Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][O:14]C(=O)C)[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O-].[Na+].C(O)(=O)C>CO>[Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Yield: 54.9 %

Procedure:
A solution of N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (41.7 g, 0.154 mol) in anhydrous methanol (415 ml) is stirred under a N2 atmosphere with ice-bath cooling. A solution of sodium methoxide (415 mg, 7.7 mmol) in anhydrous methanol (15 ml) is added and the resulting solution is stirred in the cold for 2 more hrs. Acetic acid (2.2 ml) is then added and the solvents are evaporated in vacuo (i.v.). The residue is taken up EtOAc (300 ml), washed with H2O (4×75 ml), 5% NaHCO3 (75 ml) and brine, dried with MgSO4 and evaporated i.v. to a clear oil (21.3 g). This material is purified by chromatography on a Baker silica gel column (425 g, packed under EtOAc). After a 100 ml forefraction, 25 ml EtOAc fractions are collected every 2.5 mins. Fractions 41-49 yield starting material and fractions 51-90 afford N-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin-2 -one (19.4 g) as a clear oil: ir (neat) 2.88, 5.73, 5.80, 7.52, 7.67, 7.99, 8.40, 11.95, and 12.18 cm-1 ; nmr (CDCl3)δ 0.25 (s, 6), 0.98 (s, 9), 1.82 (m, 2), 2.67 (dd, 1), 3.17 (dd, 1), 3.67 (t, 2), and 3.67 (m,1); mass spectrum m/e 172.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10]N1C(=O)CCC1=O>>[Br:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Product: Brc1c[nH]c2ccccc12

Procedure:
In step 3 indole compound k undergoes bromination by treatment with N-bromosuccinimide or other bromime source (not shown) to yield 3-bromo indole compound l. Bromoindole l is then subject to oxidation in step 4 to provide dihydroindolone compound m. Compound m is a compound of formula I in accordance with the invention.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][CH2:11][CH2:10][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[N:15]=1
Reactant: OCCn1ccc2ccccc21
Reactant: Clc1cncc(Cl)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1cncc(OCCn2ccc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (0.67 g, 5.93 mmol) was added to a stirred solution of the product obtained in step 1 above (0.67 g, 5.93 mmol) in dioxane (20 mL) at 0° C. (ice-bath). After being stirred for 7 min at 0° C. and 5 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (2.62 g, 17.6 mmol) was added. The yellowish reaction mixture was stirred at 0° C. for 20 min and at room temperature for 10 min and then diluted with dichloromethane. Drying (K2CO3), filtration, and concentration in vacuo furnished a beige oil. This material was purified by chromatography on silica gel (13×4 cm) using n-hexane/ethyl acetate (80:20). This furnished 1.39 g (94%) of the title compound as an oil that solidified upon standing. HRMS m/z calcd for C14H12ClN3O (M)+ 273.0669, found 273.0671. Anal. (C14H12ClN3O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc(F)cc4)nc(Cl)nc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(Nc4ccc(F)cc4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
To a mixture of 2-chloro-N-(4-fluorophenyl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (230 mg, 0.423 mmol), pyridine-4-boronic acid (57 mg, 0.463 mmol) and Pd(Ph3P)2Cl2 (30 mg, 0.042 mmol) in dioxane (4 mL), aq. Na2CO3 (135 mg, 1.27 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 2 h. It was concentrated in vacuo. The residue was triturated. The solid was collected by filtration (86 mg). The filtrate was purified by HPLC to give 2-chloro-N-(4-fluorophenyl)-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH2:36](Br)[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:7]([CH2:36][CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: BrCC=Cc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC=Cc1ccccc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.9 %

