Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N+:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[OH:26][C:27]1[CH:34]=[C:33]([CH3:35])[C:30]([CH:31]=O)=[C:29]([CH3:36])[CH:28]=1.C(N(CC)CC)C>CO>[CH3:12][O:11][C:9]([C:4]1[CH:5]=[CH:6][C:7]2[N:2]([N:1]=[C:31]([C:30]3[C:33]([CH3:35])=[CH:34][C:27]([OH:26])=[CH:28][C:29]=3[CH3:36])[N:8]=2)[CH:3]=1)=[O:10]
Reactant: COC(=O)c1ccc(N)[n+](N)c1
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)nn2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18 %

Procedure:
To a stirred solution of methyl 1,6-diaminopyridin-1-ium-3-carboxylate; 2,4,6-trimethylbenzenesulfonate (8 g, 21.68 mmol) in methanol (100 mL) is added 4-hydroxy-2,6-dimethyl-benzaldehyde (3.25 g, 21.68 mmol) and triethylamine (8.77 mL, 65.04 mmol) at 0° C. and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is concentrated and extracted with EtOAc (100 mL). The combined organic extracts are washed with water (2×100 mL), saturated ammonium chloride solution (50 mL), brine solution (50 mL), and dried over anhydrous sodium sulphate, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash 40 g redisep Rf column) and is eluted with 40-60% EtOAc in hexane to give the title compound as a pale yellow solid (1.2 g, 18%). LCMS m/z 298 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(S(=O)(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 90 °C
Yield: 114.3 %

Procedure:
A mixture of 10-[(4-bromophenyl)sulfonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step C (0.500 g, 0.93 mmol), 2-methoxyphenylboronic acid (0.212 g, 1.40 mmol) and potassium carbonate (0.386 g, 2.79 mmol) in dimethoxyethane:water (8 mL:2 mL) was purged with nitrogen for 10 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium[II] (38 mg, 0.0465 mmol) was then added and the reaction mixture heated to 90° C. for 21 hours. The cooled reaction mixture was partitioned between ethyl acetate (100 mL) and 1 M sodium hydroxide (100 mL). The separated organic phase was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a brown syrup (0.60 g). Purification by flash chromatography using a solvent gradient of 0 to 3% methanol in dichloromethane gave the title compound (0.520 g, 99%) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25]([OH:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[C:37](Cl)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]4[O:27][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)OC1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-one Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0° C. under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83% of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[N:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:19])([F:32])[F:31])[CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)nc1N
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: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)nc1N
Yield: 74 %

Procedure:
To a solution of the product from Step 1 (0.452 g, 1.45 mmol) in toluene (4 mL) were added 2-trifluoromethoxyphenylboronic acid (0.450 g, 2.18 mmol), tetrakis(triphenylphosphine)palladium (0.050 g, 3 mol %) and 2M sodium carbonate (1.45 mL, 2.9 mmol). The reaction was refluxed for 16 hours, then cooled and partitioned between EtOAc and water. The organic phase was washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo, and the crude product was purified by silica-gel chromatography using 4% EtOAc in hexanes to yield 0.42 g of the product (73% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)(Cl)Cl>[CH2:28]([NH:35][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCCCCCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -15° C. during 20 minutes. After stirring for 5 minutes, 10.14 g (0.088 mol) of heptylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -11° C. and -16° C. during 50 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then allowed to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.0 g (70.5%) of the named product as orange yellow crystals, m.p.: 118°-120° C.
Reaction SMILES: C([N:5]1[C:20](=[O:21])[C:9]2[CH:10]=[N:11][C:12]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:6]1=[O:27])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:22]1([N:7]2[C:8]3[C:17]4[CH:16]=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=4[N:11]=[CH:10][C:9]=3[C:20](=[O:21])[NH:5][C:6]2=[O:27])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1cccc2c1ncc1c(=O)n(C(C)(C)C)c(=O)n(C3CCCC3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1ncc1c(=O)[nH]c(=O)n(C3CCCC3)c12
Yield: 51.4 %

