Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:20][CH3:21])[C:10]2=[O:22])[CH2:7][CH2:6][C:5](=[O:23])[NH:4]1.[CH3:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(Cl)Cl>[CH3:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:34])[N:20]([CH2:19][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[C:17](=[O:18])[N:9]([CH:8]2[CH2:7][CH2:6][C:5](=[O:23])[NH:4][C:3]2=[O:2])[C:10]3=[O:22])[CH3:21])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: CNCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N(C)Cc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a suspension of 2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride (0.65 g, 1.93 mmol) and 3,4-dimethylphenyl isocyanate (0.32 mL, 2.31 mmol) in dry CH2Cl2 (80 ml), was added diidopropylethylamine (0.47 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (1 mL). The suspension was filtered, and the resulting solid cake was rinsed with CH2Cl2 (5 ml). The solid was reslurried with ether (I 5 mL) to give 3-(3,4-dimethyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea as a solid (0.51 g, 59%)): mp 202-204° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.23 (99%); 1H NMR (DMSO-d6): δ 2.14 (s, 3H), 2.16 (s, 3H), 2.54-2.64 (m, 2H), 2.85-2.97 (m, 1H), 3.03 (s, 3H), 5.00 (s, 2H), 5.14-5.20 (dd, J=5.3, 12.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.89-7.81 (m, 2H), 8.34 (s, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 18.62, 15.54, 21.97, 30.91, 35.10, 47.46, 48.85, 117.61, 121.43, 121.83, 127.54, 129.12, 129.51, 131.78, 132.42, 134.95, 135.63, 137.93, 138.97, 155.79, 16696, 167.58, 169.80, 172.74. Anal Calcd for C24H24N4O5: C, 64.28; H, 5.39; N, 12.49. Found: C, 63.99; H, 5.26; N, 12.39.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[CH:4][CH:3]=1.[C:21]([CH:24]=[C:25]=[O:26])(=[O:23])[CH3:22]>CCOC(C)=O>[C:16]([C:15]1[CH:14]=[C:13]([CH:20]=[CH:19][CH:18]=1)[O:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:25](=[O:26])[CH2:24][C:21](=[O:23])[CH3:22])[CH:10]=2)[CH:6]=[CH:7]1)#[N:17]
Reactant: CC(=O)C=C=O
Reactant: N#Cc1cccc(OCn2ccc3ccc(N)cc32)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 3-((6-amino-1H-indol-1-yl)methoxy)benzonitrile (2.62 g, 9.95 mmol) in EtOAc (20 mL) was added acetyl ketene (1.0 g, 11.9 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (2.70 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[S:15][C:16]=2[NH2:17])=O)=[CH:6][CH:5]=1.[CH:23]1([C:26](=[O:31])[CH2:27][C:28](=O)[CH3:29])[CH2:25][CH2:24]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:27]([C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:31])=[C:28]([CH3:29])[N:17]=[C:16]3[S:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=23)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
To a stirred solution of 60 mg (0.19 mmol) 4-(2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 2 ml acetic acid was added 32 mg (0.25 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 28 mg (37%) 4-(3-cyclopropanecarbonyl-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-4-yl)-benzoic acid methyl ester as a light pink solid. ES-MS m/e (%): 406 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C)C=O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([O:18][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
A stirred suspension of sodium hydride (60% in oil, 1.00 g) in 50 ml of dimethylformamide was treated with a solution of 4.0 g of 1-acetyl-4-hydroxy-4-phenylpiperidine in 100 ml of dimethylformamide. The mixture was heated at 70° C. until evolution of gas had ceased. After cooled to ice bath temperature, a solution of 2.96 g of 1-fluoro-4-nitrobenzene in 40 ml of dimethylformamide was added, dropwise, and the reaction allowed to proceed for 20 hours. The reaction mixture was then poured into ice water and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. High pressure liquid chromatography of the oil (silica gel; elution with 20% ethyl acetate/dichloromethane) afforded 4.73 g (77.29%) of 1-acetyl-4-(4-nitrophenoxy)-4-phenylpiperidine, m.p. 145°-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22](O)=[O:23])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1(N)CC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([C:22](=[O:23])[NH:27][CH:31]3[CH2:33][CH2:32]3)[CH3:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C(=O)O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)NC1CC1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3.00 g (9.00 mmol) 4-[4-(1-carboxy-ethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (IX.1) and 3.85 mL (22.5 mmol) DIPEA in 5 mL DMF, 4.33 g (13.5 mmol) TBTU are added. The mixture is stirred for 15 min at rt. After that time, 0.94 mL (13.5 mmol) cyclopropylamine are added and the mixture is stirred for 12 h at rt. After that time, water is added and the mixture is extracted with EtOAc.
Reaction SMILES: Br[CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[CH2:4][CH2:5]2.[Mg].CN([CH:13]=[O:14])C>C(OCC)C>[CH:6]12[CH:2]([CH:13]=[O:14])[CH:3]([CH2:8][CH2:7]1)[CH2:4][CH2:5]2
Reactant: BrC1C2CCC1CC2
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: O=CC1C2CCC1CC2
Temperature: 2.5 °C
Yield: 48.4 %

