Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](O)=[O:23])[C:13](=[O:29])[CH:12]=[CH:11]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:45][C:46](=[NH:48])[CH3:47]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([C:22]3[O:23][N:48]=[C:46]([CH3:47])[N:45]=3)[CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:29])[CH:12]=[CH:11]2
Reactant: O=C(O)c1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1
Reactant: CC(=N)NO
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1noc(-c2ccc(F)c(-c3c(=O)ccn4c(-c5ccc(F)cc5F)cccc34)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 3-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-4-fluorobenzoic acid (Example 31, 50 mg, 0.12 mmol) in acetonitrile (1.2 mL) was added EDC (48 mg, 0.25 mmol), and HOBt (34 mg, 0.25 mmol). The reaction was stirred at room temperature for 1 hour and then N-hydroxyethanimidamide (46.6 mg, 0.63 mmol) was added. The reaction was heated to 90° C. for 18 hours and then cooled to room temperature. The mixture was diluted with EtOAc washed with aqueous NH4Cl, 0.5 N HCl, water, brine, dried over MgSO4, and concentrated. The crude material was purified via silica gel chromatography (100% EtOAc to give the title compound as a light yellow solid (15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([O:25]C)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>CO>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([OH:25])=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1nc(-c2cc(OC)c(OC)c(OC)c2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed methyl 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylate (1.7 g, 4.80 mmol, 1.00 equiv), methanol (10 mL) and sodium hydroxide (20%, 10 mL). The resulting solution was stirred for 30 min at 75° C. The pH value of the solution was adjusted to 2 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.8 g (49%) of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.99 (s, 3H), 4.06 (s, 6H), 7.77-7.81 (m, 1H), 7.84 (s, 2H), 8.03-8.07 (m, 1H), 8.22 (d, 1H), 9.41 (d, 1H); MS (ESI) m/z 341 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.C([Li])CCC.[Cu]C#N.[C:28]([CH2:30][CH2:31][N:32]=[C:33]=[S:34])#[N:29].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[C:28]([CH2:30][CH2:31][NH:32][C:33]([C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1)=[S:34])#[N:29]
Reactant: N#CCCN=C=S
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCCNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 0.17 h
Yield: 7.1 %

Procedure:
An amount (103 mg) of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran was dissolved in diethyl ether (0.5 ml); to the solution, 1.68 M n-butyllithium (0.18 ml) was added at −10° C. under a nitrogen atmosphere. After stirring the reaction mixture for 10 minutes, copper(I) cyanide (27 mg) and tetrahydrofuran (0.6 ml) were added and the resulting mixture was stirred for 30 minutes at 0° C. Subsequently, a tetrahydrofuran solution (0.3 ml) of 2-cyanoethyl isothiocyanate (34 mg) was added and the mixture was stirred for 4 hours at 0° C. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, followed by extraction with diethyl ether; the resulting organic layer was washed with 2 N HCl, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; dichloromethane/diethyl ether=10/1) to give the titled compound (8 mg), which was identical to the authentic sample.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][CH:10]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[OH:14][C@H:12]1[CH2:13][NH:9][CH:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CC1COc1ccccc1CCCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CNC(COc2ccccc2CCCCc2ccccc2)C1
Reaction time: 2 h
Yield: 74 %

