Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].O.[CH:7]1([CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][OH:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[O-]Cl.[Na+]>[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.C1(C)C=CC=CC=1>[CH:7]1([CH2:13][CH:14]([CH3:18])[CH2:15][CH:16]=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(CCO)CC1CCCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CC=O)CC1CCCCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
KBr (0.6 g, 0.005 mol) and NaHCO3 (6.4 g, 0.076 mol) and 0.8 g (0.00566 mols) 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) were mixed together with water (60 ml), toluene (250 g) and 4-(cyclohex-1-yl)-3-methyl butan-1-ol (96 g 0.564 mol, purity: 99% sum of the isomers) the reaction temperature maintain 0° C. with continuous stirring. NaOCl (13% w/w aqueous 426.8 g, 0.745 mol) was added to the reaction mass over 2 h. Stirring was continued for another 12 h. The aqueous phase was removed, organic phase was washed with a solution of NaHCO3 and then with water. The organic phase thus obtained was concentrated and crude product purified by fractional distillation to provide 4-(Cyclohex-1-yl)-3-methylbutanal (42.63 g, yield: 45%, GC purity: 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][N:15]([CH3:16])[C:11]=2[C:10]=1[C:19]#[N:20].Cl.[OH-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][N:15]([CH3:16])[C:11]=2[C:10]=1[CH2:19][NH2:20]
Reactant: Cn1cnc2ccc(-c3ccc(Cl)cc3Cl)c(C#N)c21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cnc2ccc(-c3ccc(Cl)cc3Cl)c(CN)c21
Temperature: 0 °C
Yield: 51 %

Procedure:
Borane-THF complex in THF (1 M, 2 mL, 2 mmol) was added to a solution of Example 6B in dry THF (6 mL) at r.t. The reaction stirred at reflux for 1 h, and was then cooled to 0° C. Concentrated HCl (0.8 mL) was added slowly, and the reaction was stirred at 60° C. for 1 h. The solution was cooled to 0° C., made basic with ammonium hydroxide, and extracted (3×) with EtOAc. Organics were dried (MgSO4) and concentrated in vacuo. Purification by Prep-HPLC gave 88 mg (51%) white solid as the HCl salt. 1H NMR (400 MHz, MeOD-d4): δ 9.59 (s, 1H), 8.04 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=2.0 Hz), 7.50-7.59 (m, 3H), 4.51 (qAB, 2H, J=142.4, 15.2 Hz), 4.45 (s, 3H). MS (ES) [m+H] calc'd for C15H13N3Cl2, 306, 308; found 306, 308.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.C1([O:38][C:39](=O)[NH:40][C:41]2[N:45]3[N:46]=[CH:47][CH:48]=[CH:49][C:44]3=[N:43][CH:42]=2)C=CC=CC=1>CS(C)=O.CCOC(C)=O>[N:43]1[CH:42]=[C:41]([NH:40][C:39]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:10]3[CH:18]=[CH:19][CH:20]=[C:8]([O:7][C:6]4[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][CH:5]=4)[CH:9]=3)[CH2:13][CH2:14]2)=[O:38])[N:45]2[C:44]=1[CH:49]=[CH:48][CH:47]=[N:46]2
Reactant: Clc1ccc(Oc2cccc(CN3CCNCC3)c2)cc1
Reactant: O=C(Nc1cnc2cccnn12)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1cnc2cccnn12)N1CCN(Cc2cccc(Oc3ccc(Cl)cc3)c2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 1-[3-(4-chloro-phenoxy)-benzyl]-piperazine hydrochloride (62.3 mg, 0.166 mmol) and diisopropylethylamine (53.7 mg, 0.416 mmol) in DMSO (2.0 mL) was added imidazo[1,2-b]pyridazin-3-yl-carbamic acid phenyl ester (42.1 mg, 0.166 mmol). The reaction mixture was stirred at 50° C. for 16 h, then diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (40 mL). The organic layer was dried (MgSO4) and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give 4-[3-(4-chloro-phenoxy)-benzyl]-piperazine-1-carboxylic acid imidazo[1,2-b]pyridazin-3-ylamide (67.1 mg, 87%). MS (ESI+): calcd for C24H23ClN6O2 m/z 462.16. found 463.5 (M+H)+. 1H NMR (d6-DMSO): 8.74 (s, 1H), 8.50 (dd, J=4.4, 1.3, 1H), 8.05 (dd, J=9.1, 1.3, 1H), 7.64 (s, 1H), 7.44 (d, J=9.0, 2H), 7.38 (t, J=7.8, 1H), 7.19-7.12 (m, 2H), 7.04 (d, J=9.0, 2H), 7.01 (br s, 1H), 6.95-6.92 (m, 1H), 3.53 (s, 2H), 3.50-3.45 (m, 4H), 2.43-2.37 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:42][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: NC1CCCCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCCCC2)no1
Yield: 58.2 %

