Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)[CH3:32])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3Cl)ccc21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of Example 441 (520 mg, 1.23 mmol) in DMF (15 mL) at 0° C. was added portionwise NaH (95 mg, 2.45 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (0.31 mL, 4.90 mmol) was added. After 18 h of agitation at rt, the excess NaH was quenched by the slow addition of NH4Cl (10% solution in water) [H2 evolution]. The resulting mixture was concentrated under reduced pressure, brought to basic pH using a saturated solution of NaHCO3, and the product was extracted with EtOAc. The combined organic layers were washed with water and brine, after which they were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (442 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H), 1.75-1.82 (m, 1H), 2.12-2.20 (m, 2H), 2.30-2.45 (m, 2H), 2.70 (dd, 1H), 2.72-2.90 (m, 2H), 3.30 (s, 3H), 3.44-3.54 (m, 1H), 3.84 (t, 2H), 3.95 (t, 2H), 4.16 (q, 2H), 6.65 (d, 1H), 6.75 (s, 1H), 7.05 (d, 1H), 8.15 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1ccc(F)cc1O[C@H]1CCOC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c2c1C

Procedure:
Prepared analogously to example 100.1. from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-4-fluoro-2-(tetrahydrofuran-3-yloxy)aniline (Intermediate XIX)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].[NH4+].[OH-]>OS(O)(=O)=O>[NH2:12][C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1cc(C(F)(F)F)cc(N)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])c(N)n1
Temperature: 25 °C

Procedure:
To a mixture of 2,6-diamino-4-trifluoromethylpyridine (173 mg) in H2SO4 (3 mL) at 0° C. was added HNO3 (0.048 mL, d=1.40). The stirred mixture was sequentially warmed to RT, aged 1.5 hours, poured onto 50 g ice, neutralized with NH4OH, extracted with EtOAc, filtered through 20 g SiO2 (washed with EtOAc until yellow color eluted), and concentrated to give 70 mg of 2,6-diamino-3-nitro-4-trifluoromethylpyridine as a yellow solid. A 1:1THF/MeOH solution of the nitro compound (65 mg) was hydrogenated (1 atm H2, Ra-Ni, 16 hours at RT), filtered, concentrated, and converted to the title compound by the method outlined in Example 21. FAB MS (M+ +1)=465; 1H NMR (300 MHz, CD3OD) δ 7.61 (t, 2H, J=7.5 Hz), 7.54-7.48 (m, 2H), 7.13-7.04 (AB q, 4H), 6.74 (s, 1H), 5.41 (s, 2H), 2.79 (q, 2H, J=7.5 Hz), 1.16 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]1COCC1.[CH:6]([C:8]1[CH:9]=[C:10](/[CH:19]=[CH:20]/[C:21]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:7].C[Mg]Br.O.[Cl-].[NH4+]>C(OCC)(=O)C>[OH:7][CH:6]([C:8]1[CH:9]=[C:10](/[CH:19]=[CH:20]/[C:21]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH3:1]
Reactant: O=Cc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)c1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Reaction time: 1 h

