Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:7][C:6]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccc4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the compound from example 5 (200 mg, 0.53 mmol) in dichloromethane (5 mL) was added triethylamine (110 μL, 0.79 mmol). The reaction was cooled to 0° C. and methanesulfonyl chloride (48.9 μL, 0.63 mmol) was added. The solution was stirred for 1 hour at room temperature and diluted with water (5 mL). The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo and azeotroped with ethyl acetate to give the product as a white crystalline solid, 196 mg (76%).
Reaction SMILES: C[N:2]=[C:3](OC)[CH3:4].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:14]1(C)C=CC=CC=1>>[CH:7]1([N:13]([CH3:14])[C:3](=[NH:2])[CH3:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccccc1
Reactant: CN=C(C)OC
Reactant: NC1CCCCC1
Product: CC(=N)N(C)C1CCCCC1
Reaction time: 72 h

Procedure:
To a solution of methyl N-methylacetimidate (8.7 g, 0.1m) in toluene (90 ml.) was added cyclohexylamine (10.5 g, 0.105m). After 72 hours at room temperature and 32 hours heating at 60°-70° C the solvent was removed by evaporation to yield an oil which crystallised on cooling. Chromatography on alumina using ether as eluent afforded N-cyclohexyl-N1 -methylacetamidine as a colourless solid (11 g), or m.p. 108.5° - 109.5° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2([CH2:9][NH:8][CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1.C(O)(=O)C.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>CO>[CH3:1][C@@H:2]1[C:6]2([CH2:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1
Reactant: O=Cc1ccccc1
Reactant: C[C@H]1NC(=O)OC12CNC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1NC(=O)OC12CN(Cc1ccccc1)C2
Temperature: 0 °C

Procedure:
A solution of (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one (937 mg, 6.6 mmol), acetic acid (0.756 mL, 13.2 mmol), and benzaldehyde (1.0 mL, 9.9 mmol) in methanol (65 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) at rt for min. The mixture was then cooled to 0° C., and 3 N hydrochloric acid (100 mL) was added. The methanol was then removed in vacuo. The resulting aqueous solution was washed with ethyl acetate. The ethyl acetate wash was back extracted with 1 N hydrochloric acid, and the aqueous acidic phases were combined and basified with potassium carbonate. The organic phase was discarded. The aqueous mixture was then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired (8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one was obtained in 93% purity as a milky colorless liquid (1.33 g, 5.73 mmol, 87% yield). MS (EI) for C13H16N2O2: 233 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]([CH2:31]N)[CH2:12][CH:13](CC2C=CC=CN=2)[NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20]C(C)=[CH:18][N:17]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][C:34]([O-])=O.[Na+].Br[C:39]#[N:40].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[C:12]([CH2:13][N:14]([CH2:15][C:16]3[C:21]([CH3:22])=[CH:20][C:34]([CH3:33])=[CH:18][N:17]=3)[CH2:8][CH2:11][CH2:12][CH2:13][NH:14][C:39]#[N:40])=[N:17][CH:16]=[CH:15][CH:31]=2)([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: N#CBr
Reactant: Cc1cnc(CNC(Cc2ccccn2)CC(CN)C(C)(C)c2ccc(Cl)cc2)c(C)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cnc(CN(CCCCNC#N)Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 123 %

Procedure:
To a solution of N-{3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl-N-(3,5-dimethyl-pyridin-2-ylmethyl)-butane-1,4-diamine (0.200 g, 0.444 mmol) in dry MeOH (4 mL), at 0° C., was added NaOAc (0.106 g, 1.29 mmol) and BrCN (0.063 g, 0.59 mmol). The mixture was stirred at 0° C. fro 30 min, then at room temperature for 2 h. Water (10 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum. The residue was purified by flash chromatography on a silica gel column (100:5:2 CH2Cl2/MeOH/NH4OH), affording a pale yellow oil (0.13 g, 62%). 1H NMR (CDCl3) δ 1.35-1.45 (m, 4H), 1.65 (s, 6H), 1.99 (s, 3H), 2.25 (s, 3H), 2.32-2.40 (m, 2H), 2.62-2.70 (m, 2H), 3.04 (s, 2H), 3.22 (s, 2H), 7.02 (d, 2H, J=8.1 Hz), 7.15-7.28 (m, 4H), 7.91 (d, 1H, J=7.8 Hz), 8.13 (s, 1H), 8.48 (s, br. 1H), 8.57 (d, 1H, J=3.9 Hz). ES-MS m/z 476 (M+H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH:18]3OCCC[O:19]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH:18]=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCCO3)CC2)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1

