Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>C(O)C.CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:28][CH2:27][CH2:26][NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCN
Reactant: BrCCCCCCCCCCCCCCCCCCc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: NCCNCCCCCCCCCCCCCCCCCCc1ccccc1

Procedure:
A solution of 15.8 grams (0.04 mole) of phenylstearyl bromide and 19.25 grams (0.32 mole) of ethylene diamine in 250 ml of ethanol was refluxed for 3 hours. The alcohol solvent was removed under reduced pressure and the resulting mixture separated into two layers. The lower layer was removed and 100 ml of water added to the top layer. The oily layer which then formed was dissolved in ether and washed free of residual ethylene diamine with water. The ether solution was dried over anhydrous sodium sulfate and the ether stripped off under reduced pressure to yield 13 grams (87% crude mass yield) of N-phenylstearyl ethylene diamine having the following analysis:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[N:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)[CH:12]=1)=[O:7])C.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[C:22]1([C@@H:20]([NH:19][C:15]2[N:14]=[C:13]([N:11]3[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[C:10]3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[CH:18]=[CH:17][N:16]=2)[CH3:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cn(-c2ccnc(N[C@@H](C)c3ccccc3)n2)c(-c2cccc(C(F)(F)F)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H](Nc1nccc(-n2cc(C(=O)O)nc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 60 °C
Yield: 88.7 %

Procedure:
LiOH (3.75 g, 0.1566 mol) dissolved in a minimum amount of water was added to (S)-1-[2-(1-phenylethylamino)pyrimidin-4-yl]-2-(3-trifluoromethylphenyl)-1H-imidazole-4-carboxylic acid ethyl ester (4.2 g, 0.0087 mol) in 20 mL THF. 3 mL MeOH was added and the solution warmed to 60° C. for 45 min. After cooling to room temperature, the reaction was acidified with pH 4.5 citric acid solution (buffered with NaOH) and extracted with ethyl acetate (2×150 mL). The ethyl acetate was dried over anhydrous magnesium sulfate and concentrated to give 3.5 g of a solid. The solid was stirred vigorously for 30 minutes as a slurry in Et2O and filtered to give the title compound (2.5 g ) as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:38]=[CH:37][C:8]([C:9]([N:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:41]I.[Cl-].[NH4+]>C1COCC1>[CH3:41][CH2:2][C:1]([NH:4][C:5]1[CH:38]=[CH:37][C:8]([C:9]([N:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28](=[O:36])[C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)=[O:3]
Reactant: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(OC)cc2)cc1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
4-Acetylamino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methoxyphenyl)benzamide (155.0 mg, 0.30 mmol) was dissolved in THF (3.0 ml) to which were subsequently added 60% sodium hydride {28.0 mg, 0.70 mmol) and methyl iodide (0.060 ml, 1.00 mmol) at room temperature, followed by 2 hours of stirring. The reaction solution was mixed with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was recrystallized from methanol-ether to obtain 128.0 mg (80.4%) of the title compound in a colorless powder form.
Reaction SMILES: O=[C:2]([C:8]1[C:25]2=[C:26]3[C:15]([C:16]4[C:27]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=5)[CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].NN.[OH-].[Na+]>C(O)COCCO>[C:8]1([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:25]2=[C:26]3[C:15]([C:16]4[C:27]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=5)[CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc2cccc3c4cccc5cccc(c1c23)c54
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Product: O=C(O)CCCc1ccc2cccc3c4cccc5cccc(c1c23)c54
Temperature: 25 °C
Yield: 99.8 %

