Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](OCCCC)=[CH2:12].ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[OH-].[Na+]>ClC1C=CC=CC=1.O>[CH3:1][N:2]([C:9]([CH:11]=[CH2:12])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: C=COCCCC
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: C=CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 25 ml of clorobenzene under stirring at 10° C., a solution of bis-trichloromethylcarbonate (24.3 g) in 50 ml of clorobenzene is added dropwise in 2 hours. The reaction mixture is kept under stirring at room temperature overnight. Water (50 ml) is added, the mixture is cooled at about 5–10° C. and the pH is corrected to about 7 by adding sodium hydroxide 30% aqueous solution (50 ml). After separation of the phases, the aqueous layer is extracted with chlorobenzene (50 ml) and the combined organic layers are washed with water (20 ml) and evaporated under reduced pressure. To the residue tert-butyl methyl ether (50 ml) is added and the mixture is cooled at −15° C. for 1 hour. The precipitate is filtered on Buchner, washed twice with tert-butyl methyl ether (25 ml×2) and dried at 30–35° C. under vacuum overnight. 24.66 g of pure compound are obtained (69% molar yield)
Reaction SMILES: [Mg].I[CH2:3][CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:9][C:10]1[C:11](=[O:22])[O:12][CH2:13][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1>O1CCCC1.C(OCC)C>[CH3:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][C@@:10]1([CH3:9])[C:11](=[O:22])[O:12][CH2:13][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:15]1
Reactant: CC(C)(C)CCI
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)CC[C@]1(C)N[C@@H](c2ccccc2)COC1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A suspension of Rieke Magnesium (343 mg, 14.1 mmol) in tetrahydrofuran (13.7 ml) was added to a solution of 1-iodo-3,3-dimethylbutane in diethylether (50 ml) over a period of twenty minutes and the reaction was stirred for 40 minutes at room temperature. The Grignard reagent solution and (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) were used according to the method of Preparation 1 to generate the title compound. The total amount of compound synthesised was 0.394 g.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1([CH2:19][OH:20])[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=O.C(Cl)(Cl)(Cl)Cl.CN.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[C:3]=1[C:4]1[O:20][CH2:19][C:7]2([C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[N:6]=1
Reactant: COc1ccc2c(c1)CCCC2(CO)NC(=O)c1c(F)cccc1F
Agent: CN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCCC21COC(c2c(F)cccc2F)=N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 600 mg (0.0017 mol) of the product of Step D in 9 mL of acetonitrile was added 1.8 mL CCl4 and 264 mg (0.0026 mol) of methylamine. Then, 678 mg (0.0026 mol) of triphenylphosphine was added. The mixture was stirred at ambient temperature for 15 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].[H-].[Na+]>CN(C=O)C.C1COCC1>[CH3:14][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6]
Reactant: Cc1ccncc1NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCNC1=O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
1-(2-Chloro-ethyl)-3-(4-methyl-pyridin-3-yl)-urea (I-14a: 8.5 g, 39.96 mmol) in dry DMF (150 mL) was added to a stirred mixture of sodium hydride (2.87 g, 59.94 mmol) in THF (150 mL) at 0° C. The reaction temperature was maintained at room temperature for 30 minutes. The reaction was monitored by TLC. The reaction mixture was quenched with MeOH at 0° C., concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 6.5 g (91% yield) of 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][CH2:24][N:10]3[C:9](=[O:25])[C:8]=2[C:26]=1[F:27]>C(O)C.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][CH2:24][N:10]3[C:9](=[O:25])[C:8]=2[C:26]=1[F:27]
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Yield: 98.5 %

Procedure:
20.7 ml (82.7 mmol) of 4N sodium hydroxide solution were added dropwise to a suspension of 22.1 g (63.6 mmol) of ethyl (5)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate in 55 ml of ethanol and 90 ml of water and heated at reflux for 45 minutes. Subsequently, the ethanol was distilled off. The aqueous phase was washed twice with methylene chloride and adjusted to pH=3 with 4N hydrochloric acid. Extraction with methylene chloride (five times), drying with sodium sulfate, filtration and evaporation yielded 20 g (98%) of (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid as colourless crystals of m.p. 214.5°-215.5° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]([CH3:34])[NH:29][CH2:28][CH2:27]3)=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)[CH:25]=4)[CH:30]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ncc(-c2ccc3c(c2)CCNC3C)c(OC)n1
Product: COc1ncc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: O[C:2]([O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)([CH:4]1[O:9][CH2:8][CH2:7][N:6]([CH:10]([CH3:12])[CH3:11])[CH2:5]1)C.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH:10]([N:6]1[CH2:7][CH2:8][O:9][CH:4]([CH2:2][O:13][C:14]2[CH:15]=[C:16]3[C:20]([C:19]([CH3:23])=[CH:18][CH2:17]3)=[CH:21][CH:22]=2)[CH2:5]1)([CH3:11])[CH3:12]
Reactant: CC(C)N1CCOC(C(C)(O)Oc2ccc3c(c2)CCC3)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC1=CCc2cc(OCC3CN(C(C)C)CCO3)ccc21
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of 3.05 g. of oily 2-(1-hydroxy-1-methyl-5-indanyloxymethyl)-4-isopropylmorpholine, 100 ml. of xylene, and 20 mg. of p-toluenesulfonic acid was refluxed with stirring for 4 hours and then the solvent was distilled off. Then, the residue formed was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform and eluted with ethyl acetate. After removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 200 ml. of the subsequent ethyl acetate eluate was collected and concentrated under reduced pressure to provide 2.1 g. (yield 73.3%) of 4-isopropyl-2-(3-methyl-6-indenyloxymethyl)morpholine. The citrate of the product had a melting point of 159°-161° C.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.[F-:25].[K+].O>CN(C=O)C>[F:25][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: CCCc1c2c(c(Cl)c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c2c(c(F)c3c(=O)cc(C(=O)OCC)oc13)CCCC2

