Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([N:9]=[C:10](OCC)[CH2:11][C:12]#[N:13])#[N:8]>CO>[C:7]([N:9]=[C:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:11][C:12]#[N:13])#[N:8]
Reactant: C1CCNCC1
Reactant: CCOC(CC#N)=NC#N
Solvent: CO
Product: N#CCC(=NC#N)N1CCCCC1
Temperature: 0 °C
Yield: 101.6 %

Procedure:
Piperidine (25.67 g, 0.0302 m) is added dropwise to an ice-cooled solution of 41.36 g (0.0302 m) of ethyl N, 2-dicyanoacetimidate in 60 ml of methanol. The reaction is heterogeneous initially, but soon becomes homogeneous and yellow. The piperidine is added at a rate that maintains a 25° C. reaction temperature. After fifty minutes, the reaction mixture is partitioned between CH2Cl2 and aqueous saturated NaHCO3. The organic phase is dried over Na2SO4 and concentrated in vacuo to give 54 g of a yellow oil which by tlc appears to be pure product. Nmr confirms the presence of product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(c1ccc(CO)cc1)c1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of oxalyl chloride (2.7 mL, 30.58 mmol) in dichloromethane (73 mL) at −78° C. under nitrogen was added dimethylsulfoxide (4.4 mL, 56.88 mmol) over 30 minutes. The mixture was stirred vigorously for a further 30 minutes then a solution of {4-[(2-bromophenyl)sulfonyl]phenyl}methanol (Step 3, 4.0 g, 12.23 mmol) in dichloromethane (24 mL) was added over 15 minutes. The reaction was stirred at −78° C. for 1 hour. Triethylamine (11.99 mL, 85.61 mmol) was added and stirring continued at −78° C. for 1 hour then the reaction was allowed to warm to room temperature. The pale yellow solution was diluted with dichloromethane, washed with sodium hydrogencarbonate solution, water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 30% ethyl acetate/isohexane, to give 4-[(2-bromophenyl)sulfonyl]benzaldehyde (3.41 g, 85%). δH (400 MHz, d6 DMSO): 10.09 (1H, s), 8.37 (1H, dd, J=1.7, 7.9 Hz), 8.10 (4H, s), 7.83 (1H, dd, J=1.2, 7.9 Hz), 7.75 (1H, td, J=1.4, 7.7 Hz), 7.66 (1H, td, J=1.8, 7.7 Hz).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]=1)([CH3:3])[CH3:2].O.[C:13]1(=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[C:14]1=[O:23]>C(Cl)(Cl)Cl>[OH:24][C:13]12[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]1([OH:23])[C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=1[N:4]2[CH:1]([CH3:3])[CH3:2]
Reactant: O=c1c(=O)c2ccccc2c1=O
Reactant: CC(C)NC1=CC(=O)CCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)N1C2=C(C(=O)CCC2)C2(O)C(=O)c3ccccc3C12O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Equimolar amounts of 3-isopropylaminocyclohex-2-enone and indanetrione hydrate (ninhydrin) were dissolved in chloroform and stirred at room temperature for 12 h. The solvent was then stripped off, and the oily residue was crystallized from acetone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[CH2:13][O:12][CH2:11][CH2:10][NH:9][CH2:8]1.Cl.[F:15][C:16]1[C:22](F)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1.O>CN(C=O)C>[F:15][C:16]1[C:22]([N:9]2[CH2:8][CH2:7][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: C1CNCCOC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N2CCCOCC2)c(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 88.7 %

Procedure:
19.4 g of potassium carbonate and 11.9 g of homomorph-oline hydrochloride are added to a solution of 5 g of 4,5-difluoro-2-nitroaniline in 98 mL of anhydrous DMF. The reaction medium is heated at 80° C. using an oil bath for 2 hours. The reaction medium is cooled to ambient temperature, then 300 mL of water are added thereto, and precipitation occurs. The precipitate is filtered through sintered glass. The yellow solid is rinsed with 3 times 100 mL of water. The solid is dried in an oven at 70° C. 6.5 g of 4-fluoro-2-nitro-5-perhydro-1,4-oxazepin-4-ylphenylamine are obtained in the form of an orange solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.91 (m, 2H); from 3.52 to 3.61 (m, 4H); 3.66 (m, 2H); 3.74 (m, 2H); 6.28 (d, J=8.5 Hz, 1H); 7.24 (broad s, 2H); 7.61 (d, J=15.5 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:15]([CH:16]=1)[C:21]#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 1 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organic layers were separated and dried over sodium sulfate and concentrated in vacuo. The product used without further purification.
Reaction SMILES: Br[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]([C:14]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]=1[OH:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[C:15](=[O:16])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19]([OH:21])([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH:20]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: BrCOc1ccccc1
Product: COc1ccccc1C1(O)C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1

