Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:42])[C@H:5]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[NH:6][C:7](=[O:34])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]3[CH2:30][CH2:29][C:28]4[N:27]=[C:26]([CH3:31])[NH:25][C:24](=[O:32])[C:23]=4[C:22]=3[CH:33]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1)C.Cl>>[CH3:31][C:26]1[NH:25][C:24](=[O:32])[C:23]2[C:22]3[CH:33]=[C:18]([S:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:42])=[O:3])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:34])=[CH:9][CH:10]=4)(=[O:16])=[O:17])[CH:19]=[CH:20][C:21]=3[CH2:30][CH2:29][C:28]=2[N:27]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2ccc3c(c2)-c2c(nc(C)[nH]c2=O)CC3)cc1)C(=O)OCC
Agent: Cl
Product: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Nc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)ccc1CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
Diethyl-N-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxobenzo [f]quinazolin-9-yl)sulfonamido) benzoyl)-L-glutamate (4.53 g, 7.6 mmole) was dissolved in N-NaOH (64 ml) and the solution stirred at room temperature for 4 hours. The pH of the solution was adjusted to 3.00 with 1N HCl, the solid collected by filtration, washed with water and dried under high vacuum to yield the product as an off-white solid (3.94 g 96%). 1HNMR (DMSO-d6,300 MHz) δ: 1.84-1.96 (m,1H,glu CH); 2.00-2.10 (m, 1H, glu CH); 2.32(s, 3H, CH3, superimposed over t, 2H, glu CH2); 2.71 (m, 2H, Ar CH2); 2.89 (m, 2H, Ar CH2); 4.28-4.36 (m, 1H, glu CH), 7.20 (d, J=9 Hz, 2H, Ar); 7.39 (d, J=8 Hz, 1H, Ar); 7.62 (dd, J=8.2 Hz, 1H, Ar); 7.74 (d, J=9Hz, 2H, Ar); 8.44 (d, J=8 Hz, 1H, gluNH); 9.21 (d, J=2Hz, 1H, Ar); 10.73 (s, 1H, SO2NH); 12.36 (br s, 2H, CO2H); 12.72 (br s, 1H, NH). Anal Calculated for C25H24N4O8S. 3/2H2O: C,52.91; H,4.79; N,9.87; S,5.65. Found: C,52.98; H,4.78; N,9.87; S,5.58.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[C:7]([CH3:10])[C:8]=1[CH3:9].[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:6]1[N:5]=[N:4][C:3]([Cl:2])=[C:8]([CH3:9])[C:7]=1[CH3:10])[CH3:13]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: CCO
Agent: [Na]
Product: CCOc1nnc(Cl)c(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.69 g(0.03 mol) of metallic sodium was dissolved in 100 ml of absolute ethanol and then 5.31 g(0.03 mol) of 3,6-dichloro-4,5-dimethylpyridazine was added thereto and completely dissolved. The reaction solution was stirred for 4 hours at room temperature and then treated according to the same manner as Preparation 5 to obtain the title compound as a pale white crystal.
Reaction SMILES: Br.Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:20])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:21]>CO>[CH3:18][CH:17]([CH3:19])[CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:21])[C:12]=2[N:13]=[C:14]1[NH2:20]
Reactant: CC(C)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Reactant: N
Agent: Br
Solvent: CO
Product: CC(C)Cn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-amine hydrobromide (8.61 g) and ammonia (131 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. The resulting solution was concentrated under reduced pressure to provide 7 g of crude product. A portion of the product was purified by flash chromatography on silica gel (eluting with 3-4% methanol in dichloromethane with 1% ammonium hydroxide added.) The isolated product was washed with methanol, purified again by flash chromatography using the same conditions, and dried under high vacuum to provide 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as a gray, crystalline solid, mp >250° C. Anal. calcd. for C14H17N5: C, 65.68; H, 6.71; N, 27.43. Found: C, 65.69; H, 6.79; N, 27.42.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:21])[C:3]=1[CH:22]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:31][C:32]#[N:33])C=CC=CC=1>C(#N)C>[NH2:33][C:32]1[CH:31]=[CH:22][C:3]2[C:4](=[O:21])[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6](=[O:14])[N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]=2[N:1]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1c(C=O)c(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Solvent: CC#N
Product: Nc1ccc2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c2n1
Yield: 44.6 %

Procedure:
A solution of 6-amino-5-formyl-1,3-diphenyluracil (5.0 g, 16.3 mmol) and 2-(triphenylphosphoranylidene)acetonitrile (5.9 g, 19.6 mmol) in anhydrous acetonitrile (100 mL) was heated to reflux for 24 hours in an argon stream. The reaction mixture was allowed to cool and the solvent was evaporated therefrom in vacuo. The crude crystals separated out therefrom were recrystallized from benzene to give 7-amino-1,2,3,4-tetrahydro-1,3-diphenylpyrido[2,3-d]pyrimidine-2,4-dione (2.4 g) in a 45% yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:37][NH2:38]>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:38][CH3:37])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CN
Reactant: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)CC1
Temperature: 65 °C

Procedure:
A solution of 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-1-piperidyl]propan-1-one and Na2CO3 (114 mg, 1.1 mmol) in tetrahydrofuran was treated with a solution of methylamine (1.3 mL of 2 M, 2.5 mmol) in THF and heated at 65° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via reverse phase HPLC (1-50% CH3CN/5 mM HCl) to provide 1-(4-(5-amino-6-(5-(4-((methylamino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)piperidin-1-yl)propan-1-one.