Procedure:
3 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 173 mg of (4R)-1-t-butoxycarbonyl-4-hydroxy-2-[2-(4-phenylbutyl)phenoxymethyl]pyrrolidine [prepared as described in step (b) above] in 3 ml of dioxane, and the resulting mixture was allowed to stand at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in methylene chloride. Ethyl acetate was added to the resulting solution and the mixture was allowed to stand. The crystals which precipitated were collected by filtration, to give mg (yield 74%) of the title compound as colorless crystals, melting at 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6].[C:27](#[N:30])[CH:28]=[CH2:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([NH:7][C:8]1([CH2:29][CH2:28][C:27]#[N:30])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6]
Reactant: CCCCCN1C(=O)C(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: C=CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCN1C(=O)C(CCC#N)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Under argon atmosphere, a mixture of 2.70 g of 3,4-dichloro-N-(2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl)benzamide, 1.30 g of acrylonitrile, 30 ml of acetone and 1.46 g of potassium carbonate was stirred at room temperature for 1 hour. After removal of solvent, the residue was treated with water and extracted with ethyl acetate. After the ethyl acetate extract was washed and dried, the solvent was removed by evaporation. The residue was crystallized from ethyl acetate-hexane to afford 2.28 g of 3,4-dichloro-N-[3-(2-cyanoethyl)-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]-benzamide as colorless crystals. Melting point: 79° to 84° C., IR (Nujol) (cm-1): 3340, 2325, 1700, 1655, 1610, MS (m/z): 445 & 443 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.O.[CH2:31](N)[CH2:32][NH2:33]>>[NH:5]1[CH2:31][CH2:32][N:33]=[C:4]1[C:3]1[C:2]([NH2:1])=[C:9]([O:10][CH3:11])[C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C#N)c(N)c1OC
Reactant: NCCN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Product: COCOc1ccc(C2=NCCN2)c(N)c1OC
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A solution of 2-amino-3-methoxy-4-(methoxymethoxy)benzonitrile 475 mg (2.28 mmol) and phosphorus pentasulfide 25.4 mg (0.11 mmol) in ethylenediamine 2.75 g was stirred at 120° C. for overnight. The reaction mixture was cooled to room temperature and poured into water. The precipitate was collected and washed with water to give the title compound 293 mg as white solid. Yield 51.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:18]=[CH:17][C:16]3[O:15][CH2:14][O:13][C:12]=3[CH:11]=2)[N:5]=[C:4]([S:19][CH2:20][C:21]#[N:22])[N:3]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([CH2:9][NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([S:19][CH2:20][C:21](=[N:24][OH:25])[NH2:22])[N:5]=3)[C:11]=2[O:15][CH2:14]1
Reactant: Cc1cc(NCc2ccc3c(c2)OCO3)nc(SCC#N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NCc2cccc3c2OCO3)nc(SCC(N)=NO)n1

Procedure:
A mixture of 6.20 g. (0.02 mole) of (4-methyl-6-piperonylamino-2-pyrimidinylthio)acetonitrile, 2.76 g. (0.04 mole) of hydroxylamine hydrochloride and 8.48 g. (0.08 mole) of sodium carbonate in 100 ml of N,N-dimethylformamide was heated on a steam bath for four hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with ether and the insoluble material was collected and recrystallized from a mixture of ethanol-N,N-dimethylacetamide to give 3.5 g. of product, m.p. 190°-192° dec.
Reaction SMILES: [CH3:1][Si](C)(C)N[Si](C)(C)C.C([Li])CCC.CCCCCC.Br[C:22]1[N:36]([Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:35]2[C:44]3[C:23]=1[CH2:24][C@@H:25]1[C:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)=[CH:29][C@H:28]([NH:45][C:46](=[O:52])[N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH2:27][N:26]1[CH3:53].NCCCCN.C([Li])(C)(C)C.FC(F)(F)S(O)(=O)=O>O.C1(C)C=CC=CC=1>[Si:37]([N:36]1[C:35]2[C:44]3[C:23]([CH2:24][C@@H:25]4[C:30]([C:31]=3[CH:32]=[CH:33][CH:34]=2)=[CH:29][C@H:28]([NH:45][C:46](=[O:52])[N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH2:27][N:26]4[CH3:53])=[C:22]1[CH3:1])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3c(c(Br)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: NCCCCN
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3c(c(C)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
Under argon, 0.3 ml (1.5 mmol) of distilled hexamethyldisilazane is added to 4 ml of absolute, freshly distilled toluene, and the mixture is cooled to 0° C. Then 0.85 ml (1.4 mmol) of 15% butyllithium/hexane is added dropwise and the mixture is stirred for 15 minutes at 0° C. To this mixture is added 531 mg (1 mmol) of 3-[2-bromo-1-(tert-butyldimethylsilyl)-9,10-didehydro-6-methyl-8α-ergolinyl]-1,1-diethylurea in 50 ml of absolute, freshly distilled toluene and agitation is continued for another 15 minutes at 0° C. After adding 1 ml of distilled tetramethylenediamine, the batch is cooled to -90° C. At this temperature, 5 ml (7 mmol) of 1.4M tert-butyllithium is added and the mixture is agitated for 2 minutes before 0.6 ml (5.4 mmol) of the methyl ester of trifluoromethanesulfonic acid is added thereto. After 11/2 hours of agitation at -70° C., water is added to work up the reaction mixture. Extraction is performed with ethyl acetate. The organic phases are washed with saturated sodium bicarbonate solution and water. The combined ethyl acetate phases are dried over sodium sulfate and concentrated. Crystallization from methanol produces 128 mg of 3-[1-(tert-butyldimetylsilyl)-9,10-didehydro-2,6-dimethyl-8α-ergolinyl]-1,1-diethylurea (27% yield).
Reaction SMILES: [Na].C([C:4](CC)(C([O-])=O)[C:5]([O-])=[O:6])C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:17]=[CH:18][C:19](=[O:21])[CH3:20]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]2[CH2:4][C:5](=[O:6])[CH2:20][C:19](=[O:21])[CH2:18]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CC(=O)C=Cc1ccc(Cl)c(Cl)c1
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)CC(c2ccc(Cl)c(Cl)c2)C1

