Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1>C(O)C.Cl>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccn2)nc1C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Solvent: CCO
Product: O=C(c1nc(-c2ccccn2)c[nH]1)c1cn(Cc2ccc(Cl)cc2)c2ccccc12

Procedure:
To a stirred solution of [1-(4-Chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone (10 mg, 18.4 mmol) in ethanol (3 mL) was added 5 drops of concentrated HCl. The resultant solution was heated to 70° C. for 10 hours. Volatile components were then removed under reduced pressure. Pure product [1-(4-Chloro-benzyl)-1H-indol-3-yl]-(4-pyridin-2-yl-1H-imidazol-2-yl)-methanonone was precipitated out from diethyl ether (7 mg, 92%). 1H NMR (CD3OD/THF-d8): 5.7 (s, 2H), 7.2–7.5 (m, 7H), 7.9 (s, 1H), 8.45–8.65 (m, 2H), 8.85 (br, 1H), 9.85 (br, 1H). ESMS calcd for (C24H17ClN4O): 412.1; found: 413.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:1][C:2]2[CH:27]=[CH:26][C:5]([O:6][C:7]3[C:8]([CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]4)=[N:9][CH:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(N)cc2)CC1
Reactant: Clc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(Cl)cn3)cc2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Into a sealed tube were added tert-butyl 4-(3-(4-aminophenoxy)pyrazin-2-yl)piperidine-1-carboxylate (0.31 g, 0.84 mmol), 2-bromo-5-chloropyridine (0.17 g, 0.92 mmol), palladium (II) acetate (0.019 g, 0.084 mmol), (rac)-BINAP (0.073 g, 0.12 mmol), cesium carbonate (0.49 g, 1.51 mmol), and toluene (4 mL). After the mixture was degassed for 5 min, the reaction was stirred at 100° C. for 18 h. The cooled reaction was diluted with CH2Cl2 and washed with water; the aqueous layer was back-extracted with CH2Cl2 (1×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (10% to 40% EtOAc (10% MeOH)/Hexanes) provided tert-butyl 4-(3-(4-(5-chloropyridin-2-ylamino)phenoxy)-pyrazin-2-yl)piperidine-1-carboxylate as a yellow foam. MS (ESI, pos. ion) m/z: 482.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=O>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: CCO
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.1 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (86.5 mg, 0.4 mmol) and 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (88.9 mg, 0.4 mmol) in ethanol (2 mL) was stirred at room temperature for 4 days. The reaction was concentrated and the residue was column chromatographed to give 54 mg (32%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[CH3:31][S:32]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(S(C)(=O)=O)C4)cc2)C(=O)O1
Yield: 20 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (100 mg, 0.28 mmol) in dry DCM (5 mL) were added triethylamine (0.15 mL, 1.12 mmol) and methane sulfonyl chloride (0.03 mL, 0.42 mmol) at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCl3) to provide the title compound (22 mg, 21.4%) as white solid.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: NCC1CC1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CO
Product: FC(F)(F)COCc1cc(NCC2CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cyclopropylmethanamine (91 mg, 1.28 mmol) a in MeOH (2 mL) was added to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (111 mg, 0.43 mmol) in acetonitrile (2 mL). The mixture was stirred at ambient temperature overnight. The solution was concentrated and purified by preparative HPLC to give the title compound as a solid, 72 mg (58%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[N:18]12[CH2:25]C[CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.[Na].C1(C)C=CC=CC=1>CCCCCCC>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[C@@H:1]([O:2][C:3]([C:5]1([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])[CH2:25]2
Reactant: COC(=O)C1(c2ccccc2)CCCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [Na]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reaction time: 72 h
Yield: 82.7 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid methyl ester (Example 1d) (1.0 g) and (R)-quinuclidin-3-ol (0.39 g) were refluxed in heptane (50 mL) containing sodium (˜5 mg in a Dean and Stark apparatus for 24 hours. Heptane (20 mL) was replaced with toluene (20 mL) and the reflux was continued for 3 days. The reaction was partitioned between water (50 mL) and ether (50 mL) and the ether layer was separated, dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica elutting with ethyl acetate/triethylamine (99/1) to afford the titled compound as an oil (0.83 g).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>CO>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: NCCCCCCO
Reactant: c1ccc(C2CO2)cc1
Solvent: CO
Product: OCCCCCCNCC(O)c1ccccc1

Procedure:
From styrene oxide and 6-amino-1-hexanol. Yield after chromatography (methanol): 30% (oil).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]([C:15]([O:17]CC(Cl)(Cl)Cl)=O)C(OC(Cl)(Cl)Cl)=O)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:25]=[C:26]([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:33][CH:34]=2)[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:23][C:24]1[CH:25]=[C:26]([C:30]2[N:31]=[C:32]([N:35]3[CH2:36][CH2:37][N:38]([C:15]([NH:7][C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:17])[CH2:39][CH2:40]3)[S:33][CH:34]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: Cn1nccc1N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
A mixture of trichloromethyl 2,2,2-trichloroethyl (1-methyl-1H-pyrazol-5-yl)imidodicarbonate (255 mg, 0.570 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (300 mg, 1.14 mmol) and diisopropylethylamine (0.198 ml, 1.14 mmol) in dimethyl sulfoxide (3.8 ml) was stirred at 70° C. for 16 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 129 mg (58.8%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:19]1([CH3:25])C=CC=C[CH:20]=1.O>CCOC(C)=O.[Na+].[Cl-]>[Br:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([CH:25]2[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: COc1cc(Br)cnc1Br
Reactant: Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Br)cnc1C1CC1
Yield: 70 %

