Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][CH:5]=2)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1Cl

Procedure:
5-Chloro-3-pyridinol (5 g, Aldrich) and 2,4-dichloronitrobenzene (7.4 g, Aldrich) were combined as described in Example 1. The title compound was isolated as the minor product using gravity chromatography on silica eluting with 10% ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH:18]2[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)[C:15](Cl)=[O:16])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH:18]2[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)N(Cc1ccc(Cl)cc1)C1CC2CCC1C2
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N(Cc1ccc(Cl)cc1)C1CC2CCC1C2
Yield: 64.4 %

Procedure:
Aniline (19 g) was dissolved in 400 ml of toluene, and with stirring and cooling, a solution of 30 g of N-4-chlorobenzyl-N-2-norbornylcarbamoyl chloride in 50 ml of toluene was added dropwise. After the addition, the temperature of the mixture was gradually raised, and it was stirred for about 10 hours at about 70° to 80° C. After cooling, the precipitated aniline hydrochloride was separated by filtration. The toluene layer was washed successively with water, a 1% aqueous solution of sodium carbonate, 1% hydrochloric acid and then water, and then dried over anhydrous sodium sulfate. Toluene was evaporated, and the residue was recrystallized from a mixture of hexane and ethanol to give 23 g of the desired 1-(4-chlorobenzyl)-1-(2-norbornyl)-3-phenylurea. mp. 111°-113° C.
Reaction SMILES: [NH:1]([C:35]([CH3:37])=[O:36])[C@@H:2]([C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@@H:21]1[C:22]([NH:24][C@@H:25]([C:29]([NH2:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.CC(O)=O.O.[H][H]>CCO.[Pd]>[NH:1]([C:35]([CH3:37])=[O:36])[C@@H:2]([C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@@H:21]1[C:22]([NH:24][C@@H:25]([C:29]([NH2:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](C(N)=O)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N[C@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](C(N)=O)C(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
107 g of Ac-D-Lys(Z)-D-Pro-D-Val-NH2 are dissolved in 535 ml of EtOH, added with 214 ml of AcOH and of 21.4 g of Pd/C at 10% at 50% water. The hydrogenation is conducted at 20° C., under a 1 bar hydrogen pressure for 16 hours. The reaction completion is CCM controlled. The catalyst is filtered and the filtrate is vacuum concentrated until refusal. The residue is recovered with 107 ml of EtOH, added with 430 ml of iPrOH and the blend is heated at 50° C., then added dropwise at 50° C. with 1500 ml of diisopropyl ether. The expected product crystallizes. The medium is cooled down to 20° C. and stirred for 1 hour. The solid is filtered and washed with 500 ml of diisopropyl ether before being vacuum dried at 25° C. so to provide 78.3 g of Ac-D-Lys-D-Pro-D-Val-NH2 under the form of an acetate salt (yield 85.4%). The thus obtained product purity is HPLC controlled.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.7 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.03 g, 0.006 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.22 g, 0.025 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-m-tolyloxy-but-2-enoic acid ethyl ester (1.50 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (495 mg, 25%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=O.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=[CH:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Chloro-4-cyclohexylbenzaldehyde (0.1 mole), malonic acid (0.2 moles), and dry pyridine (175 ml) are placed in a 1 l roundbottom flask. The malonic acid is dissolved by shaking on a steam bath and piperidine (0.5 ml) is added. The reaction is allowed to take place on the steam bath for 4 hours. After standing at room temperature overnight, the mixture is refluxed for 1 hour and cooled. The reaction mixture is poured into 250 ml of ice water and acidified with concentrated hydrochloric acid (80 ml) with stirring. The crystals of product are collected by filtration, washed with water (4 × 150 ml) and air dreid. Recrystallization from acetone-water gives 3-chloro-4-cyclohexylcinnamic acid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]([CH2:17][CH2:18][CH2:19][C:20]2([CH3:25])OCC[O:21]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:15])[C:6]=2[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[NH2:15][C:7]1[C:6]2[N:16]=[C:3]([CH3:2])[N:4]([CH2:17][CH2:18][CH2:19][C:20](=[O:21])[CH3:25])[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCC1(C)OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
Concentrated hydrochloric acid (3 mL) was added to 2-methyl-1-[3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol), and the mixture stirred for a few minutes until everything was in solution. Water (5 mL) was then added and the solution stirred for one hour at room temperature. After the addition of dichloromethane (75 mL) and water (25 mL), the solution was made basic by the slow addition of potassium carbonate (10.0 g). The layers were separated, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one, mp 194-196° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1Br)=[O:13].C(=O)([O-])[O-].[K+].[K+]>>[CH3:19][C:17]1[S:16][C:15]2[O:1][C:2]3[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=3[NH:11][C:12](=[O:13])[C:14]=2[CH:18]=1
Reactant: Cc1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1NC2=O