Procedure:
A solution of ethyl 5-chloro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (9 g) and desiccated potassium fluoride (2.32 g) in DMF (50 ml) was heated at 160° for 3.5 hours. After cooling, the reaction mixture was poured into water (250 ml) and the precipitate filtered off, washed with water and dried. Recrystallisation from cyclohexane gave the title compound as a pale-yellow solid, mp 126°-9°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:46])[C@@H:13]([NH:38]C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][NH:17]/[C:18](/[NH2:37])=[N:19]/[S:20]([C:23]2[C:24]([CH3:36])=[C:25]([CH3:35])[C:26]3[O:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]=3[C:33]=2[CH3:34])(=[O:22])=[O:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.O1CCOCC1>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:46])[C@@H:13]([NH2:38])[CH2:14][CH2:15][CH2:16][NH:17]/[C:18](/[NH2:37])=[N:19]/[S:20]([C:23]2[C:24]([CH3:36])=[C:25]([CH3:35])[C:26]3[O:30][C:29]([CH3:31])([CH3:32])[CH2:28][C:27]=3[C:33]=2[CH3:34])(=[O:22])=[O:21])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of compound F (20.2 g, 30.2 mmol) in dichloromethane (90 mL) was treated with 4.0 N HCl in 1,4-dioxane (90 mL, 363.3 mmol) and stirred at room temperature for 2 h. Next most of the dichloromethane was removed in vacuo and Et2O (˜1 L) was added. The resultant precipitate was filtered off and washed with Et2O and dried in vacuo to afford compound G (17.8 g, 30.2 mmol). LC-MS [M+H] 567.8 (C26H42N6O6S+H, calc: 567.8).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH:3]1[CH:11]=[CH:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([N:17]1[C:1](=[O:13])[CH2:2][C:3]2[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[C:5]1=[O:7])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: O=C(O)CC1C=CCCC1C(=O)O
Product: C=CCN1C(=O)CC2=C(CCCC2)C1=O

Procedure:
A mixture of tetrahydrohomophthalic acid (9.2 g., 0.05 mole) and allylamine (2.8 g., 0.05 mole) is heated by an oil bath until molten for 40 minutes. The mixture solidifies upon cooling, and is recrystallized twice from isopropanol, giving 2-allyl-5,6,7,8-tetrahydroisoquinoline-1,3(2H, 4H)-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccccc1NCCCCl
Yield: 33 %