Procedure:
0.048 g of 60% sodium hydride was added to a stirred solution of 0.45 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2-(R)-pentanetricarboxylate in 10 ml of dry dimethylformamide under a nitrogen atmosphere. The mixture was stirred for 0.75 hour at 0° and for a further 2.5 hours at room temperature. The mixture was again cooled to 0° before the addition of 0.236 g of cinnamyl bromide. After allowing the mixture to return slowly to room temperature, the solution was stirred at room temperature for 2 days. The mixture was poured into 5% aqueous citric acid solution and the product was extracted four times with diethyl ether. The combined ether extracts were washed with water and sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using hexane/ether (9:1) for the elution. There was obtained 0.542 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(3 -phenylprop-2-en-1-yl)-1,1,2-(R)-pentanetricarboxylate in the form of a colorless oil; MS: 571 (M+H)+.
Reaction SMILES: [ClH:1].Cl.CNC(C1C=CC2C=C(C3C(C)=CN=C(NCCC4CCNCC4)N=3)SC=2C=1)=O.[CH3:32][N:33]([CH3:53])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([Cl:51])[N:45]=3)[S:41][C:40]=2[CH:52]=1)=[O:35].C(OC([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][CH2:69][NH2:70])[CH2:63][CH2:62]1)=O)(C)(C)C>>[ClH:51].[ClH:1].[CH3:32][N:33]([CH3:53])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([NH:70][CH2:69][CH2:68][CH2:67][CH:64]4[CH2:65][CH2:66][NH:61][CH2:62][CH2:63]4)[N:45]=3)[S:41][C:40]=2[CH:52]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Agent: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCNCC4)ncc3C)sc2c1
Agent: Cl
Product: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1

Procedure:
Using the method of 2-[5-methyl-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid methylamide di-hydrochloride, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid dimethylamide and 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester and isolated as a foam. ES+(m/z) 438 [M(free base)+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:3]2[CH:4]=[C:5]([NH:8][C:9]([C:10]3[CH:11]=[N:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)=[O:22])[CH:6]=[CH:7][C:2]=2[Cl:1])=[O:32])=[CH:26][CH:27]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(N2CCNCC2)nc1
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CC1

Procedure:
N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(piperazin-1-yl)nicotinamide (0.182 mmol) was used in general procedure 1 with propionyl chloride (0.20 mmol). The product was purified by RP-HPLC to give N-(3-(4-fluorobenzamido)-4-chlorophenyl)-6-(4-propionylpiperazin-1-yl)pyridine-3-carboxamide. MS (Q1) 510.3 (M)+
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([CH2:18][N:19]=[C:20]=[O:21])=[CH:16][CH:15]=1>>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][C:20]([NH:19][CH2:18][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:25])[F:24])=[CH:23][CH:22]=3)=[O:21])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2nnccc12
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2nnccc12

Procedure:
Prepared from cinnolin-5-amine (Sci Pharm. 1982, 50, 246) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 347 (M+H)+.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[C:11]([O:15][C:16](=[O:36])[C@:17]1([CH2:32][CH2:33]CO)[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:36])[C@:17]1([CH2:32][CH2:33][CH2:6][CH:5]=[O:9])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@]1(CCCO)CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@]1(CCCC=O)CCCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 3.2 %

Procedure:
Dry DMSO (9.90 mL, 139 mmol) was added dropwise over 5 min to a stirred cooled (−78° C.) solution of distilled oxalyl chloride (6.3 imL, 73.1 mmol) in CH2Cl2 (150 mL). After 20 min, a solution of the alcohol 5 (26.6 g, 73.1 mmol) in CH2Cl2 (50 mL) was added over 3 h. The resultant slurry was stirred for 30 min at −78° C. and then dry diisopropylethylamine (32.0 mL, 183 mmol) was injected dropwise over 3 h. Stirring was continued at −78° C. for 30 min, the cold bath removed, and after a further 30 min, H2O (100 mL) was added. The mixture was stirred for a further 10 min and the aqueous layer was extracted with CH2Cl2 (2×400 mL). The combined organic layers were washed with 10% v/v aqueous HCl (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), and brine (1×100 mL), dried over MgSO4, and evaporated in vacuo. The residue (26.0 g, 98.5%) could be used without further purification or purified (1 g) by flash chromatograghy (SiO2; 2/8 EtOAc/hexane, Rƒ 0.32) to give 6 (880 mg, 88%) as a clear oil: IR (CH2Cl2 cast) 3032 (w), 2975 (m), 2880 (m), 1719 (s), 1698 (s) cm1; 1H NMR (200 MHz, CDCl3) δ 9.52 & 9.61 (t, 1H, J=2.0 Hz, CHO), 7.18-7.36 (m, 5H, Ar—H, 5.12 & 5.18 (d, 1H, J=10.0 Hz, 1×OCH2), 4.93 & 4.99 (d, 1H, J=11.5 Hz, 1×OCH2:), 3.51-3.78 (m, 1H, 1×δ-CH2), 3.32-3.48 (rn, 1H, 1×δ-CH2), 2.32-2.64 (m, 2H), 1.70-2.32 (m, 6H), 1.30 & 1.32 (s, 9H, C(CH3)3); 13C NMR (50 MHz, CDCl3) δ 202.05 & 201.20, 172.61 & 172.46, 154.47 & 154.44, 136.90 & 136.89, 128.27 & 128.21, 128.08 & 127.93, 127.69 & 127.60, 81.16 & 80.99, 68.11 & 67.38, 66.96 & 66.41, 49.00 & 48.08, 39.02 & 38.63, 37.14 & 35.96, 27.42, 27.02 & 26.75, 22.82 & 22.15.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:14][O:15][C:16](=[O:19])[CH2:17]Br>C(OCC)C>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(c1)C(N)CCC2
Solvent: CCOCC
Product: COC(=O)CNC1CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 70 h

