2)=[CH:17][N:16]([CH3:18])[N:15]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCS(=O)(=O)c1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3nc(NC(=O)c4ccccc4)sc3n2)c(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
To a solution of 2-(ethylsulfonyl)-6(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl) pyridine-3-amine (1.04 g, 2.89 mmol, 1.0 eq.) in THF under nitrogen at 0° C. was added benzoyl isothiocyanate (0.47 mL, 3.50 mmol, 1.2 eq.). The cold bath was removed, and the reaction mixture was stirred to room temperature for 20 min. It was then heated to 70° C. for 6 h. After cooling to room temperature, it was diluted with EtOAc and water. The layers were separated, and the organi layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with EtOAc afforded N-(5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine-2-yl)benzamide as a light tan solid (1.05 g, 85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:16][N:17]1[CH2:22][CH2:21][N:20](C[C@@H](NC(=O)C2C=CC(C)=CC=2)C(C)C)[CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[N+:1]([O-:3])=[O:2])[CH2:19][CH2:18]1
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reactant: O=[N+]([O-])C1=CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.5 %

Procedure:
A mixture of 1-nitrocyclohexene (311 mg, 2.45 mmol), dichlorobenzylpiperazine [prepared as described in Example 1](600 mg, 2.45 mmol), and triethylamine (512 μl, 3.68 mmol) in methylene chloride (10 ml) was stirred at room temperature under nitrogen atmosphere for 17 h. The reaction mixture was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed with hexanes/ethyl acetate (2:1) as the eluant to provide 1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (461 mg) as an oil.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:9])=[O:8])=[CH:3][CH:2]=1.[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C(N(CC)CC)C>C1COCC1>[O:26]=[C:21]1[CH2:22][CH2:23][C:24](=[O:25])[N:20]1[O:19][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:1]2[CH:6]=[CH:5][C:4]([C:7]([Cl:9])=[O:8])=[CH:3][CH:2]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)c1ccc(-c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of 1.67 g (6.0 mmol) of 11 in 65 mL of dry THF was treated with 710 mg (6.17 mmol) of N-hydroxysuccinimide, followed by 0.835 mL (6.0 mmol) of triethylamine. The reaction was stirred at room temperature for 2 hours after which time it was filtered to remove triethylamine HCl. The filtrate was concentrated at reduced pressure to yield 2.0 g (93%) of 12 as a pale yellow solid.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]1[C:22](=[O:27])[O:23][C@@H:24]([CH:25]=C)[C@H:17]1[CH2:16][CH2:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+].CSC>ClCCl.CO>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]1[C:22](=[O:27])[O:23][C@@H:24]([CH2:25][OH:1])[C@H:17]1[CH2:16][CH2:15]2)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C[C@@H]1OC(=O)N2c3ccc(OCc4ccccc4)cc3CC[C@H]12
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: O=C1O[C@@H](CO)[C@H]2CCc3cc(OCc4ccccc4)ccc3N12
Temperature: -40 °C
Reaction time: 8 h

Procedure:
Ozone is sparged for 3 h 30 min into a solution of 12.5 g (0.039 mol) of trans-7-benzyloxy-3-ethenyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 450 ml of dichloromethane and 350 ml of methanol, cooled to -40° C. The excess ozone is then stripped off with a stream of nitrogen, 14.8 g (0.39 mol) of sodium borohydride are added in small portions, followed by 12.6 g (0.195 mol) of dimethyl sulphide, and the mixture is left overnight at room temperature. It is extracted twice with dichloromethane, the organic phase is washed with water and then with saturated sodium chloride solution and dried, and the solvent is evaporated off under reduced pressure. After purification by chromatography on a column of silica, with a 95/5 mixture of dichloromethane and methanol, 10.9 g of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH2:13]O.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(CSc2ccccc2Br)c(OC)c1
Yield: 8.9 %

Procedure:
To a solution of 30.8 g (2,4,6-trimethoxyphenyl)methanol (155.4 mmol) and 29.2 g 2-bromobenzenethiol (155.4 mmol) in 150 ml DCM at 0° C. was added dropwise 1.3 eq TFA. The reaction was stirred 15 minutes at room temperature before saturated NaHCO3 was added until neutral. The organic volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3×150 ml). The organic layer was collected, washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure afforded a yellowish solid. The solid was washed with ethyl acetate to yield 51.3 g white solid (2-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (13.9 mmol, 89% yield).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[C:14]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]>C(O)CC(C)C>[C:14]([N:18]1[CH2:23][CH2:22][N:21]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: CC(C)(C)N1CCNCC1
Solvent: CC(C)CCO
Product: CC(C)(C)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-tert-butylpiperazine (72.5 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 and worked up; yield: 42 mg (28%), crystals.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=1.[NH4+:18].[OH-]>>[NH2:18][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: NC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Agent: [OH-]
Product: NC(=O)c1cnc(N)c2c1[nH]c1ccccc12
Temperature: 160 °C