Procedure:
1-Cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (8 mg) was prepared from 3-tert-butyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg, 0.05 mmol) with treatment of trifluoroacetic acid (20 L) in DCM (1 mL). LCMS: m/z 312 [M+1]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:26])([CH3:25])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)C>[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
157 g of N-carbobenzoxy-L-phenylalanine in 500 ml methylene chloride and 300 ml absolute diethyl ether is treated at 15°-18° C. with 85.5 g L-proline tert.-butyl ester in 100 ml diethyl ether over 5 minutes, and then with 114 g of dicyclohexylcarbodiimide in 150 ml of diethyl ether over 15 minutes, both additions being at such a rate that the reaction mixture temperature does not rise above 18° C. The resultant mixture is stirred for a further hour at room temperature, and filtered, the solid residue being washed with ether. The filtrate is washed with, in turn, 2N hydrochloric acid, water, potassium bicarbonate, and then water, each washing being extracted with diethyl ether. All the organic phases are combined, dried over sodium sulphate and concentrated to yield an oily residue. The oily residue is taken up in methylene chloride, filtered, concentrated and dried in a high vacuum to yield the heading compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].ClC1C=CC=CC=1.[Br:19]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(CBr)cc1Cl
Temperature: 142.5 °C
Yield: 70 %

Procedure:
A mixture of 1-(2-chloro-4-methylphenyl)ethanone (1.6 g, 9.50 mmol) (preparation 15) and chlorobenzene (60 ml) was prepared at room temperature and N-bromosuccinimide (NBS) (1.86 g, 10.44 mmol) added followed by a catalytic amount of benzoyl peroxide (ca. 1.5 mg, 0.005 mmol), and the resulting mixture was heated to 140-145° C. for 16 h. The mixture was then allowed to cool to room temperature, diluted with toluene (50 ml) and filtered through a celite pad. The pad was washed with toluene (2×50 ml) and the filtrate concentrated under reduced pressure and purified by column chromatography (0-10% EtOAc/Hexanes) to afford 1-(4-(bromomethyl)-2-chlorophenyl)ethanone (1.65 g, 6.65 mmol, 70%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18](SC)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.O[O:25][S:26]([O-:28])=O.[K+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[CH3:42]O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([S:26]([CH3:42])(=[O:28])=[O:25])[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3occn23)n1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3occn23)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6-(4-fluorophenyl)-5-[2-(methylsulfanyl)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazole (E) (2.0 g, 6.13 mmol) in methanol (250 mL) is slowly added Oxone™ (potassium monopersulfate) (11.3 g, 18.4 mmol) in water (50 mL). The mixture is stirred at room temperature for 24 hours. The solvent is removed in vacuo and the residue dissolved in dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solids are removed by filtration and the solvent removed in vacuo. The residue is purified by silica gel column chromatography to provide 6-(4-fluorophenyl)-5-[2-(methylsulfonyl)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazole (F) (Compound XI, Table 1)) as a white solid (1.8 g, 82%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[C:11]([NH2:15])(=[O:14])[CH2:12][CH3:13]>>[NH:8]1[C:7]2=[C:2]([NH:15][C:11](=[O:14])[CH2:12][CH3:13])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: CCC(N)=O
Reactant: Clc1nccc2cc[nH]c12
Product: CCC(=O)Nc1nccc2cc[nH]c12
Yield: 15 %

Procedure:
N-(1H-pyrrolo[2,3-c]pyridin-7-yl)propanamide (Intermediate 8, yield: 15%) was synthesized from 7-chloro-1H-pyrrolo[2,3-c]pyridine using propanamide.
Reaction SMILES: FC(F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:43])[C:24]([N:27]2[C:32](=[O:33])[CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)C(=NO)C(=C)O2)([CH3:26])[CH3:25])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(OCC)(=O)C.[N:50]1C=CC=CC=1>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:43])[C:24]([N:27]2[C:32](=[O:33])[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:6]([C:7]#[N:50])[O:5][CH2:3]2)([CH3:25])[CH3:26])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: C=C1ON(C(C)(C)C(=O)Nc2cc(Cl)cc(Cl)c2)C(=O)C(c2ccccc2)C1=NO
Reactant: c1ccncc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)N1COC(C#N)=C(c2ccccc2)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic anhydride (3 ml) was added to a stirred solution of N-(3,5-dichlorophenyl)-2-(2,3-dihydro-6-hydroxyiminomethylene-4-oxo-5-phenyl-4H-2,3-oxazin-3-yl)-2-methylpropanamide (0.4 g) in pyridine (4 ml) at -5° C. After 0.5 hours ice and ethyl acetate was added and the mixture stirred for 1 hour. The organic phase was washed (water), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with hexane/ethyl acetate to give N-(3,5-dichlorophenyl)-2-(6-cyano-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 120, 0.16 g) as a white solid, m.p. 132.5-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6](=O)[CH2:5]2.Cl.[CH3:13][NH2:14]>>[CH3:13][NH:14][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1
Reactant: CN
Reactant: O=C1Cc2ccc(Cl)cc2C1
Agent: Cl
Product: CNC1Cc2ccc(Cl)cc2C1