Procedure:
Using the method described in Example 1, 2-bromomethoxybenzene is reacted with 2,6-di(t-butyl)hydroquinone to provide 2,6-di(t-butyl)-4-hydroxy-4-(2'-methoxyphenyl)-2,5-cyclohexadienone. This product is dissolved in ethanol and reduced with hydrogen gas on a Parr apparatus using palladium on charcoal as the catalyst. The white solid product is recrystallized from benzene to provide 2,6-di(t-butyl)-4-(2'-methoxyphenyl)phenol, m.p. 98.5°-100° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42]>C(Cl)Cl>[Si:16]([O:15][CH2:14][C@@H:2]([NH:1][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
tert-Butyl (4S)-4-amino-5-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate (3.76 g, 11.3 mmol) was dissolved in 100 mL of dry CH2Cl2 and the solution was cooled to 0° C. under N2. Triethylamine (3.10 mL, 22.3 mmol) and 4-chloro-3-nitroquinoline (2.36 g, 11.3 mmol) were then added and the reaction was allowed to warm to ambient temperature and stirred for 2 days. The reaction mixture was then concentrated under reduced pressure to give a yellow solid. The solid was dissolved in 200 mL of CH2Cl2 and was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give yellow solid. Chromatography (SiO2, 20-35% ethyl acetate/hexanes) gave tert-butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[(3-nitroquinolin-4-yl)amino]pentylcarbamate (5.65 g) as a yellow syrup.
Reaction SMILES: [CH2:1]([C@H:8]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[C@@H:9](OS(C)(=O)=O)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl>O1CCCC1.ClCCl.O>[C:2]1([CH2:1][C@@H:8]([C@H:9]2[CH2:10][O:11]2)[N:17]2[C:18](=[O:27])[C:19]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]3[C:21]2=[O:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H](CO)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 20 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
2.16 g of N-[1(S)-benzyl-3-hydroxy-2(R)-(methylsulphonyloxy)propyl]phthalimide were added to a stirred suspension of 200 mg of sodium hydride (80% dispersion in mineral oil) in 50 ml of dry tetrahydrofuran and the mixture was stirred at 20° C. for 2 hours. A further 100 mg of sodium hydride were added and the stirring was continued for 3.5 hours. The mixture was diluted with dichloromethane and water and the pH of the aqueous layer was adjusted to 7 by adding 2M hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution and evaporated. The residue was chromatographed on silica gel using ethyl acetate/n-hexane (1:2) for the elution to give 0.67 g of 2(S)-[2-phenyl-1(S)-phthalimidoethyl]oxirane as a white solid, MS: m/e 294 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]([CH3:22])=[CH:9][N:8]=1)(=O)=O.[SH:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>C(O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][C:11]1[C:10]([CH3:22])=[CH:9][N:8]=[C:7]([CH2:6][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)[C:12]=1[CH3:13]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COCCOCCOc1c(C)cnc(COS(C)(=O)=O)c1C
Solvent: CCO
Product: COCCOCCOc1c(C)cnc(CSc2nc3ccccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A mixture comprising 3.0 g of {4-(2-methoxyethoxy)ethoxy-3,5-dimethylpyridine-2-yl}methyl methanesulfonate, 1.17 g of 2-mercaptobenzimidazole and 30 ml of ethanol was stirred at a room temperature for one hour and distilled to remove the ethanol. The residue was purified by silica gel column chromatography to obtain 0.8 g of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl.[Br:14][C:15]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([OH:25])=[CH:17][CH:16]=1.Cl[CH2:27][O:28][CH3:29]>O>[Br:14][C:15]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][CH2:27][O:28][CH3:29])=[CH:17][CH:16]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: COCCl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(Br)nc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Diisopropylethylamine (1.46 mL) was added to a chloroform (20 mL) solution of methyl 6-bromo-3-hydroxypyridine-2-carboxylate (970 mg) and placed in a nitrogen atmosphere. Next, the reaction mixture was cooled to 0° C., and chloromethoxymethane (0.38 mL) was added thereto. The reaction mixture was stirred at 0° C. for 5 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., diluted with water, and extracted with chloroform. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (1.22 g, yield: 100%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[CH:29]=1>>[CH3:35][C:30]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:6][CH:7]=2)[CH:33]=[C:32]([CH3:34])[N:31]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method tR=1.228, m/z=445; 1H NMR (CDCl3) 1.32 (m, 1H) 1.51 (d, 3H), 1.60-1.72 (m, 1H), 1.86-2.02 (m, 2H), 2.19 (m, 1H), 2.25-2.39 (m, 2H), 2.79 (s, 6H), 2.93 (m, 1H), 3.50 (t, 2H), 5.64 (m, 1H), 7.00 (d, 2H), 7.21 (m, 2H), 7.29 (m, 2H), 7.32 (m, 3H), 7.40 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:63][OH:64])C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:63][OH:64])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=440, obsd.=440).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:35][C:36](=[O:45])[NH:37][CH:38]1[CH2:43][CH2:42][CH:41](O)[CH2:40][CH2:39]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([NH:37][CH:38]1[CH2:43][CH2:42][CH:41]([O:12][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:9]=2)[CH2:40][CH2:39]1)=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: O=C(NC1CCC(O)CC1)OCc1ccccc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)OC3CCC(NC(=O)OCc4ccccc4)CC3)c2)cc1
Yield: 48.6 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.0 g (2.8 mmol) and (4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (0.69 g, 2.8 mmol) were used to afford 0.8 g of the required product. 1H NMR (DMSO-d6): δ 1.21 (4H, m), 1.32 (4H, m), 3.12 (1H, m), 3.32 (1H, m), 4.51 (2H, s), 5.21 (2H, s), 7.3 (10H, m), 7.89 (2H, d).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([N:15]([CH:18]([CH3:20])[CH3:19])[CH:16]=O)[C:3]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH:14]1[C:3]2=[C:2]([CH3:1])[C:10]3[C:5]([N:4]2[CH2:11][CH2:12][CH2:13]1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: Cc1c2n(c3ccccc13)CCCC2N(C=O)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)CCCC2N(C)C(C)C