Procedure:
15.9 g (81 mmol) of 7-Bromo-bicyclo[2.2.1]heptane were added dropwise to 2 g magnesium (81 mmol) in 25 ml of diethyl ether and refluxed for 2.5 h. The mixture was cooled to 0-5° C. and 6.3 ml (81 mmol) of DMF were added dropwise. The mixture was then refluxed for 2 h, cooled to room temperature and the white solid filtered off and washed with ether. The filtrate was reduced and 4.87 g of a white solid were obtained. The intermediate was used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].N1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:16]([C:17]1[CH:2]=[C:3]([CH3:4])[C:7]([O:13][CH3:14])=[C:19]([CH3:20])[CH:18]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OC)c(C)c3)nc2c1
Reaction time: 16 h
Yield: 158.8 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzamide (0.0990 g, 0.555 mmol) and pyridine (44.9 μL, 0.555 mmol) in THF (2.02 mL) was added dropwise a solution of the acid chloride (crude residue described above) in THF (925 μL). After 16 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (3×75 mL), saturated aqueous NaHCO3 (3×75 mL), and brine (75 mL). The insoluble yellow solid was isolated by filtration to provide the amide (0.150 g, 83%). A mixture of the amide (0.148 g, 0.413 mmol) and 2 M NaOH (7.00 mL) was heated at 85° C. for 19 h, cooled to 5° C., and neutralized with 4 M HCl in dioxanes. The white solid was filtered and rinsed with acetone to provide 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.144 g, 100%). Selected data: 1H NMR (300 MHz, CDCl3) δ 11.00 (s, 1H), 7.90 (s, 2H), 6.74 (d, J=2.33 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H), 2.29 (s, 6H); MS (APCI) m/z 341 [M+H]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:11]1[CH:10]=[CH:9][C:21]2[NH:20][C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Reaction time: 2 h
Yield: 76 %