Procedure:
As shown in step 6-v of Scheme 6, Compound 1020 (3.6 g, 13.5 mmol), potassium cyclopropyl-trifluoro-boron (2.5 g, 16.9 mmol), and potassium phosphate (8.6 g, 40.5 mmol) were taken up in about 80 mL of a toluene/water mixture. The reaction mixture was flushed with nitrogen gas for 10 minutes and Pd(PPh3)4 (1.4 g, (1.21 mmol) was added. The reaction mixture was refluxed for 18 hours, resulting in a mixture of products by HPLC analysis. The reaction was cooled, diluted with EtOAc and saturated NaCl. The organics were separated, dried (MgSO4), and concentrated under reduced pressure to provide a solid, which was purified by medium pressure silica gel chromatography (0-8% EtOAc/hexanes gradient) to give 5-bromo-2-cyclopropyl-3-methoxypyridine (Compound 1022, 0.54 g, 70% pure): ESMS (M+H) 227.9/229.9. This compound was used as is in subsequent reactions.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([OH:14])[C:7](C(O)=O)=[CH:8]2)=[CH:3][CH:2]=1.NC1N=C(N)C=C(N)N=1.OC1C(O)=CC=CN=1>>[CH:5]1[C:4]2[C:9](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]=1[OH:14]
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Nc1cc(N)nc(N)n1
Agent: Oc1cccnc1O
Product: Oc1ccc2ccccc2c1

Procedure:
β-oxynaphtoic acid; 2,4,6-triaminopyrimidine; 2,3-dihydroxypyridine; naphtalinsulphonic acids (e.g.: γ-acid, iso-γ acid, Neville-Winter acid).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:31])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1ccccc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)Nc4ccccc4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 63.2 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and phenylisocyanate (0.36 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-phenyl-urea as a white solid (0.77 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.38 min (99.57%); mp: 288-290° C.; 1H NMR (DMSO-d6) δ 1.99-2.07 (m, 1H, CHH), 2.44-2.62 (m, 2H, CHH, CHH), 2.82-2.96 (m, 3H, CHH, CH2), 4.47 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.3, 12.5 Hz, 1H, CH), 6.82-6.93 (m, 2H, Ar), 7.22 (t, J=7.6 Hz, 2H, Ar), 7.40 (d, J=8.0 Hz, 2H, Ar), 7.78-7.91 (m, 3H, Ar, NH), 8.72 (s, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.01, 30.93, 42.62, 48.99, 117.83, 121.26, 121.69, 123.48, 128.64, 129.67, 131.60, 133.21, 140.27, 148.79, 155.28, 167.03, 167.20, 169.83, 172.74; LCMS: MH=407; Anal Calcd for C21H18N4O5+0.2H2O: C, 61.52; H, 4.52; N, 13.66. Found: C, 61.33; H, 4.36; N, 13.46.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[S:23]([C:27]1[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][N:28]=1)(=[O:26])(=[O:25])[NH2:24]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:24][S:23]([C:27]2[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][N:28]=2)(=[O:26])=[O:25])=[O:21])=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1nnc(NC(C)=O)s1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with N-(5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-acetamide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C16H17FN5O7S2: 474.1; found: 474.1. 1H NMR (500 MHz, DMSO) δ: 2.21 (s, 3), 3.62 (s, 3), 4.72 (s, 2), 6.32 (s, 1), 6.95 (m, 2), 7.22 (m, 2).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:35][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH2:36]([NH:38][CH2:39][CH2:40][OH:41])[CH3:37]>>[CH2:36]([N:38]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:35][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:7][CH:8]=1)[CH2:39][CH2:40][OH:41])[CH3:37]
Reactant: CCNCCO
Reactant: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4ccc(C=O)cc4)cc23)cc1
Product: CCN(CCO)Cc1ccc(-c2cc3c(-c4cn(C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc3[nH]2)cc1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{4-[2-(4-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-methyl-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and 2-(ethylamino)ethanol provided the title compound. ESMS [M+H]+: 538.4
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14].N1C=CC=CC=1.O>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13](=[O:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1c[nH]c2cc(F)ccc12)C(Cl)(Cl)Cl
Temperature: 20 °C
Reaction time: 20 h
Yield: 55.2 %

