Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:22]([NH:40][CH3:41])[N:21]2[CH:42]=1>>[CH3:41][NH:40][C:22]1[N:21]2[CH:42]=[C:18]([CH3:17])[N:19]=[C:20]2[N:25]=[C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:28][CH:27]=2)[C:23]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CNc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nc(C)cn12
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Product: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5cccc(C)n5)n4)C3)cc2)nc2nc(C)cn12

Procedure:
The compound is prepared in analogy to example 60. 416 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are reacted with 270 mg (0.79 mmol) 4-(2-methyl-5-methylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)benzaldehyde to yield finally after HPLC purification 88.3 mg (20.7%) of the expected compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([SH:22])[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:23][C:24]1[N:33]=[C:32](Cl)[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:35][CH3:36])[CH:30]=2)[N:25]=1>CN(C=O)C.O>[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:32]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:35][CH3:36])[CH:30]=4)[N:25]=[C:24]([Cl:23])[N:33]=3)[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(Cl)nc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 25 °C
Yield: 13 %

Procedure:
To a slurry of sodium hydride (7.5 mg, 0.3 mmol) in DMF (3 mL) was added 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (90 mg, 0.3 mmol), and the solution stirred at room temperature When gas evolution ceased, 2,4-dichloro-6,7-dimethoxyquinazoline (78 mg, 0.3 mmol) was added and the solution heated at 50° C. overnight, cooled to room temperature, and diluted with H2O. The mixture was extracted with EtOAc, the organic layer washed with aqueous sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude solid was purified by HPLC to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (20 mg, 0.04 mmol, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.53 (s, 1H), 7.90 (s, 1H), 7.62 (d, 1H), 7.44 (t, 1H), 7.36 (s, 2H), 7.27 (d, 1H), 6.49 (s, 1H), 4.00 (s, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 514 (M+H)+.
Reaction SMILES: C[C:2]([N:5]([C@@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)[C:6](=[O:8])[O-:7])(C)C.[H-].[Na+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:2][N:5]([C@@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)[C:6](=[O:8])[O:7][C:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: C[C@@H]1C[C@@H](N(C(=O)[O-])C(C)(C)C)CN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C[C@@H]1C[C@@H](N(C)C(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 158 %

Procedure:
To 1,1-dimethylethyl[(3R,5R)-5-methyl-1-(phenylmethyl)-3-piperidinyl]carbamate (196 mg, 0.644 mmol) in DMF (3 mL) was added NaH (38.6 mg, 0.966 mmol), and the resulting mixture was vigorously stirred for 30 minutes. CH3I (0.044 mL, 0.708 mmol) was added, and the reaction mixture was stirred for 3 hours at room temperature. Saturated aqueous NaHCO3 was added carefully (˜5 mL: initial vigorous bubbling), and the resulting mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexane to 30% EtOAc/Hexane) afforded the title compound (162 mg) as a colorless oil. LC-MS (ES) m/z=319 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38]Br)[CH:29]=1.O>C(#N)C>[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:29]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
515 mg (1.67 mmol) of the compound from Example 5A and 818 mg (2.51 mmol) of cesium carbonate were suspended in 10 ml of acetonitrile, and 810 mg (1.84 mmol) of methyl 4-bromo-2-(bromomethyl)benzoate were added. The mixture was stirred under reflux for 3 h. After cooling to RT, 15 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically [Method 19]. This gave 455 mg (51% of theory) of the target compound.
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[CH2:29][N:30]2[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:43].[Na+]>CO.O>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:43])[CH2:32][CH2:31]2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](NC(=O)c1c(CN2CCC(=O)CC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@H](NC(=O)c1c(CN2CCC(N)CC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
0.477 g (1 mmol) of 3-(4-oxo-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (compound of Description 18), 0.462 g (6 mmol) of ammonium acetate were dissolved in 10 ml of methanol and stirred at room temperature for 1 h. Then 0.08 g of sodium cyanoborohydride were added and the mixture was stirred one night at room temperature. The reaction mixture was poured in 50 ml of water and the formed precipitate was filtered off. The aqueous phase was extracted with methylene chloride. The collected solid was dissolved in methylene chloride, both organic phases merged, washed with water, dried over MgSO4, concentrated to dryness. The residue was purified by micro flash chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 90/10/1) to afford 47 mg of the title compound as a white solid (yield ca 10%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:21])[NH:16]2)([OH:3])=O.[CH2:22]([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH:30]1([N:29]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)=[O:3])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)CCCCCCOc1cccc2c1CCC(=O)N2
Reactant: c1ccc(CNC2CCCCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1CCc2c(cccc2OCCCCCCC(=O)N(Cc2ccccc2)C2CCCCC2)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.9 %