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclohexylamine (198 mg, 1.98 mmol) as starting materials to afford the title compound as a colourless oil (250 mg).
Reaction SMILES: [C:1](OC)(OC)(OC)[O:2][CH3:3].[Cl:10][C:11]1[C:20]([NH2:21])=[C:19]([NH2:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[OH-].[Na+].ClCCl>C(O)(=O)C.O>[Cl:10][C:11]1[C:20]2[N:21]=[C:1]([O:2][CH3:3])[NH:22][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Nc1c(Cl)nc2ccccc2c1N
Reactant: COC(OC)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nc2c(Cl)nc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetramethyl orthocarbonate (1.24 mL, 9.3 mmol) was added to a suspension of 2-chloroquinoline-3,4-diamine, see U.S. Pat. No. 5,756,747 (Gerster) Example 30, (1.5 g, 7.75 mmol) in acetic acid (8 mL), and the reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the reaction was incomplete, and additional tetramethyl orthocarbonate (0.5 equivalent) was added. The reaction was stirred overnight at room temperature and diluted with water (100 mL). The mixture was adjusted to pH 7 with the addition of 2 N aqueous sodium hydroxide. Dichloromethane (100 mL) was added to the mixture, and a precipitate formed. The precipitate was isolated by filtration to provide 1.13 g of 4-chloro-2-methoxy-1H-imidazo[4,5-c]quinoline as a gray solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(N1CCO[C@H:32]([CH2:36][C:37]2C=CC=C(C=CC3C=NC=CC=3)C=2)[CH2:31]1)(OC(C)(C)C)=O.BrCCCC.C(O)(C(F)(F)F)=O>>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][CH2:32][CH2:36][CH3:37])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCBr
Product: CCCCOc1ccc(C[C@@H]2CNCCO2)cc1Br

Procedure:
Example 61 was prepared using the same procedure as described for example 4, starting from N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), and 1-bromobutane. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 61 as a colorless oil (28 mg, 63% over 2 steps) after purification by HPLC.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C.O>C1COCC1.[Cu]I>[N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[C:18][C:19](=[O:21])[CH3:20])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
To a solution of Compound 1c (52 mg; 0.213 mmol), acetyl chloride (46 mL, 0.647 mmol), bis(triphenyl)palladium(II)dichloride (4.49 mg, 0.0064 mmol) and copper (I) iodide (1.62 mg, 0.085 mmol) in anhydrous THF (5 mL), was added triethylamine (85 μL, 0.61 mmol) and the reaction mixture was stirred, in a closed vessel, at 60° C. for 5 h, cooled to r.t. poured into water and extracted with EtOAc. The combined extracts were washed with NaOH 0.1N, water, dried over Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (EtOAc—Petroleum Ether 25:75), afforded 17.5 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:14]([O:19][CH3:20])[CH:13]=1
Reactant: COc1cc(Br)ccc1O
Reactant: OB(O)c1ccccc1Cl
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 2-chloro-phenylboronic acid (1.54 g, 9.85 mmol) and 4-bromo-2-methoxyphenol (1.00 g, 4.92 mmol) in DCM (50.00 mL) was added cupric acetate (1.34 g, 7.39 mmol), powdered 4 A molecular sieves and TEA (3.43 mL, 24.6 mmol) at rt. The resulting mixture was then stirred at rt for 48 h at ambient atmosphere. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in hexane).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[CH:14]([CH2:15][C:16](=[O:24])[CH:17]=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:25][Al](C)C.O>C(OCC)(=O)C.C1(C)C=CC=CC=1.[Cu]Br>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH2:17][C@@H:18]1[CH3:25])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: C[Al](C)C
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cu]Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
Variant 2 (in ethyl acetate : 66.1 g (0.2 mol) of 17β-acetoxy-androst-1-en-3-one is dissolved in 350 ml of dry ethyl acetate and mixed with 1.43 g (10 mmol) of copper(I) bromide. 188 ml (0.22 mol) of a 10% solution of trimethyl aluminum in toluene is added over 15 minutes to the reaction under nitrogen atmosphere, so that the temperature does not rise above 25° C. Then it is stirred for 30 minutes more. For hydrolysis, 15 ml of water is added to the reaction and stirred for 40 minutes more. The solid is suctioned off and absorptively precipitated three times, each with 200 ml of dioxane. After concentration by evaporation of the combined organic phases, 65.6 g of 17β-acetoxy-1α-methyl-androstan-3-one (95% of theory) of a melting point of 181° C. is obtained.
Reaction SMILES: [H][H].[NH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:16]([F:27])[CH:15]=2)[CH:7]=[CH:6][N:5]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:3][C:4]1[C:9]([NH2:10])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])=[C:16]([F:27])[CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1N
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Method D2 (using hydrogen). N-(4-(2-amino-3-nitropyridin-4-yl-oxy)-2-fluorophenyl)-2,2,2-trifluoroacetamide (540 mg, 1.5 mmol) was dissolved in ethanol (15 mL) and AcOEt (5 mL). Palladium 10% on activated carbon (150 mg) was added and the reaction mixture was stirred for 2 hours under hydrogen atmosphere. The catalyst was filtered off and the filtrate evaporated to afford the title compound (490 mg, 100%). 1H-NMR (δ, ppm, DMSO-d6): 4.65 (s, 2H, NH2,Py3), 5.86 (s, 2H, NH2,Py2), 6.23 (d, 1H, HPy,6, J=5.71 Hz), 6.85 (d, 1H, Harom,Ph, J=8.80 Hz), 7.01 (d, 1H, Harom,Ph, J=11.51 Hz), 7.32 (d, 1H, HPy,5, J=5.71 Hz), 7.45 (t, 1H, Harom,Ph, J=8.76 hz), 11.37 (s, 1H, NHCOCF3).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:2]1([C:1]2[O:18][C:17]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccco1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccco1
Yield: 79.5 %