Procedure:
NBS (12.77 g, 71.8 mmol) in DMF was added to 9H-carbazole (12 g, 71.8 mmol) in 200 mL at 0° C. dropwise. The reaction was monitored by HPLC. After 2 h, HPLC indicated 76% of desired product and 6% of dibrominated compound. The reaction was quenched by adding 500 mL of ice water. The internal temperature was controlled to be lower than 10° C. The precipitate formed was collected by filtration. The solid was stirred in 400 mL of warm methanol. (˜40° C.). The solid was collected by filtration. The solid was dissolved in 150 mL of DCM. 200 mL of methanol was added. The DCM was boiled off. The solvent level was down to 150 mL. The slurry was stirred at room temperature overnight. The solid was collected by filtration. 9 g (51% yield) of solid was collected.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][N:7]=1>C(O)C>[CH2:1]([O:3][C:12]([C:10]1[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=1)=[O:13])[CH3:2]
Reactant: O=C(O)c1ccnc(O)c1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
Acetyl chloride (20 mL) was added slowly to ethanol (80 mL) at room temperature. The clear solution was stirred for 5 minutes and then 2-hydroxy-4-pyridinecarboxylic acid (5.0 g, 35.9 mmol) was added as a solid. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and the majority of the ethanol was evaporated. The residue was diluted with chloroform and water and the aqueous layer was neutralized by the careful addition of K2CO3. The organic layer was separated and the aqueous layer was extracted further with chloroform. The combined organic layer was dried over sodium sulfate and concentrated to give the title compound (5.74 g, 96%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-:12].[Na+].C(Cl)(=O)C>CC#N>[I:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [I-]
Reactant: Clc1ccc2ccccc2n1
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Ic1ccc2ccccc2n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
2-Iodoquinoline was prepared according to the procedure of Kimber, et. al. (Tetrahedron 2000, 56, 3575). To a solution of 2-chloroquinoline (10.0 g, 61.5 mmol) in CH3CN (100 mL) was added sodium iodide (14 g, 92.3 mmol) and acetyl chloride (8.8 mL, 123 mmol). The reaction mixture was stirred at 100° C. for 5 hours, then cooled to room temperature and quenched with 10% aqueous K2CO3 (100 mL) and 5% aqueous NaHSO3 (50 mL). The aqueous layer was extracted twice with dichloromethane then the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 20% EtOAc in hexanes) to provide 9.7 g (70%) of 2-iodoquinoline as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:11]2([CH2:14][CH:13]([OH:15])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:12][CH:13]([O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:14]2)[CH2:16][CH2:17]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 106 mg of 7-(tert-butoxycarbonyl)-2-hydroxy-7-azaspiro[3.5]nonane in 10 ml of tetrahydrofuran, 0.04 ml of methanesulfonyl chloride and 0.07 ml of triethylamine were added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After adding water to the residue, extraction was performed with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (148 mg, 100% yield).
Reaction SMILES: C(N1C(=O)C(N[C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])(C)C(=O)NC1=O)C.[NH2:26][C:27]1([CH2:42][CH3:43])[C:32](=[O:33])[N:31]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:30](=[O:40])[NH:29][C:28]1=[O:41]>>[CH:34]1([N:31]2[C:32](=[O:33])[C:27]([NH:26][C:12](=[O:23])[C:13]3[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=3[F:22])([CH2:42][CH3:43])[C:28](=[O:41])[NH:29][C:30]2=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Reactant: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Product: CCC1(NC(=O)c2cc(F)c(F)c(F)c2F)C(=O)NC(=O)N(C2CCCCC2)C1=O

Procedure:
Compound 20i was prepared by the same method described for 20f using 5-amino-1-cyclohexyl-5-ethylbarbituric acid (0.51 g, 2 mmol). The crude 1-cyclohexyl-5-ethyl-5-(tetrafluorobenzamido)barbituric acid (20i) was obtained as yellow crystals and did not require further purification.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[SH:50].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([CH:25]=[C:3]([CH2:2][S:50][C:41]4[CH:42]=[CH:43][C:44]5[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=5)[N:40]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Reactant: Sc1ccc2ccccc2n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CSc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 75b (70.2 mg, 0.209 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (10 mL) and DIEA (72.7 μL, 0.417 mmol) were added. MsCl (24.3 μL, 0.313 mmol) was added, and then the reaction was stirred at rt for 3 days. Additional MsCl (24.3 μL, 0.313 mmol) and DIEA (72.7 μL, 0.417 mmol) were added and the reaction was stirred for 2 h. The solvent was removed under reduced pressure. The crude material was placed in a 50 mL round bottom flask equipped with a stir bar, followed by addition of ACN (25 mL). 2-Quinolinethiol (38.2 mg, 0.230 mmol) and K2CO3 (43.3 mg, 0.313 mmol) were added and then the reaction was stirred at rt for 1 h. The temperature was increased to 80° C. and the reaction was stirred for 18 h. The reaction was cooled to rt, diluted with DCM (20 mL), and filtered. The solvent was removed under reduced pressure. The crude produced was purified by flash column chromatography on silica gel (25-g SiO2 pre-packed column, 0-100% EtOAc/heptanes) to afford compound 75c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.84 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.81-7.89 (m, 2H), 7.78 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.46-7.53 (m, 1H), 7.35 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 4.69 (s, 2H), 4.30-4.43 (m, 4H), 3.82-3.91 (m, J=4.5, 4.5 Hz, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H21N7OS: 480.2 (M+H). found: 480.1.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH:2]=[CH2:3].[H][H]>[Pd]>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:2][CH3:3]
Reactant: C=CCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Reactant: [H][H]
Agent: [Pd]
Product: CCCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1

