Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[N:4][N:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][Cl:11].Cl.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[ClH:11].[Cl:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[N:5]([CH3:12])[N:4]=[C:3]2[C:2]=1[C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:16]=[C:13]2[NH2:14]
Reactant: Nc1ccccc1B(O)O
Reactant: Cn1nc(C#N)c(Br)c1CCCCCl
Agent: Cl
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Temperature: 115 °C

Procedure:
The method described in Part F of Example 46 was used to couple 4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile (16.0 g, 60.0 mmol) and 2-aminophenylboronic acid hydrochloride (20.8 g, 0.120 mol). After the mixture was heated at 115° C. for 24 hours, it was cooled to ambient temperature and filtered through a plug of silica gel (eluting with 3:2 chloroform/methanol). The filtrate was concentrated under reduced pressure and dissolved in ethanol (300 mL). Hydrogen chloride (45 mL of a 4 M solution in ethanol) was added to the solution, and the reaction was heated at reflux for two hours and then cooled to ambient temperature. A precipitate formed and was isolated by filtration and washed with ethanol to provide 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride. The filtrate was concentrated under reduced pressure and the resulting solid was dissolved in dichloromethane and water. The pH of the solution was raised to 14 using 50% aqueous NaOH while keeping the temperature at 0° C. by adding ice. The layers were separated, the aqueous layer was extracted with additional dichloromethane, the organic layers were combined, dried over Na2SO4, filtered and concentrated to a dark yellow oily solid. The residue was purified by chromatography using a HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine. This solid was purified as light tan crystals, mp 188-189° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:8])[CH2:6][OH:7].C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>C1COCC1>[CH2:4]([CH:5]1[CH2:6][O:7][C:16](=[S:17])[NH:8]1)[CH2:3][CH2:2][CH3:1]
Reactant: CCCCC(N)CO
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC1COC(=S)N1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a stirred cold solution of DL-2-amino-1-hexanol (1.1 ml) in dry THF (10 ml) was added triethylamine (2.8 ml) followed by dropwise addition of thiophosgene (0.81 ml) in dry THF (9 ml). The mixture was then stirred for 18 h at 20° C., evaporated under reduced pressure and the residue partitioned between water and diethyl ether. The ether extract was dried with sodium sulphate filtered and evaporated. The residue was dissolved in the minimum of hot 1:1 dimethylether-hexane and crystallised on cooling to give 4-butyloxazolidine-2-thione, mp 71-2°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:28]#[C:27][CH2:26][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: C#CCN1CCCC1
Reactant: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1
Product: O=C1Cc2cnc(Nc3ccc(C#CCN4CCCC4)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-36) and 1-(prop-2-ynyl)pyrrolidine were converted to I-47 (52%): HRMS Calcd. for C25H22ClN5O: 444.1591, Found 444.1589.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:14]([CH3:27])[C:15]3[N:19]([CH3:20])[C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[N:17][N:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:27][N:14]([CH2:13][C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:28]#[N:29])[N:9]=1)[C:15]1[N:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:17][N:16]=1
Reactant: CN(Cc1nnn(-c2cccc(I)c2)n1)c1nnc(-c2ccncc2)n1C
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(Cc1nnn(-c2cccc(C#N)c2)n1)c1nnc(-c2ccncc2)n1C

Procedure:
The title compound is prepared from [2-(3-Iodo-phenyl)-2H-tetrazol-5-ylmethyl]-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.[I-].[Na+]>>[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: O=C(CCCCl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Product: C[C@@H]1CCC[C@H](C)N1CCCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 619 g. of γ-Chlorobutyrophenone, ethylene ketal, 700 g. of cis-2,6-dimethylpiperidine and 16 g. of sodium iodide is stirred and heated at reflux for 48 hours. The mixture is cooled, diluted with 1 l. of anhydrous ether and filtered to remove cis-2,6-dimethylpiperidine hydrochloride. The filter cake is washed with 1 l. of ether and the filtrate and washings combined. The resulting ether solution is washed five times with 500 ml. portions of water, then extracted with a solution of 300 ml. of concentrated hydrochloric acid in 3 l. of water. The acid extract is washed with 500 ml. of ether, then heated to 70°-80° and allowed to cool to room temperature over a period of 16 hours. The resulting solution is basified with 50% aqueous sodium hydroxide and the organic layer is separated. The aqueous layer is extracted with 500 ml. of ether and the extract is combined with the organic layer. The combined extract is washed several times with water, dried and evaporated. The oily residue is distilled at reduced pressure to give cis-γ-(2,6-dimethylpiperidino)butyrophenone; b.p. 138°-141° C./0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](C2C=CC=CC=2S([O-])(=O)=O)=[C:4]([CH3:21])[CH:3]=1.[OH-:22].[Na+].Cl>O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:22])=[C:4]([CH3:21])[CH:3]=1
Reactant: [OH-]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1-c1ccccc1S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Reaction time: 2 h