Procedure:
4.37 g (32.32 mmol) of 6-fluoroindole are added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 4 cm3 (35.55 mmol) of trichloroacetyl chloride in 44.5 cm3 of 1,4-dioxane and 2.9 cm3 (35.55 mmol) of pyridine. After stirring at a temperature in the region of 20° C. for 20 hours, the reaction mixture is poured into 125 cm3 of demineralised water. The precipitate which appears is isolated by filtration, washed with 3 times 20 cm3 of water and then dried at 40° C. under reduced pressure to provide 5 g of 6-fluoro-3-trichloroacetyl-1H-indole in the form of a purple powder melting at 244° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH2:10].[C:11](Cl)(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of 2,4,6-trimethyl-phenylamine (1) (50 g, 0.370 moles) in CH2Cl2 (500 mL) was cooled to 0° C. (ice-water bath). To this was added acetyl chloride (29.8 g, 27 mL, 380 mmol) during 5 minutes via an addition funnel; this was followed by portion-wise addition of Et3N (38.5 g, 53 mL, 380 mmol). The ice-bath was removed and the solution was allowed to warm to room temperature and stir for 2 h. The resultant ivory colored solid was collected by filtration and dried in vacuo. To remove residual Et3N.HCl, the solid was suspended H2O (600 mL) stirred for 0.5 h, collected by filtration and dried to a constant weight. The original organic filtrate was washed with H2O (3×100 mL) and brine (1×100 mL), dried (MgSO4), filtered and concentrated providing additional product. Combined with material collected from the water afforded 60.2 g (99% yield) of the desired acetamide. RP-HPLC Method: 2-100 B in 2 minutes.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]>ClCCl>[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:35]=[CH:36][C:37]([CH:38]=[C:1]([Br:5])[Br:2])=[CH:40][CH:41]=2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](c2ccc(C=C(Br)Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
26.9 g of carbon tetrabromide was dissolved in 82 ml of dichloromethane, and 42.6 g of triphenylphosphine was added at 0° C. or less. Next, 10 g of 4-(trans-4'-propylcyclohexyl)benzaldehyde was dissolved in 41 ml of dichloromethane, which then was added dropwise to the first dichloromethane solution over a period of one hour. The combined solutions were then agitated at room temperature for one hour. After completion of the reaction, the dichloromethane was distilled off, and 500 ml of hexane was added to the residue. The resulting crystals were filtrated and washed with hexane three times. The residue was subjected to recrystallization with hexane to obtain 16 g of 4-(trans-4'-propylcyclohexyl)-β,β-dibromostyrene.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][NH:16][C:15](=[O:18])[CH:14]([N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:13][S:12]1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][N:16]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:15](=[O:18])[CH:14]([N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])[CH2:13][S:12]1
Reactant: O=C1NCC(c2ccc3ccccc3c2)SCC1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN1CC(c2ccc3ccccc3c2)SCC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
4.15 g of 2-(2-naphthyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (e) above] were treated with t-butyl bromoacetate in same manner as described in Example 36(f), to give 3.35 g of the title compound as a crystalline solid, melting at 208°-209.5° C.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH3:9]>>[CH2:8]([C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: CCBr
Reactant: O=C(O)C1CCC1
Product: CCC1(C(=O)O)CCC1

Procedure:
The title compound was prepared according to the procedure described for intermediate 2.1 from cyclobutanecarboxylic acid and ethylbromide.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[C:28]([N:38]2[C:50]3[CH:49]=[CH:48][C:47]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[CH:46][C:45]=3[C:44]3[C:39]2=[CH:40][CH:41]=[C:42]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:43]=3)[N:27]=1>CN(C)C=O>[C:57]1([C:42]2[CH:41]=[CH:40][C:39]3[N:38]([C:28]4[N:29]=[C:30]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:31]=[C:26]([N:13]5[C:12]6[CH:11]=[C:10]7[C:2]([CH3:22])([CH3:1])[C:3]8[C:8]([C:9]7=[CH:21][C:20]=6[C:19]6[C:14]5=[CH:15][CH:16]=[CH:17][CH:18]=6)=[CH:7][CH:6]=[CH:5][CH:4]=8)[N:27]=4)[C:50]4[C:45]([C:44]=3[CH:43]=2)=[CH:46][C:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:48][CH:49]=4)[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: Clc1nc(-c2ccccc2)nc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)n1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5ccccc5)nc(-n5c6ccc(-c7ccccc7)cc6c6cc(-c7ccccc7)ccc65)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.7 g (66.3 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 200 ml of dimethylformamide under a protective-gas atmosphere, and 5.3 g of 60% NaH in mineral oil (73 mmol) are added. After 1 h at room temperature, a solution of 9-(4-chloro-6-phenyl-1,3,5-triazin-2-yl)-3,6-diphenyl-9H-carbazole (40.5 g, 79.5 mmol) in 150 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 21.4 g (28 mmol, 42%).
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[O:22])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3)c1ccc(F)cc1
Yield: 42.3 %

Procedure:
The title compound (0.16 g, 42%) was prepared by the general method of Example 402 from (7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol), 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. The 1H NMR was identical to that of Example 402, 4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone