Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:18])[C:16]=2[CH3:17])=[CH:13][CH:12]=[CH:11][C:10]=3[C:19](O)=[O:20])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH2:42])[CH3:38]>O1CCCC1>[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH:42][C:19]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[O:8][C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)=[C:16]([CH3:17])[C:15]2=[O:18])=[O:20])[CH3:38]
Reactant: CCN(CC)CCN
Reactant: COc1ccc(-c2oc3c(C(=O)O)cccc3c(=O)c2C)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)c(C)c(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 6.00 g of 4'-methoxy-3-methylflavone-8-carboxylic acid and 2.70 ml of triethylamine in 70 ml of anhydrous tetrahydrofuran was added a solution of 2.03 ml of ethyl chlorocarbonate in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1 hour under ice-cooling. To the reaction mixture was added a solution of 2.25 g of N,N-diethylethylenediamine in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1.5 hours under ice-cooling and further 16 hours at room temperature. The reaction mixture was treated by the same procedure as in Example 3(b), to give 3.55 g of pale yellow crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 125.5°-127° C. This compound was identical with the product obtained in Example 36(a) in NMR and IR spectra, and mixed m.p.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:39]([O:44]C)(OC)[O:40]C>C1COCC1.C1CCCCC1>[C:28]1([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]3[C:9]4=[C:10]([C:6]5[CH:5]=[CH:4][CH:3]=[CH:2][C:7]=5[N:8]4[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=4)[CH:11]=[C:12]([B:39]([OH:44])[OH:40])[CH:13]=3)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc2c3cccc4c3n(c12)-c1ccccc1C4(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OB(O)c1cc2c3c(c1)c1ccccc1n3-c1ccccc1C2(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
125.9 g (259 mmol) of bromo-8,8-diphenyl-8H-indolo[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:20])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCO>CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([NH:11][C:12](=[O:20])[CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(NC(=O)CN2CCOCC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1c(N)cccc1NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(2-Methyl-3-nitrophenyl)-2-morpholinoacetamide (0.25 g, 0.9 mmol) was dissolved in 20 ml of MeOH, and to this was added a slurry of 10% Pd/C (0.025 g) in a minimal amount of EtOH. The reaction vessel was evacuated and purged with H2, and the reaction was stirred at room temperature for 16 hours. The mixture was purged with N2 for 30 minutes and then filtered through a pad of celite. Solvent evaporation afforded N-(3-amino-2-methylphenyl)-2-morpholinoacetamide as a gray solid. MS m/z=250.1 [M+H]+; Calc'd for C13H19N3O2: 249.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To a solution of 5-bromo-2-(tert-butoxycarbonyl)aminopyridine (25.0 g, 91.5 mmole) in DMF (400 mL) was added portionwise with stirring a 60% dispersion of NaH in mineral oil (4.0 g, 100 mmole). The reaction was stirred for 15 min, then methyl bromoacetate (15 mL, 158.5 mmole) was added dropwise over 15 min. After stirring for 18 h at room temperature the reaction was concentrated to dryness. The remaining residue was taken up in EtOAc (200 mL) and H2O (200 mL) and filtered to remove insoluble material. The EtOAc phase was separated, washed with brine, dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (10% EtOAc/Hexane) gave the title compound (16.56 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1 H), 7.73 (d, J=2.5 Hz, 1 H), 7.71 (d, J=2.5 Hz, 1 H), 4.69 (s, 2 H), 3.75 (s, 3 H), 1.51 (s, 9 H).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cu][C:26]#[N:27].C(N)CN>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#C[Cu]
Reactant: CCCCCc1cnc(-c2ccc(-c3ccc(Br)cc3)cc2)nc1
Solvent: NCCN
Solvent: CN(C)C=O
Product: CCCCCc1cnc(-c2ccc(-c3ccc(C#N)cc3)cc2)nc1

Procedure:
1.5 G. of 5-n-pentyl-2-(4'-bromo-4-biphenylyl)-pyrimidine are heated at reflux for 22 hours with 2.5 g. of copper-(I) cyanide (content 70%) in 50 ml. of dimethylformamide. After cooling, 25 ml. of 10% aqueous ethylenediamine solution are added and, after stirring for a short time, the mixture is extracted with methylene chloride. The organic extract is shaken with a further 25 ml. of ethylenediamine solution and then washed until neutral. The crude concentrate is chromatographed on silica gel with toluene/1% acetone. Recrystallization of the pure fractions from ethyl acetate yields 5-n-pentyl-2-(4'-cyano-4-biphenylyl)-pyrimidine, having a melting point of 123.5°-124° C. and clearing point of 204.5°-205° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[C:20]([NH:28][C:29]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:20]([NH:28][C:29]1[CH:38]=[C:37]([O:39][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
82 mg of potassium carbonate and 0.047 mL of benzyl bromide were added to 1 mL of N,N-dimethylformamide solution containing 80 mg of methyl 2-(benzamido)-4-hydroxybenzoate at room temperature and stirred at the same temperature for 3 hours. Ethyl acetate and 1.0 mol/L hydrochloric acrd were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 75 mg of methyl 2-(benzamido)-4-(benzyloxy)benzoate as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16](O)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16]([Cl:28])[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(O)c2CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(Cl)c2CC1
Temperature: 25 °C