Procedure:
The compound 72 (0.390 g, 1.11 mmol), 0.4 ml of 79% aqueous hydrazine, and 0.290 g (7.25 mmol) of sodium hydroxide were dissolved in 3.0 ml of diethylene glycol, followed by 90-minute refluxing in a 180-° C. oil bath. The excess hydrazine and water were distilled away, and the refluxing was continued for two more hours. After the reaction was completed, the solution was cooled back to room temperature, to precipitate a solid substance. The solid substance was collected by filtration, and was washed with ion-exchange water and 2M hydrochloric acid, followed by drying under reduced pressure. This solid substance was dispersed in 10 ml of xylene, and was heated to 140° C. In this manner, the solid substance was dissolved. After that, the substance was cooled slowly back to room temperature, to precipitate a solid substance. The solid substance generated here was collected by filtration, and was dried under reduced pressure, to obtain 0.375 g of the black solid substance 73.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]1[C:15]2([CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CCO>CS(C)=O>[CH2:14]1[C:15]2([CH2:19][CH2:18][N:17]([C:8]3[C:2]([Cl:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH2:6])[CH:7]=3)[CH2:16]2)[CH2:13]1
Reactant: C1CC2(CC2)CN1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: ClCCl
Product: Nc1cc(N2CCC3(CC3)C2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4,5-dichloro-2-nitroaniline (470 mg, 2.3 mmol), 5-aza-spiro[2.4]heptane (320 mg, 3.3 mmol) and potassium carbonate (470 mg, 3.4 mmol) in DMSO (5 mL) in analogy to example 3, step (a). Yield: 550 mg (91%). Rf(TLC): 0.85 (silica gel, DCM:EtOH 99:1). HPLC-method F: Rf=1.01 min. MS m/z: 533 [2M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:9]3=[CH:10][N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]3[CH:14]=[CH:13]2)=[CH:17][CH:18]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 143, 50 mg, 0.15 mmol) in methylene chloride (2 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.11 mL, 0.23 mmol) and stirred at 0° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminopyrazine (29 mg, 0.30 mmol) and pyridine (0.06 mL, 0.76 mmol) in tetrahydrofuran (2.5 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 50/50 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide (53 mg, 86%) as a white foam: EI-HRMS m/e calcd for C19H22ClN3O3S (M+) 407.1070, found 407.1073.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[N+:5]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])([O-:7])=[O:6].[N:15]#[C:16][NH2:17]>C(O)C>[N+:1]([O-:4])([OH:3])=[O:2].[N+:5]([C:8]1[CH:9]=[C:10]([NH:11][C:16]([NH2:17])=[NH:15])[CH:12]=[CH:13][CH:14]=1)([O-:7])=[O:6]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1cccc([N+](=O)[O-])c1

Procedure:
42 ml (0.6 mol) of nitric acid (65%) are added dropwise to a yellow suspension of 82.88 g (0.6 mol) of 3-nitroaniline in 200 ml of ethanol. After the exothermic reaction has subsided, 75.7 g (0.9 mol) of cyanamide (50% in water) are added and the reaction mixture is boiled at reflux for 21 hours. After cooling to 0°, the mixture is filtered and washed six times with ethanol/diethyl ether (1:1). Drying under HV at 40° yields 3-nitrophenyl-guanidine nitrate; m.p. 205°-207°.
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C3CCCCO3)=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:10](/[CH:9]=[CH:8]/[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C[C@H](/C=C/Cc1ccccc1)c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)C[C@H](/C=C/Cc1ccccc1)c1ccc(O)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of 83.5 (405.8 mg, 1.03 mmol, MW 394.50) in EtOH (11 mL) at 23° C. was added PPTS (catalytic). Stirring was continued for 16 hours. The reaction was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing a colorless oil. The desired product was contaminated (˜5%) with a further olefinic product (believed to contain a terminal double bond) and was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH:13](S(CC)(=O)=O)[CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O>>[CH2:13]([S:10]([N:9]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:22]2[N:21]([CH3:20])[C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=1)[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])(=[O:12])=[O:11])[CH3:14]
Reactant: CCS(=O)(=O)C(C)S(=O)(=O)NCc1cncc(Br)c1
Reactant: Cn1c(B(O)O)cc2ccccc21
Product: CCS(=O)(=O)N(Cc1cncc(-c2cc3ccccc3n2C)c1)S(=O)(=O)CC