Procedure:
In the same manner as in Example 98 and using N-(2-hydroxy-4-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate, 2-methyl-8-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one is obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](N)=[C:4]([CH3:13])[CH:3]=1.[ClH:14].N([O-])=O.[Na+]>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:14])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Br)c2ccccc2c1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)c2ccccc2c1Cl
Temperature: 60 °C
Yield: 58 %

Procedure:
To a solution of 4-bromo-2-methyl-1-naphthlamine (10 g) in a mixture of concd. hydrochloric acid (14 ml) and water (14 ml) was added dropwise a solution sodium nitrite (2.8 g) in water (7 ml) at -5°-0° C. The diazonium solution was stirred at 0°-5° C an hour. There was added to it an ice-cooled solution of cuprous chloride (4.4 g) in concd. hydrochloric acid (25 ml). The mixture was stirred at 60° C an hour, and the precipitate was extracted with ether and dried. After evaporating the solvent, the residue was distilled to give a colorless oil(5.4 g, 58 %), bp11 127°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:4][CH:3]=1.Cl[C:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[C:23]=1[Cl:31])=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:20]([C:22]2[S:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:23]=2[Cl:31])=[O:21])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cc2)c1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2sc3ccccc3c2Cl)c(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-amino-5-methylbenzamide (0.11 g, 0.42 mmol) in pyridine (5 mL) at 0° C. was added 2-chlorocarbonyl-3-chlorobenzo[b]thiophene (0.15 g, 0.64 mmol), and the mixture allowed to warm to ambient temperature with stirring. After 16 hours, the mixture was poured onto water (5 mL) and the resulting white solid collected by filtration and dried in vacuo. Recrystallization from acetonitrile afforded 0.095 g (50% yield) of N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide, as a white crystalline solid; NMR (DMSO-d6/TFA) 11.4 (s, 1), 10.7 (s, 1), 8.2 (d, 1), 7.4-8.2 (m, 10), 2.4 (s, 3) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO.O>[OH:17][N:16]=[CH:1][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C=Cc1ccc(C=NO)cc1
Reaction time: 8 h

Procedure:
4.0 g of methyl 4-formylcinnamate are dissolved in 40 ml methanol and then 1.6 g hydroxylamine-hydrochloride and 1.9 g sodium acetate are added. The mixture is stirred overnight and then diluted with 300 ml water. The precipitate is filtered by suction, dried in vacuo and crystallized from ethyl acetate/petrolether. This gives 3.56 g of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][C:18]2[CH:13]=[CH:14][C:15]([CH3:20])=[CH:16][CH:17]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (0.13 g, 0.79 mmol) was dissolved in N,N-dimethylformamide (6.7 mL), and p-cresol (0.22 g, 2.0 mmol) and potassium carbonate (0.27 g, 2.0 mmol) were added thereto, followed by stirring at 25° C. for 1.5 hours. After a conventional treatment, the residue was purified by silica gel chromatography (eluted with chloroform), to obtain 5-nitro-2-(4methylphenoxy)benzaldehyde (0.20 g, 98%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([F:24])([F:23])[F:22])=[CH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl.FC(F)(F)[C:28]1[NH:29]C2C(C=1)=CC(CN)=CC=2>>[C:2]([C:3]1[N:29]=[CH:28][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([F:24])([F:23])[F:22])=[CH:15]3)=[O:9])=[CH:5][CH:4]=1)#[N:7]
Reactant: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1cccc(Br)n1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: Cl
Product: N#Cc1ccc(C(=O)NCc2ccc3[nH]c(C(F)(F)F)cc3c2)cn1

Procedure:
The title compound was prepared by a similar procedure to that described for Compound 3 using the appropriate carboxylic acid with 2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5):
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O.O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: NC(=O)c1ccc2nc3cscc3c(=O)n2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc2nc3cscc3c(=O)n2c1
Temperature: 95 °C

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (3.8 g., 0.015 mol), p-toluenesulfonyl chloride (4.4 g., 0.023 mol) and pyridine (3.8 ml, 0.046 mol) in dimethylformamide (50 ml) is heated at 95° C. for 1 hour. The mixture is cooled, diluted with water (5 ml) and stirred. The precipitate is filtered, washed with water and dried. Recrystallization from 2-propanol gives golden crystals (2.5 g.) mp 233°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: OCCCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 107.7 %