Procedure:
To a suspension of 3.0 g (8.86 mmol) 10-hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester in 6 mL toluene was added 7 mL (74.06 mmol) of phosphorus oxychloride and 1.28 mL (7.35 mmol) of DIPEA, and the reaction was heated at reflux for 40 minutes. The mixture was cooled to room temperature and poured into ice. The aqueous phase was extracted with DCM (3×20 mL) and the combined organic layers were dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 7:3).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#N)[CH:14]=1.Cl.CC[O:24]CC>ClC1C=CC=CC=1>[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:24])[CH:14]=1
Reactant: CCOCC
Reactant: N#Cc1cccc(CBr)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Clc1ccccc1
Product: O=Cc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of diisobutylaluminum hydride (92 ml, 1M in hexanes, 92 mmol) was added dropwise via syringe pump injector over a period of 45 min to a solution of α-bromo-m-tolunitrile (15.000 g, 76.5 mmol) in 155 ml of chlorobenzene at 0° C. The resulting mixture was stirred at 0° C. for 1 h, then 100 ml of 10% aqueous HCl was added and stirring continued at 0° C. for 10 min. The layers were separated and the aqueous layer extracted with ether (2x). The organic solutions were combined and washed vigorously with 10% HCl for 10 min, then water (2x) and brine, dried over MgSO4 and evaporated to give a crystalline solid which was then dissolved in a minimal amount of ether (10-15 ml) and layered with petroleum ether (30-40 ml). The resulting spiny white crystals were collected and washed with ice-cold petroleum ether to yield 10.791 g (71%) of aldehyde 1: m.p. 46°-49° C.; 1H NMR δ 4.54 (s, 1, CH2Br), 7.52 (t, 1, J=8 Hz, H-5), 7.67 (br d, 1, J=8 Hz, H-4), 7.82 (dt, 1, J=8, 1 Hz, H-6), 7.90 (br s, 1, H-2), 10.02 (s, 1, CHO); 13C NMR δ 32.0 (CH2Br), 129.6, 129.7 and 129.8 (C-2, C-5 and C-6), 134.8 (C-4), 136.8 (C-1), 138.9 (C-3), 191.6 (CHO); IR ν 1595 and 1610 (m, C=C), 1710 (s, C=O), 2740 and 2820 (m, CHO) cm-1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C1COCC1>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl bromoacetate (24.0 mL, 254 mmol) in anhydrous THF (264 mL) was added dropwise triethylamine (35.3 mL, 254 mmol). The cloudy mixture was treated rapidly with 4-fluorobenzylamine, and the resulting viscous mixture was stirred at ambient temperature under inert atmosphere for 18 h. THF was removed in vacuo, and the resulting residue was suspended in diethyl ether. The mixture was filtered and the solids washed with excess diethyl ether. Concentration of the filtrate in vacuo afforded the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 2H), 7.04-6.99 (m, 2H), 3.77 (s, 2H), 3.74 (s, 3H), 3.41 (s, 2H), 1.82 (br s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:12].C(Cl)(Cl)Cl>O1CCCC1>[C:1]1([C:7]2[CH:11]=[CH:10][SH:9]([CH:6]([OH:12])[CH2:1][CH2:2][CH3:3])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: c1ccc(-c2ccsn2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCC(O)[SH]1C=CC(c2ccccc2)=N1
Reaction time: 1 h

Procedure:
Dissolved in 60 ml of anhydrous tetrahydrofuran were 3.1 g (19.1 mmol) of 3-phenylisothiazole, followed by the addition 18.2 ml of an n-butyl lithium-hexane solution (1.57 mol/l) under a nitrogen gas stream at -78° C. over a dry ice-acetone bath. After the resulting mixture was stirred for 1 hour, 1.51 g (21 mmol) of butylaldehyde were added dropwise. The solution was stirred for 1 hour at the same temperature, whereby the reaction was completed. Water and chloroform were added. The reaction product was extracted into an organic layer. The organic layer was concentrated and the concentrate was purified by silica gel chromatography (eluent: 20:1 n-hexane/ethyl acetate), so that 3-phenyl-5-(1-hydroxybutyl)isothiazole was obtained as yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26]Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:26][C:9]1[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: BrBr
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(-c2ccccc2)nc(-c2ccncc2)c1Br
Reaction time: 0.67 h
Yield: 98.7 %