Procedure:
To a THF (0.5 mL) solution of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-ylacrylamide (23 mg) obtained in Example 437, methyl magnesium bromide (3M ether solution, 0.04 mL) was added under nitrogen atmosphere under ice-cooling and the reaction mixture was agitated for 1 hour. A saturated ammonium chloride water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:methanol-ethyl acetate system), and 10 mg of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH2:35][CH2:34]2>>[CH3:40][N:36]1[CH2:35][CH2:34][C:33]2[C:38](=[C:29]([NH:28][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=4)[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[C:37]1=[O:39]
Reactant: CN1CCc2cccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)CC4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (52.9 mg, 0.125 mmol) and 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 132A, 25 mg, 0.14 mmol). The crude material was adsorbed onto a pre-filled solid loading cartridge and purified using the Teledyne/ISCO Combiflash system, eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo, giving the title material as a white solid, 42.0 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.55 (br s, 1H), 9.82 (br s, 1H), 8.44 (s, 1H), 8.56 (br s, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.19 (dd, J=8.6, 2.3 Hz, 2H), 6.97 (d, J=7.3 Hz, 1H), 3.95 (qd, J=7.4, 7.2 Hz, 4H), 3.56 (t, J=6.7 Hz, 2H), 3.18 (d, J=21.2 Hz, 2H), 3.06 (s, 3H), 2.97 (t, J=6.6 Hz, 2H), 1.18 (t, J=7.1 Hz, 6H). MS (ES+): m/z 564.16 (100) [MH+]. HPLC: tR=3.50 min (ZQ3, polar—5 min).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>C(O)CCC>[N:13]1([C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CCN2
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Solvent: CCCCO
Product: Cc1[nH]c2ncnc(N3CCc4ccccc43)c2c1C

Procedure:
Under an argon atmosphere, 0.2 g (1.1 mmol) of 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (see Liebigs Ann. Chem. 1986(9), 1485-1505; CAS-Reg. No. 82703-38-6) and 0.15 ml (1.32 mmol) of 2,3-dihydroindole (Fluka, Buchs, Switzerland) in 5 ml of abs. n-butanol are heated at reflux for 2 hours until the starting material is no longer present in TLC. The reaction mixture is concentrated by evaporation in vacuo at 50° C. The brown residue is dissolved in 30 ml of ethyl acetate, and 10 ml of 1 N NaOH solution are added. The organic phase is separated off and washed three times with a small amount of water, dried and concentrated by evaporation. The crude product is dissolved in 10 ml of THF, and n-hexane is added until crystallization begins. Stirring is carried out at 0° C. and the product is filtered off with suction and dried under a high vacuum. Pure 4-(2,3-dihydroindol-1-yl)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine is obtained in the form of colorless crystals having a melting point of 220-221° C. FAB-MS: (M+H)+ =265 (corresponds to C16H16N4); Rf value (toluene-acetone--4:6)=0.46.
Reaction SMILES: C(OCC)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2.C([Li])CCC.[CH3:23][C:24]([CH3:26])=[O:25]>O>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][C:24]([CH3:26])([OH:25])[CH3:23])[CH:11]=[CH:10]2
Reactant: CC(C)=O
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)Cc1ccc2cc(Br)ccc2n1
Reaction time: 0.08 h

Procedure:
20 ml of diethylether was added to 2.22 g of 6-bromoquinaldine, and 3.76 ml of 2.66 M normal butyl lithium was dropped thereto at −78° C. The obtained suspension was stirred for 5 min, 2 ml of anhydrous acetone was added and the mixture was further stirred for 10 min, and water was added. The products were extracted with ethyl acetate, organic layer was dried with anhydrous sodium sulfated and the solvents were distilled outunder reduced pressure. The obtained residues were separated and purified by silicagel colum chromatography (hexane:ethyl acetate=2:1) to obtain 1.14 g of the above compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: Cn1ccc(Cl)cc1=O
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCO[C@@H]1CN(c2ccn(C)c(=O)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 16 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (50 mg, 0.15 mmol), 4-chloro-1-methylpyridin-2(1H)-one obtained in Example (137a) (25 mg, 0.17 mmol) and sodium carbonate (78 mg, 0.74 mmol) were suspended in DMSO (1 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 9.8 mg of the title compound as a pale brown amorphous solid (16%).
Reaction SMILES: [H-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>C1COCC1>[F:26][C:15]([F:14])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:19]2=[N:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a stirred solution of sodium hydride (6.2 g, 156 mmol, 60% dispersion), tosyl chloride (27 g, 141.8 mmol), in anhydrous THF (200 mL) under a nitrogen atmosphere was added a solution of 5-trifluoromethyl-lH-pyrrolo[2,3-b]pyridine (26.38 g, 141.8 mmol) in THF (150 mL) dropwise at a rate which maintained the internal temperature of the reaction below 40° C. The reaction mixture was stirred overnight at room temperature and analysis by LCMS showed no starting material remained after this time. The reaction mixture was concentrated to remove most of THF and diluted with DCM and water. The organic layer was separated and the aqueous layer further extracted with DCM. The organic layers are combined and washed with brine, dried over magnesium sulphate and concentrated to a volume which was appropriate to load onto the top of a silica plug (300 mL) pre-wet with DCM, and the silica was washed with 2.5 L DCM. The filtrate was concentrated to give the product as a slightly brown solid (44.1 g, 92% yield).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C@H:6]([OH:8])[CH3:7].[C:15]([O-])(=[O:19])[CH2:16]CC.C(OC(=O)C)(=O)C.N1C=CC=CC=1>>[C:15]([O:8][C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@H:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:7])(=[O:19])[CH3:16]
Reactant: CCCC(=O)[O-]
Reactant: CC(C)=CCC[C@@H](C)C/C=C/[C@@H](C)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H](C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99 %