Procedure:
To a solution of 2.9 g of 5-(6-carboxyhexyloxy)-3,4-dihydrocarbostyril and 1.9 g of N-benzylcyclohexylamine in 100 ml of DMF is added gradually dropwise a solution of 2.1 g of N,N'-dicyclohexylcarbodiimide in 10 ml of DMF at room temperature and under agitation. After this agitation, the mixture is further agitated at room temperature for 5 hours. After the reaction, the insolubles are filtered off and the mother liquor is concentrated. The residue is dissolved in chloroform and subjected to silica gel thin-layer chromatography (solvent: chloroform-methanol (8:1) to scrape out the portion with Rf value of 0.8. The silica gel is extracted with chloroform, and after distilling off chloroform, the residue is recrystallized from benzene-ligroin to obtain 1.1 g of 5-[6-(N-cyclohexyl-N-benzylaminocarbonyl)hexyloxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 49°-52° C.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][CH:2]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=2)[CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(C(O)COc2ncnc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(COc2ncnc3ccccc23)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 4 h

Procedure:
A 15 ml round bottom flask is charged with 4-(2-hydroxy-2-(4-tert-butylphenyl) ethoxy) quinazoline (0.25 g, 0.77 mmol) is dissolved in pyridine (5 ml). p-Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate/hexanes)to give the product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:15][C@H:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@H:6]1[CH2:15][C@H:14]([NH:16][C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5]
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)CCC(=O)O)c2c(Cl)cc(Cl)cc2N1

Procedure:
To a suspension of trans-2-methoxycarbonyl-5,7-dichloro-4-amino-1,2,3,4-tetrahydroquinoline hydrochloride (Example 9a) (225 mg, 0.819 mmol) in ethyl acetate (50 ml) was added a solution of potassium carbonate (50 ml). The mixture was shaken until no solid remained (5 min). The organic layer was retained and washed with brine (50 ml) before drying (Na2SO4). The solvent was removed in vacuo. The residue was redissolved in xylene (20 ml) and succinic anhydride (90 mg, 0.901 mmol) was added. The mixture was heated, with stirring, in an oil bath (80° C.) for 16h. The precipitate was removed by filtration and washed with ether to give the title compound as a colourless crystalline solid. δ (DMSO, 250 MHz), 1.65 (1H, ddd, J=13.0, 12.7 and 3.7 Hz, CHACHBHCCHD), 2.15 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 2.18-2.41 (4H, m, CO(CH2)2CO), 3.73 (3H, s, CH3), 3.94 (1H, dd, J 13.0 and 3.0 Hz, CHACHBHCCHd), 5.01 (1H, m, CHACHBHCCHD), 6.69 (1H, J=2.1 Hz, 6-H or 8-H), 6.86 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.91 (1H, s, ArNHCH), 8.23 (1H, d, J=7.2 Hz, NHCO).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:23]2[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[F:26][C:27]([F:41])([F:42])[C:28]1[CH:29]=[C:30]([C:2]2[O:6][C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:20])([F:22])[F:21])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH:23]3[CH2:25][CH2:24]3)=[CH:4][CH:3]=2)[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 310D using (1-[(5-bromo-2-furanyl)methyl]-2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 310C) and [3,5-bis(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 543 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][CH2:11][N:12]1[C:20]2[N:19]=[CH:18][NH:17][C:16]=2[C:15](=[O:21])[NH:14][C:13]1=[S:22].C(N(CC)CC)C.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>>[CH3:8][N:9]([CH2:40][C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1)[CH2:10][CH2:11][N:12]1[C:20]2[N:19]=[CH:18][NH:17][C:16]=2[C:15](=[O:21])[NH:14][C:13]1=[S:22]
Reactant: CNCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: O=Cc1ccnc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(CCn1c(=S)[nH]c(=O)c2[nH]cnc21)Cc1ccnc2ccccc12
Yield: 14.1 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 26(c) by using 3-[2-(methylamino)ethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate (0.10 g, 0.29 mmol, obtained from Example 28(c)), triethylamine (0.032 mL, 0.32 mmol), 4-quinoline carboxaldehyde (0.060 g, 0.38 mmol) and sodium cyanoborohydride (0.028 g, 0.44 mmol) which yielded 0.015 g (14% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]([OH:15])=O)=[CH:7]2.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]([Cl:18])=[O:15])=[CH:7]2
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2cccc(O)c2oc1=O

