Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:47]=[CH:46][C:24]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]([CH3:37])[C:32](=[O:38])[CH:31]=[C:30]3[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[OH:26][C:25]([C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:47][CH:46]=1)([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[C:32](=[O:38])[CH:31]=[C:30]2[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1
Reactant: Cn1ccnc1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C

Procedure:
Herein, in step 1, the intermediate 1-methyl imidazole in tetrahydrofuran, is mixed with a solution of n-butyllithium in a hexane solvent to which is added chlorotriethylsilane (triethylsilyl chloride), followed by a further addition of n-butyllithium in hexane, the resulting mixture being cooled to −78° C. before the addition of a solution of a compound of formula (I), i.e. 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone in tetrahydrofuran. The reaction mixture is subsequently brought to room temperature, and then hydrolysed, extracted with ethyl acetate and the organic layer worked up to obtain a compound of formula (II), i.e. (±)-6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[N:7](=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)[OH:8]>CCOCC.C(N(CC)CC)C>[CH2:1]([NH:4][C:5]([O:8][N:7]=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN=C=O
Reactant: CC1OCSC1=NO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 3 ml of allyl isocyanate was caused to react with 3 grams of 4-oximino-5-methyl-1,3-oxathiolane dissolved in 50 ml of ether containing 2 drops of triethylamine over a period of 20 hours at room temperature. Conventional workup and recrystallization from isopropyl ether afforded 3 grams of product, mp 66.0°-67.5°, structure confirmed by spectral analysis.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C:6](=O)[CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C.Br[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=O.BrCC(C1C=CC=CC=1)=O.C(OC[N:49]1C(C2C=C(N)C=CC=2)=NN=N1)(=O)C(C)(C)C.CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>O.O.O1CCOCC1.C(Cl)Cl>[CH:8]1([CH2:7][C:6]2[NH:49][C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:18][C:5]=2[C:4]([OH:3])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)CC(=O)CC1CCCCCC1
Reactant: CC(C)(C)C(=O)OCn1nnnc1-c1cccc(N)c1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(CBr)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)c1cc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1

Procedure:
2-Cycloheptylmethyl-5-naphthalen-2-yl-1H-pyrrole-3-carboxylic acid was prepared according to the procedure of Example 1, steps a, b and c, using 4-cycloheptyl-3-oxo-butyric acid ethyl ester and 2-bromo-1-naphthalen-2-yl-ethanone instead of 4-adamantan-1-yl-3-oxo-butyric acid ethyl ester and 2-bromo-1-phenyl-ethanone in step a. The acid was then reacted with 3-(1-pivaloyloxymethyl-1H-tetrazol-5-yl)-phenylamine using essentially the same procedure as in Example 1, step d. Deprotection was performed following essentially the procedure of Example 2, step b, with the exception that after acidification the product was isolated by extraction with DCM. 1H NMR (300 MHz, d6-DMSO) 11.63 (1H, s), 9.72 (1H, s), 8.59 (1H, s), 8.15 (1H, s), 7.88 (5H, m), 7.67 (2H, d), 7.48 (3H, m), 7.34 (1H, s), 2.95 (2H, d), 1.99 (1H, br s), 1.68-1.23 (12H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 63.03; H, 6.96; N, 13.71%; C37H47N7O6.1.0 H2O requires: C, 63.14; H, 7.02; N, 13.93%.
Reaction SMILES: [C:1](#[N:3])[CH3:2].O1CCCC1.C([Li])CCC.[CH:14]([N:17]1[C:21]2[CH:22]=[C:23]([C:26](=O)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH2:34])([CH3:16])[CH3:15]>C(OCC)(=O)C.O>[CH:14]([N:17]1[C:21]2[CH:22]=[C:23]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:2][C:1]#[N:3])[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH2:34])([CH3:16])[CH3:15]
Reactant: CC(C)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Reactant: CC#N
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(N)nc2ccc(C(=CC#N)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Forty millimoles (2.1 ml.) of dry acetonitrile were added to 30 ml. of tetrahydrofuran. A nitrogen blanket was applied and the temperature of the solution lowered to about -78° C. by means of an external acetone/dry ice bath. Twenty-five milliliters of a 1.6M solution of n-butyl lithium were added. After stirring at -78° C. for 30 minutes, a solution of 2.8 g. (10 mmoles) of 1-isopropyl-2-amino-6-benzoylbenzimidazole in 30 ml. of tetrahydrofuran was added. The reaction solution was allowed to warm to about -20° C. and was then stirred for 5 hours at -20° to -5° C. Water and ethyl acetate were then added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was dissolved in 100 ml. of 98% formic acid. After stirring on a hot water bath for 2.5 hours, the solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic solution was dried over magnesium sulfate, filtered, and evaporated. The residue was chromatographed over silica gel, eluting first with ethyl acetate to remove non-polar impurities, then with 10% methanol/90% ethyl acetate to elute the title product. The product was further purified by reverse phase chromatography, eluting with 60% aqueous methanol, followed by crystallization from methyl ethyl ketone, resulting in 350 mg. of the title product, M+ =302.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[NH2:32][CH2:31][C:30]1[C:25]([CH:22]2[CH2:23][CH2:24][N:20]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:21]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCc1cccnc1C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: NCc1cccnc1C1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 86 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.80 g, 3.0 mmol) and 2-(3-pyrrolidinyl)-3-pyridinemethanamine, a procedure analogous to that given in Example 1 provided the title compound (1.09 g, 86%) as an off-white solid, mp 246°-248° C.