Procedure:
In 3.0 l of toluene was dissolved 300 g (930 mmol) of the 2-(2-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)ethyl)-1,3-dioxane obtained by the procedures described above, 428 g (9300 mmol) of formic acid was added thereto, and they were heated to reflux for 4 hours. The reaction mixture was washed with 600 ml of saturated aqueous sodium bicarbonate solution twice and with 1.0 l of water five times, and the solvent was distilled off under a reduced pressure to obtain 240 g of a crude 3-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)propanal.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[O:27]=[C:28]1[C:33](C(Cl)=O)=[CH:32][CH:31]=[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:29]1.[CH2:42]([N:44]1[C:56]2[CH:55]=[CH:54][C:53]([NH2:57])=[CH:52][C:51]=2[C:50]2[C:45]1=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH3:43]>>[CH2:42]([N:44]1[C:56]2[CH:55]=[CH:54][C:53]([NH:57][C:24]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH2:12][N:8]3[C:6]([C:33]3[C:28](=[O:27])[O:29][C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:31][CH:32]=3)=[O:7])=[O:26])=[CH:52][C:51]=2[C:50]2[C:45]1=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH3:43]
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccc(OC)cc3)C[C@H]2C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 57% purity by LC/MS. MS(ESI+): m/z=649.4.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])[S:5][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].S([CH2:42][N+:43]#[C-:44])(C1C=CC(C)=CC=1)(=O)=O>CO.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])[S:5][C:6]=1[C:7]1[O:8][CH:44]=[N:43][CH:42]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1-c1cnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carbaldehyde (0.32 g, 0.86 mmol) in methanol (20 mL) was added potassium carbonate (0.30 g, 2.17 mmol) and tosylmethyl isocyanide (0.23 g, 1.17 mmol). The reaction mixture was stirred at ambient temperature for 1 h, heated to reflux for 1 h, and then cooled to ambient temperature. The mixture was diluted with ethyl acetate, washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a colorless solid in 47% yield (0.32 g): mp 160-162° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.85 (s, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.07 (s, 1H), 4.53 (s, 2H), 4.12-4.06 (m, 2H), 3.49-3.44 (m, 2H), 2.43 (s, 3H); 1H NMR (75 MHz, CDCl3) δ 157.5, 155.6, 149.8, 145.4, 145.1, 139.8, 130.5, 128.5, 125.9, 122.4, 122.1, 111.7, 47.6, 42.1, 42.0, 16.7; MS (ES+) m/z 409.1 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:3][CH2:2]1.[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C.O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][N:9]2[C:10](=[S:11])[NH:14][N:13]=[N:12]2)[CH2:5][CH2:6]1
Reactant: S=C=NCCN1CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: S=c1[nH]nnn1CCN1CCOCC1
Temperature: 20 °C
Yield: 53 %

Procedure:
To a mechanically stirred slurry of 25.8 g (0.15 mole) of 2-morpholinoethylisothiocyanate (S-7) in 250 ml ethanol under a nitrogen atmosphere was added in a slow stream 19.5 g (0.3 mole) of sodium azide dissolved in 600 ml water. The resultant solution was refluxed for 16 hrs, cooled to room temperature (20° C.) and filtered. The filtrate was extracted twice with ether, and then acidified to pH=1 with concentrated hydrochloric acid. The resultant solution was extracted three times with ether. The pH of the aqueous solution was adjusted to 4.5 using a 50% NaOH solution and a fine white precipitate formed. The precipitate was collected by filtration to yield 17.1 grams of intermediate S-8 with a melting point of 226°-8° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 38.6 %