Procedure:
A flame-dried 100 mL, three-necked flask with magnetic stirring bar was charged under argon with 2.0 g (10.2 mmol) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol [(2R,6R)/(2S,6R)=90:10 by GC diastereomer analysis of butyrate derivative]. Then, after cooling in an ice-bath, 1.5 g (1.4 mL, 15 mmol) of acetic anhydride, 1.58 g (1.6 mL, 20 mmol) of dry pyridine and 12.3 mg (0.1 mmol) of 4-N,N-dimethylaminopyridine were added, and the reaction was stirred for 75 minutes at ambient temperature. Work-up as described in Example 9 followed by Kugelrohr distillation at ca. 110°/0.25 mm afforded 2.35 g (99%) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol acetate as colorless liquid; GC purity 90%; [α]D25 =+47.17° (5.3% in CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][OH:25])[O:21][C:20]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[O:21][C:20]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: COCCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (1.0 g) was dissolved in pyridine (25 ml), and cooled to 0° C. Triethylamine (0.46 ml) and methanesulfonyl chloride (0.23 ml) were added, and stirring continued at ambient temperature for 2 hours. Solvent was evaporated and the residue dissolved in ethyl acetate, washed with water, dried (MgSO4), and evaporated to give (5R)-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (1.01 g) which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2]1.C(N(CC)CC)C.ClCCl.[CH3:27][CH:28]([CH3:34])/[CH:29]=[CH:30]/[C:31](Cl)=[O:32].ClCCl.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>>[CH3:27][CH:28]([CH3:34])/[CH:29]=[CH:30]/[C:31]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2]1)=[O:32]
Reactant: CC(C)/C=C/C(=O)Cl
Reactant: c1ccc2c(N[C@H]3CCNC3)ccnc2c1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)/C=C/C(=O)N1CC[C@H](Nc2ccnc3ccccc23)C1
Yield: 39 %