Reaction SMILES: [CH2:1]([N:4]([C:15]1[C:20](=[O:21])[N:19]2[C@H:22]([C:28](=[O:50])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([NH:39][C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[NH:38])=[CH:33][CH:32]=3)[CH2:23][C@@H:24]([CH2:25][CH:26]=[CH2:27])[C:18]2=[N:17][CH:16]=1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[CH2:51]([C:54]1(CC=C)C2=NC=C(N(CC=C)C(OCC3C=CC=CC=3)=O)C(=O)N2[C@H](C(O)=O)C1)[CH:52]=C.Cl.C(OC(=O)NC(C1C=CC(CN)=CC=1)=N)C1C=CC=CC=1>>[CH2:1]([N:4]([C:15]1[C:20](=[O:21])[N:19]2[C@H:22]([C:28](=[O:50])[NH:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([NH:39][C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[NH:38])=[CH:35][CH:36]=3)[CH2:23][C:24]([CH2:54][CH:51]=[CH2:52])([CH2:25][CH:26]=[CH2:27])[C:18]2=[N:17][CH:16]=1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@@H](C(=O)NCc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)CC2(CC=C)CC=C
Agent: Cl
Agent: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)CC2(CC=C)CC=C
Yield: 41 %

Procedure:
According to the procedure for the preparation of 28e, 29d (162 mg, 0.360 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester hydrochloride to afford after flash chromatography (66% EtOAc/hexanes) 105 mg (41%) of 29e. MS (ESI) 715.5 (M+H+), 737.5 (M+Na+).
Reaction SMILES: [CH:1]([C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1)=[O:2].[CH:11]([O-])([O-])[O:12]C.[C:16]1(C)C=CC(S(=O)=O)=CC=1.C[O-].[Na+].CO>CO>[CH3:16][O:2][CH:1]([O:12][CH3:11])[C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1
Reactant: O=Cc1ncc2sccn12
Reactant: Cc1ccc([SH](=O)=O)cc1
Reactant: COC([O-])[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ncc2sccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of 650 mg (4.23 mmol) of the above-obtained 5-formylimidazo[5,1-b]thiazole in 10 ml of methanol were added 30 ml of methyl orthoformate and 486 mg of p-toluenesulfonic acid monohydride. The mixture was refluxed for 4 hours, and then cooled to room temperature. To this was added 2 ml of a 28% sodium methoxide/methanol solution, and the mixture was stirred for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was dissolved in methylene chloride, and the solution was successively washed with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting with a 1:9 mixture of hexane and ethyl acetate to give 694 mg (yield 83%).of the title compound as an red-brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][N:8]([CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CS(C)=O>[CH3:7][NH+:8]([CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:3]([NH:4][C:5]([NH2:8])=[O:6])[CH3:2]
Reactant: O=C=NCCCl
Reactant: CCCCCCCCCCCCN(C)C
Solvent: CS(C)=O
Product: CCCCCCCCCCCC[NH+](C)C
Product: CCNC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroethylisocyanate (0.2 ml; 2 mmol) was added to a solution of BHAlyslys2lys4lys8lys16.32CF3COOH (300 mg) in dry DMSO (5 ml) and then N,N-Dimethyl-N-dodecylamine (3.0 ml) was added and the solution stirred overnight at room temperature under nitrogen. The resulting inhomogeneous mixture was then heated at 80° C. for 3 days. The mixture was then cooled and concentrated under high vacuum to give viscous oil. The crude product was purified by gel filtration (Sephadex LH20; 2.5×50 cm; MeOH) to give the product as a viscous oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[C:2]#[CH:3].Cl[C:19]([O:21][C:22]1[CH:27]=CC([N+]([O-])=O)=CC=1)=[O:20].C(N(CC)CC)C.[C:38](OCC)(=[O:41])[NH:39][NH2:40].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:38]([NH:39][NH:40][C:19]([O:21][CH2:22][CH3:27])=[O:20])=[O:41])=[CH:13][CH:12]=1)[C:2]#[CH:3]
Reactant: C#CCOCCOCCOc1ccc(N)cc1