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)C=C.[CH:16]1[CH:21]=CC=C[CH:17]=1>>[CH3:15][CH:6]([CH:7]([C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)[C:16]([CH3:21])=[CH2:17])[CH:5]=[O:4]
Reactant: c1ccccc1
Reactant: C=CCOC/C(C)=C/c1ccc(C)cc1
Product: C=C(C)C(c1ccc(C)cc1)C(C)C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
The 1-[(1E)-3-(Allyloxy)-2-methyl-1-propenyl]-4-methylbenzene (72.7 g, 0.359 mol), [RuCl2(PPh3)3] (1.1 g), BHT (50 mg) and benzene (250 ml) were heated together in an autoclave placed in an oil bath at 165-170° C. for 24 hours. After cooling to room temperature, the benzene was evaporated under vacuum and the residue chromatographed on silica gel (eluent: heptanes/ethyl acetate 25:1 to 4:1), then distilled under vacuum through a 20-cm Widmer column. 21.3 g of the desired product were obtained (yield=29%) as a 40:60 mixture of diastereoisomers. B.P.=95° C./0.001 mbar
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (3.7 g, 29 mmol) and pyridine (7.3 mL, 90 mmol) in dichloromethane was added 2-nitrobenzoyl chloride (5.7 g, 30 mmol). After stirring for 4 h, the solvents were removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. After standing at room temperature overnight, the mixture was filtered to give 6.4 g (79%) of a white solid.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH:23]([OH:25])[CH3:24])=[CH:18][C:17]=3[Cl:26])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:17]1[CH:18]=[C:19]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:40]#[C:39][C:37]([OH:41])([CH3:38])[CH3:36])[CH:28]=[CH:27][C:5]=2[N:6]=1
Reactant: CC(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)c1cc(Cl)c(Nc2nc3ccc(C#CC(C)(C)O)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 65 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (292 mg, 0.61 mmol) in DMF (3 mL) were added triethylamine (0.255 mL, 1.83 mmol), copper iodide (23 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol), and 2-methyl-3-butyn-2-ol (0.179 mL, 1.83 mmol). The solution was degassed by bubbling nitrogen gas and heated to 65° C. for 14 hr. The solution was diluted with EtOAc and washed with water, dried with Na2SO4, filtered, and concentrated under reduced pressure. Purification with column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) provided 5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}-9-(3-hydroxy-3-methylbut-1-yn-1-yl)benzo[c]-2,6-naphthyridin-1(2H)-one as a mixture of enantiomers. The enantiomers were separated on Chiral Technology AD 2×25 cm column at 12 mL/min using 1:1 iPrOH/Heptane in a 25 min run. First enantiomer has a retention time of 7.57 min and the second enantiomer has a retention time of 15.74 min. For both enantiomers: 1H NMR (500 MHz, CD3OD) δ 9.80 (d, 1H), 7.60 (d, 1H), 7.50-7.40 (m, 3H), 7.34 (d, 1H), 3.90 (m, 1H), 1.48 (s, 3H), 1.47 (s, 3H), 1.12 (d, 3 H). LRMS (ESI) calc'd for C25H22Cl2N3O3 [M+H]+, 482.1; found 482.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Br)cc1)n1cccc1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
Pyrrole (1.05 mL, 15.0 mmol) was added to a slurry of sodium hydride (0.71 g, 60% in mineral oil, 17.8 mmol) in dry THF (10 mL) at room temperature. 4-Bromobenzene sulfonyl chloride (1.5 g, 6.0 mmol) dissolved in dry THF (5 mL) was added dropwise. The reaction mixture was stirred overnight. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified via Isco chromatography (the Redisep™ column, silica, gradient 5-50% ethyl acetate in hexane) to give 1-[(4-bromophenyl)sulfonyl]-1H-pyrrole (0.27 g, 16%). MS (ESI) m/z 286. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:22][C:23]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C#N)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(C#N)cc21
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (101.4 mg, 28.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 362.2.