Procedure:
84.2 (0.26 mol) of the ester from step 2 are suspended in 1 l of water and mixed with 30.8 g (0.77 mol) of sodium hydroxide platelets. After 2 hours cooking under reflux the starting material is cooled and the solution is adjusted to a pH value of 2.1 with 2 N hydrochloric acid. The precipitated material is filtered by suction, washed with water and dried in vacuum at 50° C. The yield amounts to about 45.6 g 95.4% of the theoretical yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1>O1CCCC1>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)(=[O:11])=[O:10]
Reactant: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
89 μl of triethylamine and 50 μl of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 321 mg of (2S,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinyl carbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 3.2 ml of dry tetrahydrofuran, and the resulting mixture was stirred at between 0° C. and 5° C. for 30 minutes and then at room temperature for a further 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate; the mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 345 mg of the title compound as a powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>ClCCl>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:20](=[O:22])[CH3:21])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2]
Reactant: CC(=S)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Yield: 95 %

Procedure:
A solution of 5-(S)-thioacetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one (0.070 g, 0.247 mmol), acetic anhydride (0.25 mL), pyridine (0.38 mL), and dichloromethane (0.75 mL) was stirred at r.t. for 4 h. Solvent was removed under vacuum and the crude product purified by PTLC (10% MeOH in DCM) to give a white solid (0.076 g, 95%). M.p. 200-1° C.; MS (m/z): (M+H)+=326.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:18]=1.C1COCC1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)oc1cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)oc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a mixture of methyl 3-bromo-dibenzofuran 7-carboxylate (3.2 g, 10.5 mmol) in 2:1 THF:methanol (90 ml) was added 2.5N NaOH (60 ml). After stirring at room temperature for 1 hour, the reaction was complete. Nearly all the THF:methanol was evaporated off and then the mixture was adjusted to pH=1 with concentrated HCl and extracted with ethyl acetate. Drying (MgSO4) and evaporation yielded 3.1 g (100%) of the title compound which was used in the next reaction without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][NH2:22])=[CH:12]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)[N:7]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(NCCc2c[nH]c3ccccc23)nc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine-5-carbonitrile (2.0 g, 11.5 mmol), 2-(1H-indol-3-yl)-ethylamine (1.83 g, 11.4 mmol), and DIEA (1.94 g, 15.0 mmol) in THF (50 mL) was stirred at 50° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was diluted with ethyl acetate (150 mL). The organic layer was washed with saturated aqueous ammonium chloride, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuum to give the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound as a brown solid (1.3 g, 4.38 mmol, 38% yield). MS (ESI) m/z 298.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:16]O>S(=O)(=O)(O)O>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C(=O)C2CC2)cc1
Reaction time: 24 h
Yield: 68 %

Procedure:
Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in methanol (100 mL) containing concentrated sulfuric acid (10 drops). Stir 24 hours. Add triethylamine (2 mL) and concentrate the solution. Dissolve the residue in water/ethyl acetate. Wash the organic phase with saturated sodium hydrogen carbonate solution, dry over anhydrous magnesium sulfate and concentrate. Purify by silica gel chromatography (400 mL silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (4.6 g, 68%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[CH3:17][CH:18]1[CH2:27][C:26]2[C:25]([OH:28])=[CH:24][CH:23]=[CH:22][C:21]=2[O:20][CH2:19]1>CN(C)C=O>[CH3:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:28][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[O:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1COc2cccc(O)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1COc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2C1
Temperature: 110 °C
Yield: 195.9 %