Reactant: CCOC(=O)NN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOCCOCCOc1ccc(NC(=O)NNC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To 4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)aniline (I-7b: 1.339 g, 5.69 mmol) in THF (37.9 mL) at 0° C. was added 4-nitrophenyl chloroformate (2.064 g, 10.24 mmol) and triethylamine (1.420 mL, 10.24 mmol). The mixture was stirred at room temperature for 1 hour. Then ethyl carbazate (1.540 g, 14.79 mmol) and more triethylamine (1.420 mL, 10.24 mmol) were added. The mixture was stirred at room temperature for 16 hours, followed by the addition of aqueous saturated sodium bicarbonate. The mixture was then extracted twice with ethyl acetate, dried over MgSO4, filtered, and then concentrated in vacuo. The crude product was purified by silica gel chromatography (40-100% ethyl acetate/heptane) giving ethyl 2-(4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenylcarbamoyl)-hydrazinecarboxylate (I-7c: 1.31 g, 63%) as a foamy colorless oil. LC-MS (M+1) 366.1, t=0.95 minute.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:22]3=[CH:23][N:24]=[CH:25][CH:26]=[C:21]3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)CCN(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.CCCCCCC.C1COCC1>[C:36]1([CH:35]([C:19]2[N:18]([S:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:17])=[O:16])[C:22]3=[CH:23][N:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[OH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccncc21
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=S(=O)(c1ccccc1)n1c(C(O)c2ccccc2)cc2ccncc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To a solution of lithium diisopropylamide (1.2 mL of a 2 M solution in THF/heptane, 2.3 mmol) in THF (3 mL) was added a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (300 mg, 1.2 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.18 mL, 1.2 mmol) in THF (5 mL), dropwise at −25° C. After 0.5 h, a solution of benzaldehyde (0.24 mL, 2.3 mmol) in THF (6 mL) was added dropwise. After 1 h, the reaction mixture was warmed to 10° C. and quenched by the addition of saturated NH4Cl (5 mL). The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×40 mL). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 9:1 hexanes/EtOAc to EtOAc) gave phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (155 mg, 37%) as a mixture of enantiomers: 1H NMR (500 MHz, DMSO-d6) δ 6.36 (1H, d, J=5.5 Hz), 6.43 (1H, d, J=5.5 Hz), 6.75 (1H, s), 7.32-7.36 (5H, m), 7.53 (2H, dd, J=8.4, 7.6 Hz), 7.59 (1H, d, J=5.2 Hz), 7.66-7.70 (1H, m), 7.82-7.85 (2H, m), 8.35 (1H, d, J=5.2 Hz), 9.22 (1H, s); ESI MS m/z 365 [C20H16N2O3S+H]+; HPLC (Method A) 91.9% (AUC), tR=16.5 min.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1.CC1C=CC=CC=1>O>[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN2C(=O)c3ccccc3C2=O)C[C@H]1OC
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of 1.85 parts of 1,3-isobenzofurandione, 4.4 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 45 parts of methylbenzene was stirred for 3 hours at reflux temperature, using a water separator. The reaction mixture was evaporated. The residue was taken up in trichloromethane. The organic phase was washed with a saturate solution of sodium carbonate and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.5 parts (42,4%) of cis-4-amino-5-chloro-N-[1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 208.2° C. (compound 88).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[N:22]3[CH:21]=1)=O>>[CH3:32][C:23]1([CH3:33])[CH2:24][CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:21][N:22]13)[CH:29]=[CH:28][CH:27]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2(C)C
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Product: CC1(C)CCc2cccc3c(C4=C(c5c[nH]c6cc(F)ccc56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (6-fluoroindol-3-yl)acetamide and (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1cnc(C(F)(F)F)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a solution of 5-(azidomethyl)-2-(trifluoromethyl)pyrimidine (Description 120; 660 mg, 3.26 mmol) in anhydrous THF (10 ml) was added triphenylphosphine (1.71 g, 6.52 mmol) and water (0.059 ml, 3.26 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was evaporated and the residue purified by column chromatography on silica elution with 5% MeOH in DCM+0.5% NH4OH to give the title compound (320 mg, 55%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.Cl>CS(C)=O.O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1cc2cc(O)ccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc4oc(C(=O)O)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-hydroxybenzofuran-2-carboxylic acid (Step a, 2.00 g, 11.23 mmol) in DMSO (23 mL) at RT was added cesium carbonate (11.0 g, 33.7 mmol). The reaction was stirred for 10 min followed by the addition of 4-chloro-6,7-dimethoxyquinoline (prepared by the method described in WO 03/33472) (1.75 g, 7.86 mmol). The reaction was stirred at 100° C. for 16 h. After cooling to RT, water was added. The aqueous layer was acidified with a 6M aqueous hydrochloric acid solution until pH=5, filtered and the solid was suspended in EtOAc. The organic phase was extracted with a 3M sodium hydroxide aqueous solution. After acidification of the aqueous layer, the title compound was isolated by filtration and dried under high vacuum.