Procedure:
N-((5-Bromopyridin-3-yl)methyl)-1-(ethylsulfonyl)ethanesulfonamide and N-methyl-indole-2-boronic acid are processed according to the procedure described in Example 100 to give N-(ethylsulfonyl)-N-((5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide. MS (ESI) m/z 422.0 (M+H)+.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([NH:36][CH2:37][CH2:38]O)[CH2:33][CH2:34][CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:38][CH2:37][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:38][CH2:37][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCCCNCCO
Solvent: CCO
Product: CCCCNCCB(c1ccccc1)C(OC(B(CCNCCCC)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (38 mg) was obtained by allowing 44 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 24 mg of N-butylethanolamine to act in 1 mL of ethanol.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]1.Br[CH2:24][CH2:25][CH:26]1[O:30][CH2:29][CH2:28][O:27]1>O1CCCC1.O.C(Cl)Cl>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([S:19]([CH2:22][CH2:24][CH2:25][CH:26]2[O:30][CH2:29][CH2:28][O:27]2)(=[O:21])=[O:20])[CH2:17][CH2:18]1
Reactant: CN1CCN(S(C)(=O)=O)CC1
Reactant: BrCCC1OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)CCCC2OCCO2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
At 0° to 5° C., 87.5 ml of 1.6 molar BuLi solution in hexan (0.14 mol) are added dropwise to 23 g (0.13 mol) of methanesulphonic acid-N'-methylpiperazide dissolved in 200 ml of anhydrous tetrahydrofuran, the resulting suspension is stirred for 90 minutes at ambient temperature and then 23.4 g of 2-(2-bromoethyl)-1,3-dioxolan (0.13 mol) in 200 ml of anhydrous tetrahydrofuran are added dropwise, forming a clear solution. After 5 hours' stirring the solvent is eliminated, the residue is taken up with water/methylene chloride and the aqueous phase is extracted several times with methylene chloride. The methylene chloride solution is dried and the solvent is drawn off. The oil residue is filtered over a column of silica gel using methylene chloride/methanol 9:1 as eluant. After the solvent has been driven off again, 20.7 of the desired compound are obtained as a light coloured oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Br:17])[CH:3]=1.[C:18]1(=[O:28])[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>O1CCCC1>[Br:17][C:4]1[CH:3]=[C:2]([NH:1][C:18]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)CON(Cc2ccc(N)cc2Br)C1=O
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2Br)C1=O
Yield: 93.4 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 2.0 grams (0.0067 mole) of 2-[(4-amino-2-bromophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.0 gram (0.0067 mole) of phthalic anhydride in 50 ml of tetrahydrofuran. The reaction mixture was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethyl acetate-hexane to yield 2.8 grams of 2-[[2-bromo-4-[(2-carboxyphenyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone, m.p. 177° C., dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]2[CH2:16][CH2:17][CH:7]1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[CH2:14]2)=[O:5])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH2:1]([O:3][C:4]([N:6]1[CH:15]2[CH2:16][CH2:17][CH:7]1[C:8]1[CH:9]=[C:10]([NH:18][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=4[C:29](=[O:30])[NH:31][CH3:32])[C:23]([Cl:37])=[CH:22][N:21]=3)[CH:11]=[CH:12][C:13]=1[CH2:14]2)=[O:5])[CH3:2]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCOC(=O)N1C2CCC1c1cc(N)ccc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)N1C2CCC1c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc1C2
Temperature: 140 °C
Yield: 49.3 %