Procedure:
4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (100 mg, 0.41 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (152 mg, 0.416 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (83 mg, 38%) as a green solid: 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.06 (dd, J=8.3, 2.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.03 (dd, J=7.1, 1.8 Hz, 1H), 4.66 (s, 2H), 3.85 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:31][NH:32][S:33]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1)(=[O:35])=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][S:33]([NH:32][CH3:31])(=[O:35])=[O:34])=[CH:38][CH:39]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNS(=O)(=O)Cc1ccc(CN)cc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CNS(=O)(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 70 %

Procedure:
Prepared analogously to Example 6d) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4-(methylamino-sulphonylmethyl)benzenemethanamine and TBTU in a yield of 70% of theory. Colourless amorphous substance.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:11]1[C:16]([Cl:17])=[N:15][CH:14]=[CH:13][N:12]=1)C(OCC)=O)C.[OH-].[Na+].Cl.C(OCC)C>C(O)C>[Cl:17][C:16]1[C:11]([CH2:5][C:4]([OH:18])=[O:3])=[N:12][CH:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)Cc1nccnc1Cl
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of 2-(3-chloro-pyrazin-2-yl)-malonic acid diethyl ester (10.0 g) in ethanol (100 ml) was added 2M sodium hydroxide (100 ml) and the reaction mixture heated to 60° C. for 4 hours. The reaction mixture was cooled to ambient temperature then poured onto water and 1M hydrochloric acid followed by extraction with ethyl acetate (3×). The combined organic layers were dried (magnesium sulfate), filtered and the filtrate concentrated to give the crude title compound as a yellow solid. The solid was slurried with diethylether to give (3-chloro-pyrazin-2-yl)-acetic acid (4.35 g). MH+=173, RT=0.72 min (Method A).
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:20]=[CH:19][C:13]2[NH:14][C:15](=O)[CH2:16][O:17][C:12]=2[CH:11]=1)[CH:3]([CH3:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(Cl)(Cl)Cl.O=P(Cl)(Cl)[Cl:27].[CH3:30][N:31]([CH3:34])[CH:32]=O>>[O:1]=[C:2]([C:10]1[CH:20]=[CH:19][C:13]2[N:14]=[C:15]([Cl:27])[C:16](=[CH:30][N:31]([CH3:34])[CH3:32])[O:17][C:12]=2[CH:11]=1)[CH:3]([CH3:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)C(=O)c1ccc2c(c1)OCC(=O)N2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)OC(=CN(C)C)C(Cl)=N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-oxo-4-(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-3-methylbutyrate (10 g) was added to chloroform (100 ml) containing POCl3 (3.5 ml) and dimethylformamide (2.8 ml) at 0° C. The mixture was heated at reflux for 3 hours then stirred at room temperature overnight. The solvent was removed at reduced pressure, the residue was basified with 10% NaOH solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was chromatographed on silica gel and eluted with methylene chloride. The fractions containing the Product were evaporated to dryness and the residue used without further purification.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].[CH:25]([O:38][C:39]1[C:40]2[C:52](=[O:53])[N:51]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)[CH2:50][C:41]=2[C:42]([OH:49])=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOC(C)=O.CCCCCC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:25]([O:38][C:39]1[C:40]2[C:52](=[O:53])[N:51]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)[CH2:50][C:41]=2[C:42]([O:49][S:21]([CH2:20][CH2:19][N:10]2[C:9](=[O:8])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:18])(=[O:22])=[O:23])=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1c2c(c(O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(c(OS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Triethylamine (50 μl), DMAP (catalytic amount) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (27.4 mg, 0.10 mmol) were added to 0.034 mmol 45. The reaction mixture was stirred at room temperature for 18 hours under an inert atmosphere. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 44=0.5, Rf 45=0, Rf 268=0.4) and LC/MS. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethylacetate/hexane—3/7) to afford 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 268 (12.2 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][O:34][C:33](=[O:35])[CH2:32][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=3[CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:21][C:20]3=[O:31])[C:2]([O:1][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([Cl:36])=[CH:38][CH:39]=3)=[CH:3][CH:4]=2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCc2ccc(Cl)cc2)ccc1OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 14, Step 3, using the following starting materials: [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid and 4-chlorobenzyl bromide.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][C:20]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][C:20]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1(C)CNc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.7 %