Procedure:
A mixture of 1-chloro-5H-pyrido[4,3-b]indole-4-carboxamide in conc. NH4OH (0.07 M) was heated in a microwave reactor at 160° C. for 1 h in a sealed tube. The reaction mixture was cooled to room temperature and partitioned between THF/EtOAc and saturated NaHCO3. After separation of the organic phase, the aqueous phase was extracted again with THF/EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4 and filtered. After evaporation of the organic solvents, the residue was purified by flash chromatography (0-10% MeOH in EtOAc) to provide the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[C:5]([Cl:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]1[C:24](=O)[C:25](=[O:30])[C:26]=1[O:27]CC)[CH3:21]>C(O)C>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:25](=[O:30])[C:26](=[O:27])[C:23]=2[O:22][CH2:20][CH3:21])=[C:7]([OH:8])[C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10]
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2O)c(=O)c1=O
Temperature: 50 °C
Yield: 73.4 %

Procedure:
A mixture of 1.98 g (6.5 mmol, 1 eq) of 6-amino-3-chloro-2-(4-methylpiperazine-1-sulfonyl)phenol and 2.20 g (48.8 mmol, 2 eq) of 3.4-diethoxy-3-cyclobutene-1,2-dione in solution in 20 ml of ethanol. The reaction medium was heated at 50° C. for 16 hours. The insoluble material was filtered off, washed with ethanol and dried under vacuum at 45° C. 2.05 g of 3-[4-chloro-2-hydroxy-3-(4-methylpiperazine-1-sulfonyl)phenylamino]-4-ethoxycyclobut-3-ene-1,2-dione were obtained in the form of a yellow solid. Yield=74%.
Reaction SMILES: CS(O)(=O)=O.[CH:6]1([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:28])[C:17]3[NH:22][C:21](=[O:23])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:7]1.[OH2:29].[CH:30]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:25][C:24]([F:27])([F:26])[C:20]([OH:35])=[O:29].[CH:30]1([O:28][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([S:9][CH:6]3[CH2:8][CH2:7]3)=[CH:11][CH:12]=2)[C:17]2[NH:22][C:21](=[O:23])[C:20]([C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=c1[nH]c(C(O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Reactant: O
Reactant: OC1CCCC1
Agent: CS(=O)(=O)O
Product: O=C(O)C(F)(F)F
Product: O=c1[nH]c(C(OC2CCCC2)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
Methanesulfonic acid (250 μL) was added to a solution of 6-{[4-(cyclopropylsulfanyl)phenyl](hydroxy)methyl}-3-(trifluoromethyl)pyridin-2(1H)-one (40 mg) in cyclopentanol (500 μL), and the mixture was stirred at 100° C. for six hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire 19×150 mm 5 μm, rate: 20 mL/min, eluent: A=acetonitrile, B=0.1% trifluoroacetic acid solution, gradient: 10 to 90%) to give the title compound as a colorless amorphous (25 mg, 52%).
Reaction SMILES: Cl[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[Na].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:2]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Agent: [Na]
Product: N#Cc1ccc(C(CCc2ccc(F)cc2)n2ccnc2)cc1

Procedure:
1-[1-(4-cyanophenyl)-3-(4-fluorophenyl)propyl]-1H-imidazole is prepared according to the same procedure using 1-chloro-1-(4-cyanophenyl)-3-(4-fluorophenyl)propane and 1H-imidazole sodium derivative as starting materials.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:18]([O:20]C)=O.Cl.[CH3:23][O:24][C:25](=[O:31])[C@H:26]([CH:28]([CH3:30])[CH3:29])[NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:29][CH:28]([CH3:30])[C@H:26]([N:27]1[CH2:2][C:3]2[C:4](=[CH:5][C:6]([C:9]3[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)=[CH:7][CH:8]=2)[C:18]1=[O:20])[C:25]([O:24][CH3:23])=[O:31]
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O