Procedure:
Following the procedure of Example 5, 5-chloro-2-indanone and methylamine hydrochloride gave N-methyl-5-chloro-2-indanamine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.Cl.[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:23][C:16]1[CH:21]=[CH:20][C:19]([C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)=[C:18]([CH3:22])[CH:17]=1
Reactant: Cc1cccc(C)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of anhydrous aluminum chloride (19.5 g) dispersed in m-xylene (150 ml) was added dropwise 4-fluorobenzoyl chloride (21.1 g) under ice-cooling. The mixture was stirred at 0-10° C. for 3 hr and poured into 6N hydrochloric acid. The reaction mixture was partitioned and the obtained organic layer was washed successively with water, 10% aqueous sodium hydroxide solution and water. The solvent was evaporated to give a 96:4 mixture (30.2 g, 99%) of 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene and 1,3-dimethyl-2-(4′-fluorobenzoyl)benzene as pale-yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH2:10]=[O:11].C(O)(=O)C(O)=O>O>[OH:11][CH2:10][C:4]1([CH3:9])[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: C=O
Agent: O=C(O)C(=O)O
Solvent: O
Product: CC1=C(O)C(=O)C(C)(CO)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 10 g of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone, 20 ml of a 37% formaldehyde aqueous solution, 50 ml of water and 0.7 g of oxalic acid was stirred for 18 hours at room temperature. After working up the reaction mixture, the crude reaction product was purified by column chromatography over polyamide. Elution with pentane-dichloromethane 80/20 yielded the pure 2-hydroxymethyl-2,5-dimethyl-4-hydroxy-3-(2H)-furanone, which was recrystallized from ethyllactate m.p. 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(CC(O)C)N=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH:22]([OH:24])[CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(O)Cn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: CC(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 106 mg, 0.32 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 170 μL, 0.33 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (80 μL, 0.64 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-(3-amino-pyrazol-1-yl)-propan-2-ol (45 mg, 0.32 mmol) in methylene chloride (1 mL) and the reaction was allowed to warm up to 25° C. and stirred for 45 minutes. After this time the reaction was diluted with a small amount of methanol in methylene chloride and washed with aqueous 1 N hydrochloric acid solution (1×15 mL) and then a saturated aqueous brine solution (1×15 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (88 mg, 61%, diastereomeric mixture 1:1) as a white foam: ES-HRMS m/e calcd for C21H28N3O4SCl (M+H)+ 454.1562, observed 454.1559.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(OCC)C>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
100 g of 11-bromoundecanol (Fluka) is dissolved in 240 ml of tetrahydrofuran and mixed at 25° C. with 58 g of imidazole as well as 74.3 g of tert-butyldimethylsilyl chloride in 80 ml of tetrahydrofuran and stirred for 2 hours at 25° C. For working up, 700 ml of diethyl ether is added, the precipitated hydrochloride is filtered off, evaporated to dryness in a vacuum and chromatographed on silica gel with hexane/toluene. 136.9 g of 11-bromoundecyl-tert-butyldimethylsilyl ether is obtained as oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[C:10]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:25][CH:26]=3)[CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccnc(NCC3CC3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2ccnc(NCC3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Dissolve 4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-(tert-butoxycarbonyl)-benzylamine (195 mg, 0.55 mmol) in DCM (3 mL) and add trifluoroacetic acid (1.5 mL). Stir at room temperature for 3 h. Concentrate in vacuo and purify the crude mixture by SCX chromatography (5 g) to obtain the title compound (140 mg, 93%) suitable for use without additional purification. MS (ES+) m/z: 255 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[ClH:12].[CH2:13]=O>>[Cl:12][CH2:13][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: C=O
Reactant: Cl
Reactant: Oc1cccc2cccnc12
Product: Oc1ccc(CCl)c2cccnc12

Procedure:
As shown in Scheme A below, 8-hydroxyquinoline (A1) is treated with hydrochloric acid and formaldehyde to give 5-chloromethyl-8-hydroxyquinoline (A2). The chloro group of A2 is substituted with propargylamine to afford 5-(1-propargylamino)methyl-8-hydroxyquinoline (A3). Bromination of A3 employing N-bromosuccinimide (NBS) provides the bromide A4 which is then treated, for example, with the modified peptide [D-Cys6]GnRH to give the target compound A5, which is the compound M22A in Appendix I.