Procedure:
The product is prepared according to the procedure described in example 5, using 177 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 236 mg of 3,3-dimethylindoline (which can be prepared according to T. W. Ramsay et al., Synth. Commun. 1995, 25, 4029) and 169 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.11 ml of pyridine and 5 ml of N,N-dimethylformamide. The reaction mixture is stirred for 15 h at ambient temperature and then concentrated to dryness under reduced pressure. 40 ml of water are added to the residue and triturated with a spatula at ambient temperature. The precipitate formed is filtered off, and then solubilized with a dichloromethanemethanol mixture and dried. After concentration to dryness under reduced pressure, the crude product is purified by chromatography on a 30 g silica (0.02-0.045 mm) column, eluent: 90/10 v/v dichloromethanemethanol. After the various fractions have been evaporated, the pink solid residue is triturated from 10 ml of diisopropyl ether, filtered off, and then dried under a bell jar (1h40° C./20 mbar). 134 mg of 2-[2-(3,3-dimethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are thus obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1[C:26](=[O:27])[CH2:25][CH2:24]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]3[CH2:24][CH2:25][CH2:26][O:27][C:13]=23)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCN1CCCCC1)c1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCN1CCCCC1)c1c2n(c3ccccc13)CCCO2
Yield: 29 %

Procedure:
N-[2-(1-Piperidyl)ethyl] 1H-indole-3-carboxamide (D2) was treated initially with N-chlorosuccinimide then with 3-bromo-1-propanol, then with potassium carbonate in acetone following the method described in Example 3. The crude product was chromatographed on silica gel eluting with chloroform/methanol (19:1) to give a pale yellow oil, which crystallised from ether to afford the title compound (E5) as a white solid (29%) mp 124-127° C.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:27]C(C)([O-])C.[K+].[CH:33]1([NH:39][C:40]2[C:45](C=O)=[CH:44][N:43]=[C:42]3[N:48]([S:51]([C:54]4[CH:60]=[CH:59][C:57]([CH3:58])=[CH:56][CH:55]=4)(=[O:53])=[O:52])[CH:49]=[CH:50][C:41]=23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>C1COCC1>[O:4]1[CH2:5][CH2:6][O:2][CH:3]1[CH:7]=[CH:27][C:45]1[CH:44]=[N:43][C:42]2[N:48]([S:51]([C:54]3[CH:60]=[CH:59][C:57]([CH3:58])=[CH:56][CH:55]=3)(=[O:52])=[O:53])[CH:49]=[CH:50][C:41]=2[C:40]=1[NH:39][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(C=O)cnc32)cc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(C=CC4OCCO4)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
An oven dried flask under nitrogen was charged with ((1,3-dioxolan-2-yl)methyl)triphenylphosphonium bromide (2.23 g, 5.19 mmol) and THF (14 mL). The flask was cooled to about 0° C. in an ice bath and potassium tert-butoxide (0.591 g, 5.00 mmol) was added. The mixture was stirred for about 30 min at about 0° C. and a solution of 4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.750 g, 1.89 mmol) in THF (4 mL) was added dropwise over about 10 min. The reaction was allowed to warm to ambient temperature and stirred for about 16 h. Water (10 mL) was added and the reaction mixture was extracted with Et2O (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The crude oil was purified by silica gel chromatography eluting 0-50% EtOAc in DCM to give 5-(2-(1,3-dioxolan-2-yl)vinyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine (0.590 g, 67%) as a mixture of E and Z isomers: LC/MS (Table 1, Method c) Rt=1.69 min, 1.73 min; MS m/z: 468 (M+H)+, 468 (M+H)+.