Procedure:
A mixture of the compound of example 4 (1.54 g, 0.0044 mol) and L-valine methyl ester hydrochloride (0.813 g, 0.0048 mol) was taken in toluene (30 mL) in a round bottom flask. To this reaction mixture, triethyl amine (0.98 g, 0.0097 mol) was added and refluxed for 3-4 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain an oily material, which was purified by column chromatography (silicagel, 30% ethyl acetate in petroleum ether).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.Cl>C(O)C>[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 20g 2-chloro-5-nitrobenzoic acid, 28.6g methyl octadecylamine and 20 ml triethylamine was heated on a steam bath for 6 hours. The resulting solid was dissolved in aqueous ethanol, and then 6N HCl was added to give a pH of 3. The product was filtered and recrystallized from ethanol and then from acetone. m.p. = 108°-109°.
Reaction SMILES: O.NN.[CH3:4][C:5]([CH3:28])([CH3:27])[CH2:6][C:7]([C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][CH:10]=1)=[O:8]>CO>[CH3:4][C:5]([CH3:28])([CH3:27])[CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:25][CH:26]=1)=[O:8]
Reactant: CC(C)(C)CC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)CC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Add hydrazine hydrate (0.189 mL, 3.913 mmol) to a stirred suspension of 2-[4-(3,3-dimethyl-butyryl)-benzyl]-isoindole-1,3-dione (875 mg, 2.609 mmol) in methanol (15 mL). Heat the mixture to reflux overnight. Cool the mixture to room temperature and concentrate in vacuo. Partition the residue between EtOAc and 5N aqueous HCl and wash the acidic aqueous phase again with 5N aqueous HCl. Basify with 5N aqueous NaOH to pH 12. Extract the basic aqueous solution three times with chloroform. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the title compound as a yellow oil (411 mg, 77%) that was used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:12]1[NH:13][C:14]([C:16]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:17]=3Br)=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([Cl:27])=[CH:6][C:5]2=1.[C:28]([Cu])#[N:29].[CH3:31][N:32](C=O)C>[Cl-].[Na+].O.C(OCC)(=O)C>[Br:1][C:2]1[CH:26]=[C:25]2[C:24](=[CH:4][CH:3]=1)[C:12]1[NH:13][C:14]([C:16]3[C:17]([C:28]#[N:29])=[CH:18][CH:19]=[CH:20][C:21]=3[C:31]#[N:32])=[N:15][C:11]=1[C:10]1[CH:5]=[CH:6][C:7]([Cl:27])=[CH:8][C:9]2=1
Reactant: N#C[Cu]
Reactant: Clc1ccc2c(c1)c1cc(Br)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(C#N)c1-c1nc2c3ccc(Cl)cc3c3cc(Br)ccc3c2[nH]1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 26 g of 9-bromo-6-chloro-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole from Step 4 in 200 mL of dry DMF, was added 14.2 g of CuCN. The reaction was stirred overnight at 85° C., cooled down to room temperature, brine was added and the mixture stirred for 30 minutes. The solution was diluted in ethyl acetate, washed with 10% ammonium hydroxide, brine, dried over sodium sulphate and volatiles were removed under reduced pressure to afford 26 g of 2-(9-bromo-6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile as a solid. 1H NMR (Acetone-d6): 9.19 (s, 1H), 9.02 (s, 1H), 9.71 (bs, 1H), 8.49 (bs, 1H), 8.39 (d, 2H), 8.07 (t, 1H), 7.97 (d, 1H), 8.81 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH:11]1[C:19]2[N:18]3[C:20]([CH:23]4[CH:27]([CH3:28])[CH2:26][CH:25]([NH2:29])[CH2:24]4)=[CH:21][N:22]=[C:17]3[CH:16]=[N:15][C:14]=2[NH:13][CH:12]=1>CN(C=O)C>[CH:11]1[C:19]2[N:18]3[C:20]([C@@H:23]4[C@H:27]([CH3:28])[CH2:26][C@H:25]([NH:29][S:5]([CH2:4][CH2:3][C:2]([F:10])([F:9])[F:1])(=[O:7])=[O:6])[CH2:24]4)=[CH:21][N:22]=[C:17]3[CH:16]=[N:15][C:14]=2[NH:13][CH:12]=1
Reactant: CC1CC(N)CC1c1cnc2cnc3[nH]ccc3n12
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NS(=O)(=O)CCC(F)(F)F)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 144 h
Yield: 5.1 %