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH3:5][C:6]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:7][CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH2:11]([C:10]([OH:13])([CH2:9][CH2:8][CH:7]=[C:6]([CH3:5])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH:2]=[CH2:3])[CH3:12]
Reactant: C=CBr
Reactant: CCC(=O)CCC=C(C)CC(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(O)(CC)CCC=C(C)CC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Grignard solution, prepared from 12.5 g. of magnesium and 57.8 g. of vinyl bromide in 130 ml. of tetrahydrofuran, is slowly added dropwise at 0°-5° C. a solution of 40.11 g. of 7,9-dimethyl-6-decen-3-one in 90 ml. of tetrahydrofuran. The mixture is left to stir for 2 hours at room temperature, then poured on to 300 ml. of ice-water, acidified with dilute sulphuric acid and extracted three times with ether. The extracts are washed with 10% by weight aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3-ethyl-7,9-dimethyl-1,6-decadien-3-ol; nD24 = 1.4631; boiling point - 71° C./0.65 mm Hg.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19](OCC)=[O:20].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[NH2:34][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:19]([C:3]1[C:4](=[O:18])[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:20])(=[O:32])=[O:33]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCC1(CCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCC1(CCC)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A suspension of the product of Example 1F (490 mg, 1.55 mmol) and 2-aminobenzenesulfonamide (Aldrich) (267 mg, 1.55 mmol) in toluene (25 mL) was stirred at reflux for 18 hours, cooled to 25° C. and concentrated in vacuo. The residue was recrystallized from ether-hexane solution to afford the title compound (410 mg, 60%). 1H NMR (300 MHz, CDCl3): δ 17.76 (d, J=12.13 Hz, 1 H), 12.67 (s, 1 H), 8.34 (m, 1 H), 8.09, (dd, J=8.09, 1.47 Hz, 1 H), 7.63 (m, 1 H), 7.38 (m, 3 H), 6.83 (m, 1 H), 5.57 (s, 2 H), 4.85 (s, 1 H), 2.32 (m, 2 H), 1.93 (m, 2 H), 0.97 (m, 2 H), 0.68 (m, 8 H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:26][C:25]=3[CH3:37])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCNCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[C:14]([CH3:16])[N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C1CCN2C(=NCCC2)CC1>>[CH3:16][C:14]1[N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][S:17][C:18]3=[O:23])[N:12]2[CH:13]=1
Reactant: Cc1cn2c(SCCCCCl)cccc2n1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn2c(SCCCCN3C(=O)CSC3=O)cccc2n1

Procedure:
Using 0.76 g (3.0 mmol) of 5-(4-chlorobutylthio)-2-methylimidazo[1,2-a]pyridine, 0.35 g (3.0 mmol) of thiazolidine-2,4-dione and 0.45 ml (3.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene, the same procedure as in Reference Example 2 was followed, to yield 0.78 g (77.7%, light yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](Br)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[C:15]([O:19][C:20]([N@@:22]1[CH2:24][CH:23]1[CH3:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][C@H:23]([CH3:25])[CH2:24][C:5]1[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1cc(Br)c2occc2c1
Reactant: CC1CN1C(=O)OC(C)(C)C
Product: C[C@H](Cc1cc(C(F)(F)F)cc2ccoc12)NC(=O)OC(C)(C)C
Yield: 24.9 %

Procedure:
Beginning with 0.256 gm (0.97 mMol) 5-trifluoromethyl-7-bromobenzofuran and 0.142 gm (0.90 mMol) (R)-(−)-N-tert-butoxycarbon-yl-2-methylaziridine, 0.077 gm (23%) of the desired compound were prepared essentially as described in Example 10.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:15]([F:21])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[F:21][C:15]1[CH:16]=[C:17]([CH2:19][CH2:20][OH:31])[CH:18]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH:10]=[N:9][C:8]([C:11]([F:12])([F:13])[F:14])=[N:7][CH:6]=1