Procedure:
In analogy to the procedure of Example XXXIV, the title compound is prepared from 7.5 g (0.0225 mol) of the compound from Example XXXVII and 0.8 g of Pd/C (5%) using hydrogen.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:19][C:18]([CH2:20][CH3:21])=[N:17][C:16]=3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:5]1([N:8]([C:9]2[CH:14]=[C:13]([C:15]3[S:19][C:18]([CH2:20][CH3:21])=[N:17][C:16]=3[C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:12]=[CH:11][N:10]=2)[C:1](=[O:3])[CH3:2])[CH2:7][CH2:6]1
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(NC3CC3)c2)s1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(N(C(C)=O)C3CC3)c2)s1
Reaction time: 4 h

Procedure:
At 40° C., 35 mg (0.44) mmol of acetyl chloride are added dropwise to a solution of 100 mg (0.29 mmol) of N-cyclopropyl-4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine-2-amine and 80 mg (0.58 mmol) of potassium carbonate in 5 ml acetonitrile. After 4 h, 30 ml of water are added, and the reaction mixture is extracted with ethyl acetate (3×25 ml). The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 39 mg (31%) of the desired product; 1H-NMR(MeCN-d3) δ: 8.40 (d, 1H), 7.49 (m, 2H), 7.16 (d, 1H), 7.108 (m, 3H), 3.05 (q, 2H), 2.99 (m, 1H), 2.07 (s, 3H), 1.40 (t, 3H), 0.79 (m, 2H), 0.44 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>O>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[N+:16]=[N-:17]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reaction time: 1 h

Procedure:
13.7 g of p-aminobenzoic acid was dispersed in a solution of 100 cc of water and 30 cc of 30% hydrochloric acid in an ordinary manner and the dispersion was cooled with ice. A solution of 8.3 g of sodium nitrite in 50 cc of water was added dropwise to the dispersion to effect the diazotization reaction. A solution of 10.1 g of sodium azide in 70 cc of water was added dropwise to the mixture, stirred for about one hour, filtered and vacuum-dried to obtain p-azidobenzoic acid. 5.4 g of the thus obtained p-azidobenzoic acid was dissolved in 10 cc of dimethylformamide and 25 g of thionyl chloride was added dropwise to the solution. The mixture was stirred for about one hour and the product was added dropwise to ice-water. After filtration followed by washing with water and vacuum drying, p-azidobenzoyl chloride was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](=O)[CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[N:22][C:21]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[N:23]=[N:22][C:21]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C(C)=O)cc2n1C(=O)OC(C)(C)C
Reactant: CN1CCNCC1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C(C)N3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Temperature: 65 °C

Procedure:
180 mg resin bound (2.57 mmol/g) sodium cyano borhydride are added to a solution of 80 mg 6-acetyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester, 22 mg N-methyl-piperazine and 0.062 ml acidic acid and the mixture stirred over night at 65° C. The crude product is isolated by filtration and evaporation of the solvent and is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.[CH2:25]([O:27][C:28]([C:30]1[NH:31][CH:32]=[N:33][C:34]=1[CH3:35])=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1[N:31]([CH2:23][CH2:22][C@@H:20]2[CH2:19][S:18][C:17]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:21]2)[CH:32]=[N:33][C:34]=1[CH3:35])=[O:29])[CH3:26]
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CCOC(=O)c1[nH]cnc1C
Product: CCOC(=O)c1c(C)ncn1CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and 5-methyl-3H-imidazole-4-carboxylic acid ethyl ester were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.C1(O)C=CC=CC=1.[Na].[K].[OH-]>O>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: COCCc1ccc(O)cc1
Agent: [K]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: Oc1ccccc1
Product: COCCc1ccc(OCC2CO2)cc1

Procedure:
p-(2-Methoxyethyl)phenol (A) and epichlorohydrin (B, 1.4-2.0 eqv.) are reacted in water, at least 1.5 kg, preferably about 2 kg of water per kg of phenol, during the addition of sodium (or potassium) hydroxide solution, (1.3-1.7 eqv.) to form 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)benzene; (p-methoxyethyl-epoxypropoxybenzene). The reaction is preferably performed at a temperature of 50-70° C.