Procedure:
A solution of 1.3 g of sodium metal in 30 ml of ethanol is treated with 9 g of diethylmalonate and an ethanolic solution of 12.1 g of 3,4-dichlorobenzalacetone, heated under reflux for 15 min, cooled and concentrated to dryness in vacuo. The residue is treated with 400 ml of water containing 7 g of 80% potassium hydroxide pellets and heated under reflux for 2 hr. Insoluble material is removed and the filtrate is acidified with concentrated sulfuric acid, heated under reflux until carbon dioxide evolution ceases, cooled, filtered, washed with water and dried. Recrystallization from 2-propanol gives 5-(3,4-dichlorophenyl)-1,3-cyclohexanedione; mp 198°-200° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][N:25]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:18][CH2:17][C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)([CH3:20])[CH3:19])=[N:6][CH:7]=1
Reactant: Fc1ncc(Br)cn1
Reactant: CC(C)(CN)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(CNc1ncc(Br)cn1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 63.3 %

Procedure:
To a solution of 5-bromo-2-fluoropyrimidine (1.0 g, 5.6 mmol, 1.0 equiv) and 2-(4-fluorophenyl)-2-methylpropan-1-amine (1.05 g, 6.3 mmol. 1.1 equiv) in isopropanol (12 mL) in a microwave vial equipped with a stir bar was added potassium carbonate (3.68 g, 11.2 mmol, 2.0 equiv). The vial was fitted with a microwave vial cap and heated to 120° C. for 45 min. The reaction mixture was filtered to remove the solid potassium carbonate and concentrated in vacuo. After the residue was redissolved in EtOAc and water, the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (3%-5% MeOH/DCM) provided the title compound as a yellow solid (1.15 g, 65%), (m/z [M+H]=324.2).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[CH:12][CH:11]=1)[CH3:2].C1C=CC=CC=1.[CH3:25][SiH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29].C(O)C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C1COCC1>[CH3:25][Si:26]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:15][CH:14]=1
Reactant: C=CCc1ccc(OCCOCCOCC)cc1
Reactant: CCO[SiH](C)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOCCOCCOc1ccc(CCC[Si](C)(OCC)OCC)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
This compound was made by first heating a mixture of 2.8 g (0.011 mol) of 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-1 -propene (prepared as in Example 1), 5 g of benzene and 1.1 equivalent of methyldiethoxysilane under an argon atmosphere at 85° C. for one hour. After one hour, a trace amount (0.01 μL) of 1 part chloroplatinic acid in 1 part ethanol and 98 parts THF was added and the mixture was heated overnight at 85° C. The product was isolated by distillation to give 4.2 g (97%) of methyl diethoxy 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propysilane, bp 135° C./0.08mm; NMR (δ): 0.20(3H,s), 0.65(2H,m), 1.05(9H,t), 1.50(2H,m), 2.70(2H,t), 3.90(12H,m), 7.0(2H,d), 7.15(2H,d).
Reaction SMILES: [OH:1][CH:2]([CH2:41][N:42]1[C:46](=[O:47])[C:45]2([CH2:52][C:51]([CH3:54])([CH3:53])[NH:50][C:49]([CH3:56])([CH3:55])[CH2:48]2)[NH:44][C:43]1=[O:57])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:40])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]4)[NH:26][C:25]3=[O:39])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C>[C:17]([O:40][CH:22]([CH2:23][N:24]1[C:28](=[O:29])[C:27]2([CH2:34][C:33]([CH3:35])([CH3:36])[N:32]([C:2](=[O:1])[CH3:3])[C:31]([CH3:37])([CH3:38])[CH2:30]2)[NH:26][C:25]1=[O:39])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([O:1][C:5](=[O:4])[CH3:6])[CH2:41][N:42]3[C:46](=[O:47])[C:45]4([CH2:48][C:49]([CH3:56])([CH3:55])[N:50]([C:28](=[O:29])[CH3:27])[C:51]([CH3:54])([CH3:53])[CH2:52]4)[NH:44][C:43]3=[O:57])=[CH:10][CH:9]=2)([CH3:13])[CH3:12])=[CH:15][CH:16]=1)(=[O:20])[CH3:16]
Reactant: CC1(C)CC2(CC(C)(C)N1)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)NC(C)(C)C5)C4=O)cc3)cc1)C2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(COc1ccc(C(C)(C)c2ccc(OCC(CN3C(=O)NC4(CC(C)(C)N(C(C)=O)C(C)(C)C4)C3=O)OC(C)=O)cc2)cc1)CN1C(=O)NC2(CC(C)(C)N(C(C)=O)C(C)(C)C2)C1=O
Reaction time: 6 h