Procedure:
A solution of N-(6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-yl)-N-(1-methylethyl)formamide (37.1 mmol) in tetrahydrofuran (50 mL) was added dropwise at 25° C. to a suspension of lithium aluminum hydride (1,6 g, 42.1 mmol) in the same solvent (50 mL). The reaction mixture was refluxed overnight under the exclusion of moisture. The metal complex was decomposed with a solution of water (3 mL) in the (20 mL) under nitrogen. The resulting suspension was filtered and the filtrate evaporated in vacuo. The residue was dissolved in CHCl3 (100 mL), dried over MgSO4, filtered, and evaporated in vacuo. The oily residue was chromatographed on silica gel (200 g). Elution with 2% MeOH in CHCl3 afforded the title base.
Reaction SMILES: [CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[C:13]([N:15]4[CH2:20][CH2:19][C:18]5([O:24][CH2:23][CH2:22][O:21]5)[CH2:17][CH2:16]4)[N:12]=[C:11](Cl)[N:10]=3)[CH2:5][CH2:4]2)[O:2]1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[C:13]([N:15]4[CH2:20][CH2:19][C:18]5([O:24][CH2:23][CH2:22][O:21]5)[CH2:17][CH2:16]4)[N:12]=[C:11]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:10]=3)[CH2:5][CH2:4]2)[O:2]1
Reactant: Clc1nc(N2CCC3(CC2)OCCO3)cc(N2CCC3(CC2)OCCO3)n1
Reactant: C1CNCCN1
Product: c1c(N2CCC3(CC2)OCCO3)nc(N2CCNCC2)nc1N1CCC2(CC1)OCCO2
Yield: 58.9 %