Procedure:
To N-[(3S)-Pyrrolidin-3-yl]quinolin-4-amine (32 mg, 0.15 mmol) dissolved in 1.5 ml anhydrous dichloromethane triethylamine (0.9 mmol, 91 mg) was added with stirring followed by (E)-4-methylpent-2-enoyl chloride dissolved in anhydrous dichloromethane (29.8 mg, 0.23 mmol). The mixture was stirred at room temperature for 5 minutes after which polymer-supported toluenesulfonyl chloride (600 mg, 1-2 mmol/g) was added and the mixture was shaken for 15 minutes, filtered and the filtrate evaporated to dryness under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 18 mg of a solid (0.58 mmol, 39%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:18][C:19]3[C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>CO>[C:26]([C:25]1[C:19]2[O:18][C:17]([CH:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:12]3)=[N:21][C:20]=2[CH:22]=[CH:23][CH:24]=1)(=[O:27])[NH2:30]
Reactant: N
Reactant: COC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)piperidin-3-yl)benzo[d]oxazole-7-carboxylate (180 mg, 0.46 mmol) was added to ammonia in methanol (20 mL) and the mixture was stirred at room temperature for 2 days. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4), the organic phase was dried with anhydrous sodium sulfate and evaporated under reduced pressure. 100 mg of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate was obtained. Yield: 57%. LC-MS (ESI) m/z: 380 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](O[C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1.C([O-])(=O)C.[NH4+:34]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([NH:34][C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1
Reactant: [NH4+]
Reactant: COc1cc2[nH]cc(C3=C(c4c[nH]c5ccccc45)C(=O)OC3=O)c2cc1OC
Agent: CC(=O)[O-]
Solvent: O
Product: COc1cc2[nH]cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2cc1OC
Yield: 40.1 %

Procedure:
3.0 g (7.72 mmol) 2-(1H-indol-3-yl)-3-(5,6-dimethoxy-1H-indol-3-yl)-maleic acid anhydride, together with 75 g ammonium acetate, are heated to 140° C. for 1 hour. After cooling, the reaction mixture is mixed with 1.5 l of water and the dark red precipitate is filtered off with suction. There is obtained a crude yield of 2.61 g. For purification, 1.75 g thereof is chromatographed on silica gel with dichloromethane/ethyl acetate (8:1 v/v) as elution agent. There are obtained 1.20 g 2-(1H-indol-3-yl)-3-(5,6-dimethoxy-1H-indol-3-yl)-maleinimide×0.5 ethyl acetate in the form of dark red crystals; m.p. 120° C. (decomp.); RF=0.32 (dichloromethane/ethyl acetate 3:1 v/v). Yield 54% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:33][CH:34]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (17.75 g, 58.0. mmole) in dry DMF (150 mL) at was added 4-benzyloxybenzylchloride (14.85 g, 63.8 mmole). After 10 min, 60% NaH (2.78 g, 69.6 mmole) was added and the reaction slurry was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a waxy solid. Purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (27.13 g, 93%) as a white solid: MS (ES) m/e 503 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[C@H:28]([CH3:29])[CH2:27][CH2:26][S:25]2(=[O:31])=[O:30])[CH:3]=1.[O:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:35][CH2:36][O:32][C:33]4=[O:37])=[CH:3][C:4]=3[N:24]3[C@H:28]([CH3:29])[CH2:27][CH2:26][S:25]3(=[O:31])=[O:30])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3[C@H](C)CCS3(=O)=O)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3[C@H](C)CCS3(=O)=O)CC2)c(C)c1
Yield: 15.1 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using (R)-[4-chloro-2-(3-methyl-1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (95.1 mg) described in Preparation Example 125 and oxazolidin-2-one (17.9 mg), the title compound (15.9 mg) was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Br:29][CH:30](Br)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][Br:29])=[CH:32][CH:33]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(C(Br)Br)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1ccc(CBr)cc1)Nc1c(C(C)C)cccc1C(C)C
Yield: 39.1 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 8.7 g (0.03 mole) of α,α-dibromo-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and the concentrated for the purpose of recovering the solvent to obtain a slightly brown powder. The powder was then recrystallized from acetone to obtain 6.6 g of white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH:13]1([C:19]([C:7]2[C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:9][C:8]=2[CH3:10])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccc2cc(C)oc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1ccc2c(C(=O)C3CCCCC3)c(C)oc2c1
Reaction time: 1 h
Yield: 47 %

Procedure:
To a mixture of 6-methoxy-2-methyl-1-benzofuran (1.50 g), cyclohexanecarbonyl chloride (1.36 mL) and nitromethane (15 mL) was added aluminum chloride (1.85 g) at 0° C., and the mixture was stirred for 1 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (1.18 g, 47%) as a yellow oil.