Procedure:
A mixture of 13.6 parts of 2-aminobenzamide, 31.5 parts of 1-bromo-3-chloropropane, 21 parts of sodium carbonate and 200 parts of ethanol is stirred and refluxed over week-end. The reaction mixture is filtered and the filtrate is evaporated. The oily residue is stirred in methylbenzene. The mixture is filtered till clear and the solvent is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 7 parts (33%) of 2-[(3-chloropropyl)amino]benzamide; mp. ±100° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[C:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=O)#[N:17]>>[C:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:23])#[N:17]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-cyano-5-trifluoromethyl-benzoic acid after a reaction time of 94 hours. The product was purified by silica gel chromatography using a 10 g column eluting with EtOAc followed by a second chromatography on a 5 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless solid (2%). MS (ESI): m/z=396.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:29])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Product: CC(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
The desired compound was prepared according to the previous example from 4-(2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8yl)-amide (3 CF3COOH salt) and acetic anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCCOc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCOc1ccncc1
Temperature: 90 °C
Yield: 56.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 4-(3-chloropropoxy)pyridine hydrochloride (206 mg, 1.0 mmol) and potassium carbonate (303 mg, 2.2 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)quinazoline (257 mg, 56%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31][O:32]C2CCCCO2)[C:14]1=[O:39])=[O:11].Cl.O>CC(C)=O>[OH:32][CH2:31][CH2:30][N:15]1[C:16]2[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=2[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:19][CH:13]([NH:12][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[C:14]1=[O:39]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a suspension of a mixture (0.42g)of (3RS)-1,3-dihydro -3-(2-indolylcarbonylamino)-5-phenyl-1-{2-((RS)-2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl -1-{2-((SR)-2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine -2-one in acetone (10 ml) was added 6N-hydrochloric acid (0.4 ml) under stirring at ambient temperature. After the yellow clear solution was stirred for 45 minutes, the additional 6N-hydrochloric acid (0.4 ml) and water (1 ml) were added thereto. The mixture was stirred for 0.5 hour at ambient temperature. Neutralization with an aqueous solution of sodium bicarbonate and removal of acetone gave yellow precipitates, which were collected by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (5:1) to afford pure (3RS)-1,3-dihydro-1-(2-hydroxyethyl)-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one (0.28 g) as an amorphous. This was triturated in diethyl ether to give light yellow powder.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(CCN(C)C)C.Cl.C1C[O:36][CH2:35]C1>CN(C=O)C>[Si:5]([O:8][CH2:9][CH2:10][C:11]1[C:12]([O:17][CH3:18])=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH:35]=[O:36])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:6])[CH3:7]
Reactant: COc1ccccc1CCO[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl(2-methoxyphenethoxy)dimethylsilane [Aromatic Intermediate 26, step a] (2.0 g), as a solution in THF (1 mL), was added dropwise over 5 min to a stirred solution of butyllithium (2.5M in hexanes, 4.5 mL) and TMEDA (1.7 mL) in tetrahydrofuran (20 mL) at 0° C. The resulting mixture was stirred for 4 hours, and then DMF (2.9 mL) was added. The mixture was stirred for a further 30 min and allowed to warm to RT. The reaction was poured into aqueous HCl (0.5M, 20 mL) and extracted with ether (2×50 mL). The u) combined organic solutions were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate, filtered and evaporated. The resulting gum was purified by silica gel chromatography eluting with isohexane to 4:1 isohexane:ethyl acetate gradient to give the titled compound as a clear oil. Yield 0.40 g.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=1[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=4[CH3:40])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: CSc1ccc(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)c(C)c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (150 mg), 1-bromo-2-methyl-4-methylsulfanyl-benzene (60 mg), in N,N-dimethylformamide (3 mL) a 2 M aqueous Na2CO3 solution (0.29 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (19 mg) is added. The resulting mixture is stirred for 6 h at 90° C. After cooling to room temperature, water and methanol are added and the aqueous phase is extracted with ethyl acetate. The organic phase is concentrated and the residue is purified by HPLC on reversed phase (MeOH/H2O/TFA). Yield: 56 mg (56% of theory); LC (method 2): tR=1.70 min; Mass spectrum (ESI+): m/z=426 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.Cl.[CH3:15][N:16](C)C=O>O>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1)#[N:16]
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: CC1(C)c2cc(C#N)ccc2OC1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (7.3 g), prepared as in Example 5(e) and cuprous cyanide (3.2 g) were heated under reflux in dimethylformamide (10 ml) with stirring for 51/2 hours. The mixture was cooled to room temperature and a solution of ferric chloride (6 g) in water (20 ml) containing hydrochloric acid (3.7 ml conc) was added. After heating at 60°-70° C. for 20 minutes the mixture was extracted with ether. The extracts were washed with water (twice), dried over magnesium sulphate and run down under vacuum to give 4.6 g of product, which on recrystallisation from toluene gave 2.0 g pure title product, mp 124°-127° C.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CCN(CC)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(N)(=O)=O)cc1
Yield: 333.7 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in THF (0.1 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 nin. p-Toluenesulfonyl chloride (0.73 mg, 3.8 mol, 2.0 equiv) was then added in one portion to the above solution at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and then quenched with a 1:1 mixture of saturated aqueous sodium hydrogen carbonate solution and water (4 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a yellow oil, which was purified by flash column chromatography (60% ethyl acetate-hexanes) to give the 4-methylphenyl sulfonamide derivative (1.2 mg, 93%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1.[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C(O)CCC>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:28][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1
Reactant: Nc1ccccc1N
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Solvent: CCCCO
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Nc3ccccc3N)nc21

Procedure:
Analogously to Example 1, 308 mg (1.0 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine [described in Stage 1.2] and 324 mg (3 mmol) of 1,2-phenylenediamine are reacted in 10 ml of n-butanol in a glass pressure reactor for 19 h at 140° C., followed by addition of 486 mg (4.5 mmol) of 1,2-phenylenediamine and further reaction at 135° C. for 17 h. After purification by means of column chromatography, 2-[2-amino-phenyl-amino]-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine is obtained; FAB-MS: (M+H)+=380; HPLC: tret (grad20/2)=11.36 minutes.