Procedure:
At rt to a suspension of 3-(3,4-dichlorophenyl)propanoic acid (2.0 g, 9.1 mmol) in THF (40 mL) was added borane-THF (18.3 mL, 1.00M in THF, 18.3 mmol). After 12 h, the reaction mixture was cooled to 0° C. and quenched by the cautious addition of 1M NaOH. The reaction mixture was diluted with ether, washed with water twice, then brine, and the organic portion dried over MgSO4, filtered, and concentrated. Trituration with 10% Ethyl acetate/Hexane (300 mL) gave a white powder which was collected by filtration to give Intermediate 17A (2.00 g, 9.80 mmol, 100% crude). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.73-1.81 (2H, m), 2.56-2.65 (2H, m), 3.59 (2H, t, J=6.4 Hz), 6.96 (1H, dd, J=8.0, 2.0 Hz), 7.22 (1H, d, J=2.0 Hz), 7.27 (1H, d, J=8.3 Hz).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[N:10]=1)(=[O:8])[CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:3])[N:10]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1cccc(CO)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(CCl)n1

Procedure:
Phosphorus oxychloride (7.8 ml) was dropwise added to a mixture of 2-acetyl-6-hydroxymethylpyridine (10.0 g) and N,N-dimethylformamide (15.4 ml) in ethyl acetate (100 ml) under ice-cooling with stirring and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was added to water and adjusted to pH 7.5 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-acetyl-6-chloromethylpyridine (10.85 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Li].C([Li])(C)(C)C.[CH:31](=[O:33])[CH3:32]>C(OCC)C.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10]([CH:31]([OH:33])[CH3:32])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Reactant: CC=O
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(NC(=O)OC(C)(C)C)ccc1NC(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 85.1 %

Procedure:
3.3 g (0.01 mol) (4-tert.butoxycarbonylamino-3-bromophenyl)carbamic acid-tert.-butyl ester are dissolved in 200 ml diethyl ether under argon. Then first 20 ml of a 1.6 molar methyl lithium solution are added at −25° C. and then 16 ml of a 1.6 molar tert.-butyl lithium solution are added. After one hour 1.2 ml (0.02 mol) of acetaldehyde are added and the reaction mixture is slowly heated to 20° C. After halting the reaction the reaction mixture is hydrolyzed with water, the organic phase is extracted with dilute sodium hydroxide and then dried with magnesium sulfate. The solvent is distilled off in a rotary evaporator and the residue is purified with petroleum ether/acetic acid ethyl ester (8:2). 3.0 g (85% of theoretical) of (4-tert.-butoxycarbonylamino-3-(1-hydroxyethyl)phenyl)carbamic acid-tert.-butyl ester having a melting point of 189° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:44]1([S:50]([C:53]2[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=2)[C:56](O)=[O:57])(=[O:52])=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C.CN(C=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:56](=[O:57])[C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([S:50]([N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)(=[O:52])=[O:51])[CH:54]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
1-(4-aminophenyl)ethanone (151 mg), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (565 mg) and N,N-diisopropylethylamine (0.39 mL) were added in that order to a DMF (4.0 mL) solution of 3-(piperidin-1-ylsulfonyl)benzoic acid (200 mg), and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction liquid, washed three times with water, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 80%, gradient) to give the entitled compound (117 mg, 41%) as a white crystal.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:9]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])[CH2:2]2.[CH3:23][C:24]([O:27][C:28]([NH:30][C@@H:31]([C:40](O)=[O:41])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:29])([CH3:26])[CH3:25].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:24]([CH3:26])([CH3:23])[CH3:25])[C:40]([N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([N:9]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:10]([N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:11])[CH2:2]3)=[O:41])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
1.8 g of N-8-azabicyclo[3.2.1]oct-3-yl-N-cyclohexyl-N′,N′-diethylurea are dissolved in 70 ml of dichloromethane in the presence of 1.75 g of Boc-D-4-chlorophenylalanine, of 0.79 g of hydroxybenzotriazole, of 1.12 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and of 1.02 ml of diisopropylethylamine. The mixture is stirred at ambient temperature for 16 h. After evaporation to dryness, the residue is hydrolysed and extracted with ethyl acetate until the aqueous phase is completely depleted. The organic phase is washed with H2O and then with a saturated aqueous sodium chloride solution. After drying over MgSO4 and concentration to dryness, the crude is chromatographed on silica gel, elution being carried out with a 99/1 mixture of dichloromethane and methanol, to give 1.42 g of tert-butyl [(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(di-ethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.[CH3:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Reactant: CN
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (267.9 mg, 0.890 mmol) in methanol (5 mL) was added a 2M solution of methylamine in methanol (0.890 mL, 1.779 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (184.6 mg, 0.624 mmol, 70.2% yield) as brown solid. LC-MS (M+H)+=296.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([N+:16]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:6]([NH2:16])[CH:5]=1
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1N
Reaction time: 4 h

Procedure:
7.00 g of 4-(1-Ethyl-propylamino)-3-nitro-benzoic acid methyl ester were dissolved in 70 ml ethanol, 0.35 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. The catalyst was removed by filtration over celite, the filtrate was concentrated and after crystallization from diethylether 5.00 g (65%) of 3-Amino-4-(1-ethyl-propylamino)-benzoic acid methyl ester were obtained.