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([OH:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:21][N:22]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23](=[O:26])[CH:24]=[CH2:25]>C(N(CC)CC)C>[OH:14][C:5]1[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][C:2]([S:1][CH2:25][CH2:24][C:23]([N:22]([CH3:21])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[O:26])=[CH:3][C:4]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Reactant: C=CC(=O)N(C)CCc1ccccn1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared according to the method of Example 4 from the thiol of Example 16(2.78 g, 0.01 mole), N-methyl-N-[2-(2-pyridinyl)ethyl]-2-propenamide (1.90 g, 0.01 mold) and triethylamine (1.2 ml). Analysis calc. for C29H28O2N2S (468.54): Calc.: C, 74.32; H, 6.02; N, 5.98. Found: C, 73.93; H, 6.04; N, 6.16.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1)[CH2:2][CH3:3]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=CCCCCCC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: CCCc1ccc(CCCCCCCC(=O)O)cc1
Yield: 95.3 %

Procedure:
This compound was synthesized from 8-(p-propylphenyl)-7-octenoic acid (1.30 g, 5 mmol) and Pd/BaSO4 (130 mg) by a hydrogenation reaction. Crystallization (petroleum ether) afforded the product (1.25 g, 95%) as white crystals (mp 42-43° C.). IR: 3400-2500, 1705 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.45 (m, 12H), 2.50 (m, 6H), 7.05 (s, 4H), 11.40 (bs, 1H). Anal. Calcd. for C17H26O2 : C, 77.82, H, 9.99%; Found: C, 77.75, H, 10.04%.
Reaction SMILES: [C:1]1([SiH3])[CH:6]=[CH:5]C=CC=1.[F:8][C:9]([F:27])([F:26])[CH:10]=[N:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=2)[CH2:13]1.[CH2:28]1COCC1>CCOC(C)=O.C([Sn](Cl)(Cl)CCCC)CCC>[F:27][C:9]([F:8])([F:26])[CH2:10][NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][C:6]([CH3:5])([CH3:1])[CH3:28])=[O:22])=[CH:24][CH:25]=2)[CH2:13]1
Reactant: [SiH3]c1ccccc1
Reactant: O=C([O-])c1ccc(N2CCC(N=CC(F)(F)F)C2)cc1
Reactant: C1CCOC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](NCC(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
Dibutyltin dichloride (28 mg, 0.09 mmol) and phenylsilane (365 mg, 3.37 mmol) were added to a suspension of 457 (1.05 g, 3.07 mmol), in THF (6.1 mL). The reaction mixture was stirred for 48 h at room temperature, diluted with AcOEt, washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography to afford the title compound 458 (647 mg, 61% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>>[CH3:24][O:25][CH2:26][C:27]([NH:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:13]([NH:12][CH:10]3[C:11]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])[CH2:8][CH2:9]3)[O:14][CH2:15][C:16]=2[CH:22]=1)=[O:28]
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc2c(c1)COC(NC1CCc3cccc(OC)c31)=N2
Yield: 60.9 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and methoxyacetyl chloride (32 ul, 0.356 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (75 mg, 61%), MS (ISP) m/e=382.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7][NH:6][C:5]=2[S:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:13][N:6]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:10]=2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7]1
Reactant: Cc1csc2c1S(=O)(=O)N=CN2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cc1csc2c1S(=O)(=O)N=CN2C
Temperature: 65 °C

Procedure:
150 mg of the compound obtained in Step A above are suspended in 5 ml of acetonitrile. 300 mg of potassium carbonate and 0.15 ml of iodomethane are added thereto. The reaction mixture is heated at 65° C. for 30 minutes, with stirring. After evaporation of the solvents under reduced pressure, the residue is taken up in 5 ml of water and then collected by filtration, washed with water and dried.