Procedure:
367.0 g of 1-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene are solved in 1500 ml of diethyl ether. To this solution is dropwise added a solution of 158.3 g of bromoacetic acid methyl ester in 450 ml of diethyl ether. The mixture is stirred at room temperature for 70 hours. The precipitate is separated and the solution is concentrated to dryness, yielding N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) glycine methyl ester quantitatively.
Reaction SMILES: [CH:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ClCCl.O1CCOCC1.[Br:29]Br>O>[Br:29][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:1]=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC=O
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCC(Br)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred solution of 21 parts of octadecanal in 65 parts of dichloromethane and 50 parts of 1,4-dioxane there were added dropwise 34.1 parts of bromine. After stirring for 4 hours at room temperature, the reaction mixture was poured into 250 parts of water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated, yielding 28 parts (95%) of 2-bromooctadecanal (interm. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([S:20](Cl)(=[O:22])=[O:21])([CH3:19])[CH3:18].N1C=CC=CC=1>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:20]([CH:17]([CH3:19])[CH3:18])(=[O:22])=[O:21])=[CH:3][C:4]=2[F:16])=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1F
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)c(F)c1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
5-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (200 mg, 0.93 mmol) was dissolved in isopropyl sulfonyl chloride (0.50 mL, 2.8 mmol), pyridine (0.2 mL) was added and the mixture was heated to 100° C. for 6 hours. The mixture was then cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorophenyl]propane-2-sulfonamide (58 mg).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:46]([OH:48])=[O:47])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:45])[CH2:26][CH2:27][CH:28]([P:37]([CH2:42][CH:43]=[CH2:44])([CH2:39][CH:40]=[CH2:41])=[O:38])[P:29]([CH2:34][CH:35]=[CH2:36])([CH2:31][CH:32]=[CH2:33])=[O:30])=O)C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:31]([P:29]([CH:28]([P:37]([CH2:39][CH:40]=[CH2:41])([CH2:42][CH:43]=[CH2:44])=[O:38])[CH2:27][CH2:26][C:25]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:46]([OH:48])=[O:47])[NH2:18])=[O:45])([CH2:34][CH:35]=[CH2:36])=[O:30])[CH:32]=[CH2:33]
Reactant: C=CCP(=O)(CC=C)C(CCC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)P(=O)(CC=C)CC=C
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C=CCP(=O)(CC=C)C(CCC(=O)NCCCC[C@H](N)C(=O)O)P(=O)(CC=C)CC=C
Yield: 85.6 %

Procedure:
A solution of 90 (502 mg, 0.616 mmol) in piperidine/DMF (0.05:1, 5 mL) was stirred at room temperature for 18 hr. After diluting with ethyl acetate (40 mL) the organic layer was washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (methanol in ethyl acetate, 5% over 5 column volumes then 5 to 30% over 10 column volumes) using a Biotage Horizon™ apparatus resulting in the colourless liquid 91 (249 mg, 68%): 1H NMR (400 MHz, CDCl3) δ 1.39-1.74 (m, 6H), 1.45 (s, 9H), 2.21-2.35 (m, 2H), 2.51 (t, J=7.4, 2H), 2.55 (tt, J=6.9, 23.9, 1H), 3.19-3.25 (m, 2H), 3.29 (dd, J=5.2, 7.6, 1H), 4.58-4.63 (m, 8H), 5.25 (dq, J=1.3, 10.3, 4H), 5.38 (dq, J=1.4, 17.1, 4H), 5.90-6.00 (m, 4H), 6.14 (bd, J=4.9, 1H): 31P (162 MHz, CDCl3) δ 24.67 (s, 2P).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C