Procedure:
To a solution of the product of Step 1 (15 g, 42.6 mmol) in dichloromethane (300 ml) at room temperature was added bromine (6.81 g, 2.38 ml, 46.5 mmol) followed by a saturated solution of sodium carbonate (150 ml). The mixture was stirred for 40 minutes before being separated and the organic layer washed successively with water and brine. The organic layer was then dried (magnesium sulphate) and concentrated in vacuo to give the title compound (18.1 g, 99%) as a brown viscous oil which was used without further purification; MS(AP+) m/e 431/433 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].N1C=CC=CC=1>ClCCl>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Yield: 98.2 %

Procedure:
10.7 g (98.9 mmol) of ethyl chloroformate was added dropwise to a mixture of 15.0 g (94.2 mmol) of 2-fluoro-5-nitroaniline, 8.20 g (104 mmol) of pyridine and 150 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the dichloromethane layer was separated out by adding water to the reaction mixture, the dichloromethane layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Thereafter the dichloromethane was distilled off to obtain the crude product (crystals). The crude product was washed with hexane, thereby obtaining 21.1 g of the objective product (yield: 98%) in the form of ocher crystals.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:44][CH3:45])=[C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=4[C:36]([NH2:38])=[O:37])[C:17]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:18]=4[N:19]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:46]N>C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:44][CH3:45])=[C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=4[C:36]([NH:38][CH3:46])=[O:37])[C:17]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:18]=4[N:19]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(C)=O)CC2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(C)=O)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
The remaining half of the reaction mixture from the preparation of 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide was diluted with THF (100 mL) and a solution of methylamine (2M, 9 mL), 18 mmol). The reaction mixture was stirred overnight, then concentrated to dryness. The residue was sonicated in CH2Cl2 (15 mL) and filtered. The filtrate was purified by silica gel chromatography using 10% THF/CH2Cl2 to obtain 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide as a yellow solid (236 mg, 41% for 2 steps). 1H NMR (400 MHz, DMSO-d5) δ ppm 2.16 (s, 3H), 2.34 (s, 3H), 2.75 (d, J=4.4 Hz, 3H), 3.19 (d, J=8.24 Hz, 2H), 3.73 (s, 3H), 4.15 (d, J=8.33 Hz, 2H), 6.55 (d, J=3.85 Hz, 1H), 6.94 (t, J=9.25 Hz, 1H), 7.04 (s, 1H), 7.17-7.41 (m, 4H), 7.93 (d, J=8.24 Hz, 2H), 7.98 (J=8.42 Hz, 1H), 8.16 (s, 1H), 8.19 (s, 1H), 8.36-8.52 (m, 1H), 10.16 (s, 1H); ESIMS (M+H)+=644.20.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=O)[C:2]#[CH:3].[NH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][CH2:9][C:8]2[CH:11]=[C:4]([CH2:1][C:2]#[CH:3])[CH:5]=[CH:6][C:7]=2[O:12][CH3:13])[C@@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: C#CCc1ccc(OC)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: C#CCc1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 77 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:34][S:35]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:36])=[O:37])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ncccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 1) was reacted with 1-(2-methanesulfonylethyl)piperazine dihydrochloride to give cis-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H34N5O4SCl2 [(M+H)+] 630.1703, observed 603.1705.
Reaction SMILES: Cl[Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16].CCN(CC)CC.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>CCCCCC>[CH3:27][C:26]([NH:30][Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=C(C)C([Si](C)(C)NC(C)(C)C)c2cc3c(cc21)CCC3
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl) silane (3.537 g, 0.01217 moles) was stirred in hexane (50 mL) as NEt3 (1.94 g, 0.01916 moles) and t-butylamine (1.12 g, 0.01533 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a light yellow oil (3.537 g, 88.6 percent).
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[NH:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH:44]([OH:46])[CH3:45]>>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:23]2[C:9]([N:39]3[CH2:43][CH2:42][CH2:41][CH:40]3[CH:44]([OH:46])[CH3:45])=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:13][C:12]=3[CH:22]=2)=[CH:30][CH:29]=1)(=[O:33])=[O:32]
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: CC(O)C1CCCN1
Product: CC(O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid, diastereomer mixture, in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 1-pyrrolidin-2-yl-ethanol. The resulting diastereomer mixture was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) into the individual diastereomers A and B each as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][CH:15]([C:17]1[S:18][CH2:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1)[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][CH:15]([C:17]2[S:18][CH2:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=2)[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)[C@H]1CSC(C(C)N)=N1
Agent: Cl
Product: CCOC(=O)[C@H]1CSC(C(C)NC(=O)Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure A above and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-4-ethoxycarbonyl-2-thiazoline hydrochloride (Example G), the title compound was prepared as a semisolid. The reaction was monitored by tlc (Rf=0.2 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.