Reactant: [OH-]
Reactant: C=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 152.4 %

Procedure:
To the solution of 5-(2,6-difluoro-4-vinylphenoxy)-2-(trifluoromethyl)pyrimidine (1.67 g, 5.53 mmol) in dry THF (25 mL), was added 9-BBN (20 ml, 10.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (7 mL, 21.0 mmol), and 30% H2O2 (7 mL, 5.53 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (2.7 g, 8.43 mmol, 153% yield) as a white oil. LCMS: rt=2.97 min, [M+H+]=321
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21](O)=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH3:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH:39]([CH3:43])[NH:38]1>>[CH:32]([N:29]1[CH2:28][CH2:27][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:38]4[CH:39]([CH3:43])[CH2:40][CH2:41][CH2:42][CH:37]4[CH3:36])=[O:22])[C:15]=3[N:14]=2)=[O:35])[CH2:31][CH2:30]1)([CH3:33])[CH3:34]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CC1CCCC(C)N1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4C(C)CCCC4C)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2,6-dimethyl-piperidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 100 mg (0.20 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 50.0 μl (0.40 mmol) 2,6-dimethyl-piperidine. The title compound was obtained as its formiate in form of a white amorphous solid. Yield: 72 mg MS (ES+): m/e=594, chloro pattern.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C@@:9]1([C:44](SCC#N)=[O:45])[C@:40]2([CH3:41])[C@H:12]([C@H:13]3[C@H:37]([C@@H:38]([OH:42])[CH2:39]2)[C@@:17]2([CH3:43])[CH2:18][C:19]4[CH:20]=[N:21][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH2:32][O:33][CH2:34][CH:35]=[CH2:36])[CH:26]=5)[C:23]=4[CH:24]=[C:16]2[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:7].[CH3:50][NH2:51]>C(#N)C.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C@@:9]1([C:44](=[O:45])[NH:51][CH3:50])[C@:40]2([CH3:41])[C@H:12]([C@H:13]3[C@H:37]([C@@H:38]([OH:42])[CH2:39]2)[C@@:17]2([CH3:43])[CH2:18][C:19]4[CH:20]=[N:21][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH2:32][O:33][CH2:34][CH:35]=[CH2:36])[CH:26]=5)[C:23]=4[CH:24]=[C:16]2[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:7]
Reactant: C=CCOCc1cc(-n2ncc3c2C=C2CC[C@@H]4[C@H]([C@@H](O)C[C@@]5(C)[C@H]4CC[C@]5(OC(=O)c4ccco4)C(=O)SCC#N)[C@@]2(C)C3)ccc1F
Reactant: CN
Solvent: CC#N
Solvent: CCO
Product: C=CCOCc1cc(-n2ncc3c2C=C2CC[C@@H]4[C@H]([C@@H](O)C[C@@]5(C)[C@H]4CC[C@]5(OC(=O)c4ccco4)C(=O)NC)[C@@]2(C)C3)ccc1F
Reaction time: 3 h

Procedure:
In a 100 mL round-bottomed flask was dissolved the product obtained in Example 77 (75 mg, 0.11 mmol) in acetonitrile (2.5 mL) to give a yellow solution. 33% methanamine (2.5 mL, 20.19 mmol) in ethanol was added. The mixture was stirred in a closed flask for 3 hours, monitoring the reaction by LC-MS. When almost all of the starting material had been consumed, the volatiles were removed in vacuo. The crude mixture was purified on preparative HPLC (acetonitrile/water), and 15 mg (25%) was obtained of the desired product as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: NCC1CC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1nccc(NCC2CC2)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
In a microwave reaction vessel, slurry 2,4-dichloropyrimidine (0.5 g, 3.36 mmol), cyclopropylmethylamine (275 μL, 3.18 mmol), and diisopropylethylamine (1.17 mL, 6.72 mmol) in iso-propanol (2 mL). Irradiate in microwave (300 watts) at 130° C. for 15 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 1:3 over 45 min; 40 mL/min) to obtain the desired intermediate (374 mg, 65%) as a colorless oil.