Procedure:
4-Amino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid ethyl ester (J. Med. Chem. 1988, 31, 433-444)(30 mg, 0.12 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (36 mg, 0.12 mmol) were combined with 4 N HCl (0.030 mL, 0.12 mmol) in isopropanol (1 mL). The resulting mixture was heated in a microwave at 140° C. for 30 min. The resulting mixture was then made basic with saturated aqueous NaHCO3, extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 4-[5-Chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid ethyl ester as a yellow solid (30 mg, 49%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.4 (s, 1H), 8.8 (d, 1H, J=4.6 Hz), 8.7 (d, 1H, J=8.1 Hz), 8.2 (s, 1H), 7.8 (d, 1H, J=7.1 Hz), 7.7-7.5 (m, 2H), 7.4 (m, 1H), 7.1 (t, 1H, J=7.1 Hz), 7.0 (d, 1H, J=8.3 Hz), 4.7 (m, 1H), 4.4 (m, 1H), 4.1-3.9 (m, 2H), 3.2 (d, 1H, J=14.1H), 2.8 (d, 3H, J=4.6 Hz), 2.2-2.0 (m, 2H), 1.7 (t, 1H, J=9.4 Hz), 1.6 (m, 1H), 1.2 (m, 1H), 1.2-1.0 (m, 3H); MS (m/e) 507 (M+1); mp 140-144° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:13]1>>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:12][CH:13]=2)(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1csc2ccccc12
Product: COc1nc(NC(=O)NS(=O)(=O)c2csc3ccccc23)nc(OC)n1
Yield: 85.7 %

Procedure:
Using the procedure of Example 3, and substituting 1.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine and 2.4 g of benzothiophene-3-sulfonyl isocyanate, a yield of 3.4 g of the desired product was obtained melting at 152°. It showed absorption peaks by Nuclear Magnetic Resonance (60 MC) at; 3.95 δ (CH3O), 7-8 δ (benzohydrogens) and 8.3 δ (thiophene hydrogen) consistent for the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Br)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1,3-dibromo-benzene.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH3:18])[C:9]=2[N:8]=[CH:7]1.[NH:19]1[CH2:24][CH:23]=[C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[NH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:22]2[CH2:23][CH2:24][N:19]([CH2:3][CH2:4][CH2:5][N:6]3[C:14]4[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH3:18])[C:9]=4[N:8]=[CH:7]3)[CH2:20][CH:21]=2)=[CH:26]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cn1c(=O)c2c(ncn2CCCN2CC=C(c3c[nH]c4ccccc34)CC2)n(C)c1=O
Reaction time: 22 h
Yield: 98 %

Procedure:
A mixture of 5 parts of 7-(3-chloropropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione monohydrochloride, 4 parts of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, 8 parts of sodium carbonate and 240 parts of 4-methyl-2-pentanone was stirred for 22 hours at reflux temperature. The whole was stirred till room temperature was reached. The product was filtered off and stirred in water. After filtration, the product was washed with water and stirred in water and an equivalent amount of acetic acid. The mixture was treated with ammonium hydroxide. The precipitated product was filtered off, washed with water and stirred in a mixture of acetonitrile and 2-propanol. The product was filtered off, washed with acetonitrile and dried, yielding 7 parts (98%) of 7-[3-[3,6-dihydro-4-(1H-indol-3-yl)-1(2H)-pyridinyl]propyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; mp. 243.2° C. (compound 17).
Reaction SMILES: CS(O[CH2:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:25]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: CS(=O)(=O)OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(C(CCOC2CCCCO2)Cn2ccnc2)cc1Cl
Yield: 32.3 %

Procedure:
1-Methanesulphonyloxy-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (10 g) (see Preparation 29), imidazole (2.07 g) and potassium carbonate (7.65 g) were dissolved in anhydrous acetonitrile (50 ml) and heated under reflux under a nitrogen atmosphere for 3 days. The organic solvent was then removed under reduced pressure and the resulting aqueous suspension partitioned between dichloromethane and water. The organic phase was separated, washed sequentially with water and brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The crude product was chromatographed on silica gel eluting with 95:5, by volume, dichloromethane:methanol to give 1-(imidazol-1-yl)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (3 g) as an oil and as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroaniline, 0.4 ml, was slowly added to 4 ml of fuming sulfuric acid and stirred at room temperature overnight. While cooling to 0°, the reaction solution was poured onto water and the solid precipitated was separated by filtration. The solid filtered off was dissolved in 2N sodium hydroxide aqueous solution and conc. hydrochloric acid was then added to the solution to make the liquid acidic. The solid precipitated was taken by filtration to give the crude product of 4-amino-2-chlorobenzenesulfonic acid.