Procedure:
5 g of 2,2-bis{4-[2-hydroxy-3-(7,7,9,9-tetramethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane were heated at 100°-110° C. in 100 ml of acetic anhydride, with stirring, for 6 hours. After completion of the reaction, the reaction mixture was condensed by evaporation under reduced pressure and then 150 ml of benzene were added to dissolve the residue. The benzene solution was washed successively with a 2% w/w sodium carbonate solution and water. The solvent was then removed and the residue was purified by column chromatography through silica gel eluted with a 8:1:1:1 by volume mixture of ethyl acetate, benzene, ethanol, and triethylamine. The desired Compound No. 68 was obtained in the form of white crystals, melting point 147°-149° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C@@H:8]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:21])([CH3:20])[C@H:9]1[OH:22])[CH2:5][CH3:6])#[N:2].[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>N1C=CC=CC=1>[C:1]([N:3]=[C:4]([NH:7][C@@H:8]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:21])([CH3:20])[C@H:9]1[O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:5][CH3:6])#[N:2]
Reactant: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of trans-4-[N-[1-(cyanoimino)propyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (1.49 g) in dry pyridine (7.5 ml) was added dropwise mesyl chloride (0.77 g) under ice-water cooling. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and washed with 5% hydrochloric acid (twice), aqueous sodium bicarbonate and brine, successively. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give trans-4-[N-[1-(cyanoimino)propyl]amino]-3,4-dihydro-2,2-dimethyl-3-mesyloxy-2H-1-benzopyran-6-carbonitrile (1.50 g).
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]([O:12][CH3:13])=[O:11].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].N>CC(C)=O>[CH3:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: COS(=O)(=O)OC
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccccc2n1C
Reaction time: 2 h

Procedure:
A stirred suspension of methyl 1H-indole-2-carboxylate (5.0 g), dimethyl sulphate (9 ml) and potassium carbonate (10.4 g) in dry acetone (200 ml) was heated under reflux for 24 h. After cooling to room temperature 5% ammonia solution (50 ml) was added and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried and the solvent evaporated to give methyl 1-methyl-1H-indole-2-carboxylate (5.4 g) as a white solid; IR (CHBr3) max 1695 cm-1. The ester was treated with ethylenediamine and trimethylaluminium as described in Example 1(a). Purification via column chromatography on silica eluting with 5% v/v methanolic ammonia in dichloromethane gave 2-(2-imidazolin-2-yl)-1-methyl-1H-indole as a white solid. The hydrochloride salt was prepared as in Example 3 and that recrystallised from ethanol/diethyl ether; mp 290°-295° C. (decomp) (Literature mp 260°-280° C. (decomp) D. J. Hlasta, D. Luttinger, M. H. Perrone, M. J. Silbernagel, S. J. Ward and D. R. Haubrich, J. Med. Chem. 1967, 30, 1555).
Reaction SMILES: [Li+].[CH3:2][N:3]([CH3:26])[C:4]1[C:5]([F:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O-])=[O:15])[C:10](=[O:21])[CH:9]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([N:3]([CH3:2])[CH3:26])[C:5]=4[F:25])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:35]2)[CH2:30][O:29]1
Reactant: CC(C)C[C@@H](C(=O)[O-])N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid lithium salt (0.257 g, 0.73 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.160 g, 0.81 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.91 g, 4.32 mmol). The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with a saturated sodium chloride solution and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 75% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.200 g, 51%) as a yellow solid: HR-ES-MS m/z calculated for C27H36FN5O5 [M+H]+ 530.2773, observed 530.2771, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.31 (d, J=3.0 Hz, 3H), 1.38-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.85 (m, 1H), 2.82 (s, 6H), 3.74 (dd, J=8.3, 5.9 Hz, 1H), 4.01 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.15 (m, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.29-4.43 (m, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.86 (s, 1H), 4.87-4.95 (m, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.79-6.98 (m, 2H), 7.12 (t, J=8.5 Hz, 1H), 7.61 (br. s., 1H), 10.80 (s, 1H).