Procedure:
3,3,3-Trifluoropropane-1-sulfonyl chloride (0.194 g, 0.987 mmol, Matrix) was added dropwise to a solution of TEA (0.31 mL, 2.2 mmol) and 3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine (0.28 g, 1.1 mmol, Preparation #53) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for about 144 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water (20 mL each). The layers are separated and the organic layer was washed with brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified by using General Procedure AA (Table 2, Method 9, Rt=17.7 min, or =negative) to give N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (0.021 g, 4.6%) as a white solid: LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z 416 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:12])[CH:3]=1.[CH3:13][C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>O1CCOCC1>[CH:9]([N:5]1[C:4](=[O:12])[CH:3]=[C:2]([NH:21][C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[NH:7][C:6]1=[O:8])([CH3:11])[CH3:10]
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Reactant: C[C@H](N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)n1c(=O)cc(N[C@@H](C)c2ccccc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 1.0 g, 5.31 mmol) in 1,4-dioxane (20 mL) was added (S)-α-methylbenzylamine (Sigma-Aldrich, 1.43 g, 11.7 mmol, 2.2 equiv). The reaction mixture was stirred at 80° C. for 24 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residual was taken up in EtOAc (70 mL) and washed with aqueous 1N HCl (2×50 mL) and brine (40 mL). The organic layer was dried with anhydrous Na2SO4 and then concentrated under reduced pressure to half the original volume to yield a precipitate. Hexane (20 mL) was added and the mixture was stirred at room temperature. The resulting solid was collected by filtration, washed with hexane (20 mL), and dried to yield 1.0 g (69%) of the title compound as a white solid. LC/MS: m/z (ES+) 274 (M+H)+.1H-NMR (400 MHz, d6-DMSO): δ 9.77 (s, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 6.50 (d, J=6.8 Hz, 1H), 4.87 (m, 1H), 4.52 (m, 1H), 4.31 (d, J=6.8 Hz, 1H), 1.37 (m, 3H), 1.24 (m, 6H). 1H NMR (400 MHz, CD3OD) δ ppm 7.39-7.20 (m, 5H), 5.01 (m, 1H), 4.48 (m, 1H), 1.49 (d, J=6.7 Hz, 3H), 1.36 (m, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1.CN(C)[CH:37]=[O:38]>O1CCCC1.CCCCCC>[F:13][C:14]1[C:19]([CH:37]=[O:38])=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1
Reactant: CN(C)C=O
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)n2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(C=O)c(F)n2)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
2.55 ml (18.2mmol) of diisopropylamine in 30 ml of tetrahydrofuran are stirred at 0° C. with 11.4 ml (18.2mmol) of a 1.6-molar n-butyllithium solution in hexane for one hour. After addition of 170 ml of tetrahydrofuran and cooling to -78° C., 3.64 g (12.1 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine (prepared as described in EXAMPLE 2) in 90 ml of tetrahydrofuran are added dropwise, and the mixture is stirred at -78° C. for 4 hours. 1.86 ml (24.2mmol) of N,N-dimethylformamide are then added dropwise at -78° C., and the reaction mixture is stirred overnight, during which it warms to room temperature. For workup, the mixture is poured onto sodium chloride solution, the resulting mixture is extracted with ether, the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, CH2Cl2) gives 2.20 g of 2-fluoro-3-formyl-6-(4-octyloxyphenyl)pyridine. ##STR62##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[N:10][C:11]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:18]3=[O:25])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]([N:39]([CH2:41][C:42](O)=[O:43])[CH3:40])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[Cl:31][C:28]1[S:27][C:26]([C:9]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][N:39]([CH3:40])[C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:12]=[C:11]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[N:10]=2)=[CH:30][CH:29]=1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(N)c2)c(-c2ccc(Cl)s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CC(=O)Nc1cccc(-c2cnc(NCCN3C(=O)NC(=O)C3(C)C)nc2-c2ccc(Cl)s2)c1)C(=O)OC(C)(C)C

Procedure:
A solution of 50 mg (0.11 mmol) of 1-{2-[5-(3-aminophenyl)-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione, 31 mg (0.16 mmol) of N-Boc-sarcosine, 31 mg (0.16 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.1 mg (0.01 mmol) of 4-dimethylaminopyridine and 0.057 mL (0.33 mmol) of N,N-diisopropylethylamine in 1 mL of CH2Cl2 was stirred for 18 h at rt. The reaction solution was poured into 75 mL of EtOAc and washed thrice with 2% (w/v) aqueous HCl, once with a saturated aqueous solution of NaHCO3, then with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with a linear gradient of neat EtOAc to 10% MeOH in EtOAc to yield the title compound. MS (M+H)+ 628.