Procedure:
A solution of 8-hydroxycoumarin-3-carboxylic acid (2.06 g) in 10 ml thionyl chloride was heated under reflux for three hours, and 8-hydroxycoumarin-3-carboxylic acid chloride was obtained by distilling off the excess thionyl chloride. This was added in small portions to a methylene chloride solution (100 ml) containing ampicillin trihydrate (4.1 g) and triethylamine (3.5 ml) over a period of forty minutes under stirring and cooling on ice.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:34]#[C:33][CH2:32][CH2:31][OH:35]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(C#CCCO)c(OC)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
1-Bromo-2,4-dimethoxybenzene (10 g 0.046 mol), palladium chloride (0.2 g 0.11 mmol) and triphenylphosphine (0.6 g 0.0023 mol) were dissolved in diethylamine (100 mL) under a nitrogen atmosphere. Copper (I) iodide (0.44 g 0.0023 mol) and 3-butyn-1-ol (7 mL 0.092 mol) were added into the reaction mixture at once. The mixture was stirred overnight at 55° C. under a nitrogen atmosphere. The catalyst was filtered off from the reaction mixture and the same amount of palladium chloride, triphenylphosphine, copper (I) iodide and 3-butyn-1-ol were added. The reaction mixture was stirred and heated at 85° C. for 48 hours. Then the solvent was removed at reduced pressure and water (approx. 100 mL) was added to the residue. The mixture was extracted with ethyl acetate (350 mL) passed through a pad of silica gel and concentrated. The product was purified by flash chromatography (silica gel, 1:1 hexanes/ethyl acetate). Compound 75 (4.2 g, 24%) was isolated as a brown oil. 1H NMR (300 MHz, CDCl3) δ 2.24 (t, 1H), 2.73 (t, 2H), 3.80 (br s, 5H), 3.87 (s, 3H), 6.43 (m, 2H), 7.30 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(O)(=O)C.Cl>C(O)C.[Fe]>[NH2:12][C:3]1[C:2]([I:1])=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1I
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)O)c(N)c1I
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
3-Iodo-4-methyl-2-nitrobenzoic acid (46.00 g, 150 mmol) was suspended in ethanol (500 mL) and acetic acid (86 mL, 1498 mmol). The mixture was heated to 70° C. and iron (33 g, 599 mmol) was added in small portions. Stirring was continued for 3 h, and then the reaction was cooled down to RT and poured on 1.5 kg of crushed ice and 1 L of 5 N aqueous HCl. The mixture was extracted with ethyl acetate and the organic layer was dried with sodium sulfate, concentrated under vacuum and dried to give 2-amino-3-iodo-4-methylbenzoic acid (40 g, 96%) as a tan solid. MS (M+H)+ 278
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:20](=[O:28])[C@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:29][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][C:24]([F:27])([F:25])[F:26])[C:20]1=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ylcarbamate (135 mg, 0.320 mmol) in dichloromethane (5 mL). After 30 min, the solution was concentrated and azeotroped with toluene (2×). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 323.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.11-7.03 (m, 2H), 6.93-6.89 (m, 1H), 4.21-4.13 (m, 1H), 4.10-3.98 (m, 2H), 3.85 (d, J=11.0 Hz, 1H), 3.35 (d, J=15.4 Hz, 1H), 3.04-2.99 (m, 1H), 2.13-2.09 (m, 2H), 2.08-2.02 (m, 1H), 1.78-1.70 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:38])([F:37])[CH2:15][NH:16][C:17]([C:19]1([CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18]>>[F:13][C:14]([F:37])([F:38])[CH2:15][NH:16][C:17]([C:19]1([CH2:32][CH2:33][CH2:34][CH2:35][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccccn3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-pyridin-2-yl-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]2)=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-:23].[Na+].[Na+]>O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2([OH:23])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3=[N:2][CH2:3][CH2:4][CH2:5][N:6]23)=[CH:20][CH:19]=1
Reactant: NCCCn1cc2ccccc2c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCCN21

Procedure:
The 2-(3-aminopropyl)-1-(4-chlorophenyl)isoindole, hydrochloride (2 gms.) is dissolved in water and neutralized with a sodium carbonate solution. The regenerated base is extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 250 ml. of ethanol and air is bubbled through the solution for 48 hours. The precipitated white crystalline solid is separated by filtration and upon recrystallization from dimethylformamide there is obtained 6-(4-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol, m.p. 274°-6°C. dec., which is insoluble in water and soluble in dimethylacetamide.
Reaction SMILES: [CH3:1][NH:2][S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4].Cl[C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH2:29]([O:28][C:26]([N:2]([CH3:1])[S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4])=[O:27])[CH2:30][CH3:31]
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)NC)cc1[N+](=O)[O-]
Reactant: CCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCOC(=O)N(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N(CCC)CCC)c([N+](=O)[O-])c1
Yield: 80.6 %

Procedure:
A mixture of 4.5 g (0.0125 mol) N1 -methyl-3,5-dinitro-N4,N4 -dipropylsulfanilamide, 3.06 g (0.025 mol) n-propyl chloroformate, 3.5 g (0.025 mol) potassium carbonate, and 75 ml dimethoxyethane was heated at reflux for 2 hours. The reaction mixture was filtered and evaporated under reduced pressure. The residue was recrystallized from ethanol to give 4.5 g of the product, m.p. 110°-113°C, as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)=[O:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a stirred solution of 1-(6-nitro-pyridin-3-yl)-piperazine (3.00 g, 14.4 mmol) in dichloromethane (30 mL) was added triethylamine (2.91 g, 28.8 mmol) followed by the dropwise addition of pivaloyl chloride (1.90 g, 15.9 mmol) at r.t. and the resulting solution was stirred for 15 min. The reaction was quenched with sat. sodium bicarbonate solution and extracted with dichloromethane (×3). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was washed with petroleum ether to afford 2,2-dimethyl-1-[4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-propan-1-one (2.50 g, 59%) as pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]2[C:3](=[O:20])[N:4]([CH3:19])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8]2)=[O:24])=[CH:31][CH:32]=1
Reactant: CC(C(=O)O)C(=O)NCc1ccc(F)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C(=O)NCc1ccc(F)cc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=473.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(4-fluoro-benzyl)-malonamic acid.