Procedure:
4.0 g of ethyl 3-benzoylamino-3-(2-furylcarbonyl)propionate, 20 ml of chloroform and 9.7 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 3.0 g of ethyl 2-[2-phenyl-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 78.9%
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C(=O)c3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide (0.30 g, 0.95 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in mineral oil, 0.38 g, 0.95 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. To the resulting solution was added 4-fluorobenzoyl chloride (0.11 mL, 0.95 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluted with 60-80% ethyl acetate in hexanes to afford the title compound in 23% yield (0.10 g, 23%): mp 130-132° C.; 1H NMR (300 MHz, CDCl3) δ 7.66-7.61 (m, 2H), 7.29-7.23 (m, 5H), 7.10-7.04 (m, 2H), 5.86 (br s, 1H), 4.49 (d, J=5.5 Hz, 2H), 4.21-4.15 (m, 4H), 2.60 (s, 3H), MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]([C:15]#[C:16][C:17](OCC)=[O:18])=[O:14])[CH3:11]>CO>[OH:18][C:17]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[N:9]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CO
Product: CCOC(=O)c1cc(O)c2cc(OC)ccc2n1
Temperature: 55 °C

Procedure:
To a solution of p-anisidine (2.7 g, 22 mmol) in methanol (50 mL) was added diethyl-acetylene dicarboxylate (3.74 g, 22 mmol). The resulting solution was heated at 55° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in phenyl ether (40 mL) and refluxed at 240° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with hexanes and filtered. A light brown solid was obtained. LC-MS: 1.39 min; (M+H)=248.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38](F)=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=O)(C)(C)C>CN(C=O)C.O>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:38]2[CH:37]=[C:36]3[C:41]([C:32]([CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)=[N:33][CH:34]=[N:35]3)=[CH:40][CH:39]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: CN1CCN(CCCN)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(CCCNc2ccc3c(C4CCNCC4)ncnc3c2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-aminopropyl)-1-methylpiperazine (0.1 mmol), Et3N (0.1 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 12b, in DMF (1 mL) was stirred at 130° C. for 3 h. It was then diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h, then concentrated in vacuo.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccc(OC)cc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nccc(-n3cc(C(=O)O)c4ccccc43)c2c1

Procedure:
0.252 g (6 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.7 g (2.11 mmol) of 3-methoxycarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with a mixture of 50 cm3 of ethyl acetate and of 100 cm3 of dichloroethane. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.57 g of 3-carboxy-1-(6-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 318 (M+•).
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].CO.[OH-].[K+]>O>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])=[N:13][NH:12]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1n[nH]c(=S)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1n[nH]c(=S)s1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A mixture of N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-phenylalanine methyl ester (EXAMPLE 1; 528 mg, 1.56 mmol), MeOH (20 mL), H2O (5.0 mL) and KOH (350 mg, 6.24 mmol) is stirred at room temperature for 16 hours. The solution is concentrated (to remove the MeOH), acidified with 10% HCl, and extracted with EtOAc (3×20 mL). The organic layers are dried (MgSO4), filtered, and concentrated to give 490 mg (97%) of the title compound (mp 130° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[CH2:58][CH2:59][S:60][CH3:61])=[N:56][C:52]=2[CH:51]=1.BrCl>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:62][C@H:57]([C:55]1[NH:54][C:53]2[CH:63]=[CH:64][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][CH2:59][S:60][CH3:61])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 60 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropylamine in tetrahydrofuran. Yield: 60%; Rf value: 0.40 (silica gel; dichloromethane/ethanol=9:1); C23H24BrClN4O2S (535.89); mass spectrum: (M+H)+=535/537/539 (bromo-chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.[CH2:11]([CH:18]([C:24](=O)[CH3:25])[C:19](OCC)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:19]([OH:20])[C:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:24]([CH3:25])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl 2-benzyl-3-oxobutanoate(0.379 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1ccnc2ccccc12
Product: CCN(Cc1ccnc2ccccc12)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-quinolin-4-ylmethyl-amine
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30]O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH2:1]([O:8][C:9](=[O:18])[C:10]1[C:11]([OH:17])=[CH:12][CH:13]=[CH:14][C:15]=1[O:16][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1c(O)cccc1O
Reactant: CC(C)(C)OC(=O)NCCCCO
Product: CC(C)(C)OC(=O)NCCCCOc1cccc(O)c1C(=O)OCc1ccccc1

Procedure:
The title compound is prepared from 2,6-dihydroxybenzoic acid benzyl ester and 4-(Boc-amino)-1-butanol analogous to Example 1109 step A.