Procedure:
In a microwave vial, 3-methyl-3,4-dihydro-2H-chromen-5-ol (Intermediate 117, 53 mg), potassium carbonate (134 mg, 0.968 mmol) and 2-chloro-5-nitropyridine (51.2 mg, 0.323 mmol) were dissolved in N,N-dimethylformamide (2 ml) to give a light brown solution. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 hour. After cooling, the reaction mixture was quenched with 5 ml of water and diluted with 10 ml of Et2O. Phases were separated by a separating funnel. The aqueous phase was extracted with 3×10 ml of Et2O. The collected organic phase were dried using a hydrophobic frit and evaporated under vacuum to give the title compound as a brown oil (181 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].[Br:29][C:30]1[CH:31]=[C:32](I)[C:33]([NH2:36])=[N:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:32]2[C:33]([NH2:36])=[N:34][CH:35]=[C:30]([Br:29])[CH:31]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Reactant: Nc1ncc(Br)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cc(Br)cnc2N)cc1OC(C)c1ccccc1Cl
Yield: 79.4 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.1 Eq.), 5-Bromo-3-iodo-pyridin-2-ylamine (100 mg, 0.34 mmol, 1.0 Eq.) and Pd(PPh3)4 (39 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.5 mL, 1.0 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (40% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (125 mg, 0.27 mmol, 80%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.92 (3H, s), 4.71 (2H, br s), 5.81 (1H, q), 6.81 (1H, s), 7.24-7.32 (2H, m), 7.38 (1H, dd), 7.54 (1H, d), 7.66 (1H, dd), 8.10 (1H, d)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=O)[CH3:2].I[C:20]1[CH:21]=[C:22](C=C[CH:28]=1)[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:23]([C:22]1[CH:2]=[C:1]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[CH:7][C:6]=2[N+:16]([O-:18])=[O:17])[CH:28]=[CH:20][CH:21]=1)([OH:25])=[O:24]
Reactant: CC(=O)Nc1ccc(-c2ccoc2)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc(Nc2ccc(-c3ccoc3)cc2[N+](=O)[O-])c1

Procedure:
A mixture of 1e from Example 19 (5 g, 24.5 mmol), 3-iodobenzoic acid (6.69 g, 27 mmol), potassium carbonate (3.79 g, 27.5 mmol) and a catalytic amount of copper-bronze in 30 ml dry N-methyl-2-pyrrolidone is heated to 180° C. overnight. After cooling water is added and the mixture is washed twice with ethyl acetate. The aqueous phase is rendered acidic with diluted hydrochloric acid and the oily precipitate is filtered off. This precipitate is extracted with ethyl acetate, and the extract is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 2.56 g (32%). Mp 203-205° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:32]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c(Cl)s1
Yield: 70.9 %

Procedure:
To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxyimino)acetic acid (5.81 g, 13.47 mmol) in DMF (30 mL) at room temperature (1 mL) was added N-chlorosuccinimide (1.80 g, 13.47 mmol). After overnight reaction the reaction mixture was poured into water (about 500 mL) and the resulting precipitate was filtered, washed with water and then with ethyl acetate and dried in vacuum to afford 4.43 g (71%) of the title compound. 13C NMR (CDCl3) δ 108.5, 125.6, 126.2, 126.6, 12.3, 134.7, 141.8, 146.5, 162.1, 163.3.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.[C:21]([O:25][C:26](=[O:39])[NH:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:21]([O:25][C:26](=[O:39])[NH:27][CH2:28][CH2:29][N:30]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]=[CH:3][N:4]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(Cl)C1CCN(c2ncnc3ccccc23)CC1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)C1CCN(c2ncnc3ccccc23)CC1
Reaction time: 12 h
Yield: 57.5 %

Procedure:
Step 1-Quinazolin-4-yl-piperidine-4-carbonyl chloride hydrochloride (197 mg, 0.63 mmol) was added to a solution of [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol) in DCM (6.5 mL) cooled in an ice bath. After being stirred for 12 hours, the mixture was partitioned between DCM (50 mL) and H2O (80 mL) containing 1 mL of 1.0 M HCl. The DCM layer was drained off and the acidic aqueous layer was extracted 3 more times with DCM. The combined DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using EtOAc as eluent to give {2-[(4-chlorobenzyl)-(1-quinazolin-4-yl-piperidine-4-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (190 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C@@H:21]2O>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:21]3[C:22]4[C:18](=[C:17]([Br:16])[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O[C@H]1CCc2c1ccc(C(F)(F)F)c2Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21

Procedure:
The title compound is prepared from [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester and (S)-4-bromo-5-trifluoromethyl-indan-1-ol following a procedure analogous to that described in Step 2 of Intermediate 2. LC (method 5): tR=1.62 min; Mass spectrum (ESI+): m/z=471/473 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[C:16]#[CH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:21]=1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[C:16]#[C:17][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:25]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Ic1ccc(CCN2CCCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(CCN2CCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 2.1.e. from propynoic acid-(4′-chlorobiphenyl-4-yl)amide and 1-[2-(4-iodophenyl)ethyl]pyrrolidine. Yield: 70 mg (32.8% of theory); melting point: 217-218 C; C27H25ClN2O (M=428.96); calc.: molecular ion peak (M+H)+: 429/431; found: molecular ion peak (M+H)+: 429/431; Rf value: 0.3 (silica gel, dichloromethane/methanol (10:1)).