Procedure:
The reaction of 4,6-bis(4,4-ethylenedioxy-1-piperidinyl)-2-chloropyrimidine with piperazine as described in Example 4 gives the title compound in a yield of 58.9%, m.p.: 122°-126° C.
Reaction SMILES: Br[C:2]1[O:14][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]([CH3:13])[CH3:12])[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC1(C)C(C)(C)OB([C:29]2[CH:42]=[CH:41][C:32]([O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[CH:11]([NH:10][C:9]1[C:4]2[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:41][CH:42]=3)[O:14][C:5]=2[N:6]=[CH:7][N:8]=1)([CH3:13])[CH3:12]
Reactant: CC(C)Nc1ncnc2oc(Br)c(-c3ccccc3)c12
Reactant: CC1(C)OB(c2ccc(OCCN3CCCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Nc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Temperature: 75 °C

Procedure:
Into a 16×100 mm vial sparged with argon was placed 6-bromo-N-isopropyl-5-phenylfuro[2,3-d]pyrimidin-4-amine (100 mg, 0.301 mmol), 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)pyrrolidine (120 mg, 0.361 mmol), palladium tetrakistriphenylphosphine (17 mg, 0.015 mmol), potassium carbonate (125 mg, 0.903 mmol), DME (4 mL), and water (1 mL). The vial was sealed and heated to 75° C. for 24 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc2cc(Cl)cc(S(=O)(=O)Cl)c2n1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1ccc2cc(Cl)cc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-6-chloroquinoline-8-sulfonyl chloride (500 mg, 1.8 mmol), 4-aminobenzoic acid (300 mg, 2.2 mmol) and pyridine (1 mL) in 10 mL of THF was stirred at 30° C. overnight, when LCMS indicated that the reaction was complete. The resulting mixture was concentrated, and the residue was purified by a standard method to yield the title compound. LCMS (m/z): 378.8 (M+1)+
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:11]([S:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:13])[CH3:12].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH:11]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]ccc3n2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
2-bromo-5H-pyrrolo[2,3-b]pyrazine (6.5 g, 32.82 mmol), (4-isopropylsulfonylphenyl) boronic acid (7.859 g, 34.46 mmol) and palladium triphenylphosphane complex (1.896 g, 1.641 mmol) were combined in a round bottomed flask. To this mixture was added dioxane (97.50 mL) and then an aqueous solution of Na2CO3 (49.23 mL of 2 M, 98.46 mmol). The resulting suspension was stirred at 100° C. overnight, then heating was stopped and water added. The resultant precipitate was collected and dried in vacuo at 40° C., to give the sub-title compound as a brown solid (9.45 g, 95% yield). 1H NMR (400.0 MHz, DMSO) δ 12.25 (s, 1H), 9.00 (s, 1H), 8.43 (d, J=8.4 Hz, 2H), 7.99-7.96 (m, 3H), 6.74 (d, J=3.5 Hz, 1H), 3.57 (s, 1H) and 1.20 (d, J=6.8 Hz, 6H) ppm; MS (ES+) 435.2.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20](I)[CH:19]=3)[N:12]([CH3:27])[C:11]2=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31]B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH3:31])[CH:19]=3)[N:12]([CH3:27])[C:11]2=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Temperature: 80 °C
Yield: 64.6 %

Procedure:
1-(4-tert-Butyl-benzyl)-4-[3-(3-iodo-4-methoxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.300 g, 0.580 mmole), methyl boronic acid (0.069 g, 1.16 mmole) and cesium carbonate (0.264 g, 1.74 mmole) are mixed in dioxane (6.0 mL). After bubbling with nitrogen for 15 minutes, 1,1′-bis(diphenylphosphino)ferrocence palladium (II) chloride (0.060 g, 0.015 mmole) is added. The reaction is heated at 80° C. for 4 hours. The solvent is removed on rota-vapor, and the crude product is purified by column chromatography (silica gel, gradient elution 0-20% acetone in hexane) to provide a yellow oil (0.153 g, 65%). Mass [EI+] 409 (M+H)+, 817(M+H)+.