Procedure:
A mixture containing 2-(chloromethyl)-quinoline hydrochloride (100.0 g), 4-acetamidophenol (70.69 g) and milled anhydrous potassium carbonate (194 g) was stirred in DMF (1.2 L) using a mechanical stirrer for 48 hours. The mixture was carefully poured onto ice/water (3 L) with vigourous stirring. After the ice had melted, the solid was filtered and rinsed thoroughly with water. It was recrystallized from 95% ethanol and filtered to give the title compound in three crops.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 113.8 %

Procedure:
Dissolving 5.5 g (32 mmol) of 2-amino-5-bromopyridine, 4.3 g (32 mmol) of phenylboronic acid and 0.80 g of tetrakis (triphenylphosphine) palladium into 100 milliliter of 1,2-dimethoxyethane, adding 50 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 8 hours. After completion of the reaction and after filtration of the solution, washing the organic layer with water, dried it with the use of sodium sulfate. Removing the solvent by distillation, 6.2 g of crude 5-phenyl-2-amino-pyridine was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].O.C(=O)([O-])O.[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(OCC)(=O)C>[OH:7][CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: OC[C@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1CO

Procedure:
2 g (0.0198 mol) of (2R)-pyrrolidin-2-ylmethanol was dissolved in 20 mL of ethyl acetate, 20 mL of water was added thereto, and the mixture was stirred. 3.3 g (0.30 mol) of sodium hydrogencarbonate was added to the mixture, followed by stirring of the mixture for 5 minutes. 4.24 mL (0.03 mol) of benzyl chloroformate was added dropwise to the mixture, followed by stirring for 5 hours. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to quantitatively obtain the title compound.
Reaction SMILES: C(C1C=CC=C[C:5]=1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)(O)=O.[CH:28]1[N:32]2C3CC4C=CC=CC=4C=3NC(=O)[C:31]2=[N:30][CH:29]=1.CN1C=CN=C1C=O.[H-].[Na+]>CS(C)=O>[CH3:31][N:30]1[CH:29]=[CH:28][N:32]=[C:5]1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=C(O)c1ccccc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: Cn1ccnc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ccnc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12

Procedure:
The process is performed as in Example 3 for the preparation of 10-(2-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one but starting with 4.46 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one, 80 ml of dimethyl sulphoxide, 2.6 g of 1-methyl-2-formylimidazole and 1.44 g of 80% sodium hydride. After treatment of the reaction mixture with 80 ml of water and 3 ml of acetic acid, the suspension is filtered and the red solid obtained is washed with methanol and air-dried to give 5 g of 10-[(1-methylimidazol-2-yl)methylene]-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one. The dihydrochloride is formed by adding 3 ml of 3N hydrochloric acid solution in-ethyl ether to a suspension of 1.5 g of crude base in 50 ml of methanol. The yellow precipitate formed is filtered off and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). 1.75 g of 10-[(1-methylimidazol-2-yl)methylene]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one dihydrochloride are obtained, melting above 260° C. (Analysis, % calculated C: 55.68, H: 3.89, ° Cl: 18.26, N: 18.04, O: 4.12, % found C: 55.8, H: 3.9, N: 17.9).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[CH:41][C:40]=1[O:48][CH3:49])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O1CCCC1>[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])=[CH:41][C:40]=1[O:48][CH3:49])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
32.9 g of BOC-L-valine and 16.7 ml of N-methylmorpholine are dissolved in 350 ml of tetrahydrofuran and cooled to −20° C. 19.8 ml of isobutyl chloroformate are added dropwise to that solution over a period of 15 minutes. The mixture is stirred for 30 minutes, during which time the temperature rises to −7° C. The mixture is then cooled to −20° C., and 35.4 g of 2-(4-benzyloxy-3-methoxy-phenyl)-ethylamine in 50 ml of tetrahydrofuran are added dropwise over a period of 10 minutes. The reaction mixture is stirred for 30 minutes at −20° C. and then for 4 hours at room temperature. It is introduced into 300 ml of 1N hydrochloric acid. Extraction is carried out twice using 400 ml of ethyl acetate each time. The organic phases are washed once with 300 ml of 1N hydrochloric acid and once with 300 ml of saturated sodium chloride solution, dried over magnesium chloride and concentrated, yielding (S)-2-(tert-butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-amide, which is recrystallised from ethyl acetate/n-hexane, m.p. 115-118° C.