Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[CH:10][C:11]([OH:13])=[O:12].[H][H].[CH2:16](Br)[C:17]#[CH:18]>CN(C=O)C>[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[CH:10][C:11]([O:13][CH2:18][C:17]#[CH:16])=[O:12]
Reactant: C#CCBr
Reactant: Cc1ccsc1C=CC(=O)O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)C=Cc1sccc1C
Temperature: 50 °C
Yield: 51.3 %

Procedure:
At 10° C., 0.9 g of sodium hydride was added to a solution of 6.2 g of 3-(3-methylthiophen-2-yl)-propenoic acid in 100 ml of absolute DMF. When no more hydrogen evolved, 4.9 g of propargyl bromide was dripped in at room temperature and the mixture was then heated at 50° C. for 3 hours. The reaction mixture was poured onto icewater, the aqueous phase was extracted three times with ethyl acetate, and the combined organic extracts were dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was recrystallized from ethanol. There was obtained 3.9 g of propargyl 3-(3-methylthiophen-2-yl)-propenoate of melting point 84' to 86° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.CCN(CC)CC.[CH2:19]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:20]1.CCOC(C)=O>CS(C)=O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:27]2[CH2:28][CH2:29][C:24]3([CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:20][CH2:19]3)[CH2:25][CH2:26]2)=[N:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of methyl 6-chloronicotinate (800 mg, 3.15 mmol), NEt3 (1.00 mL, 7.19 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.00 g, 3.94 mmol) in 5 mL of DMSO was heated to 100° C. for 1 h with microwave irradiation. The reaction mixture was poured into EtOAc and washed with 2 N NaOH, 2H HCl, brine and dried (Na2SO4), filtered and concentrated giving tert-butyl 9-[5-(methoxycarbonyl)pyridin-2-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate.
Reaction SMILES: Cl.CO[N:4]1[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][N:17]=1.[C:24](O)(=[O:26])C.[Na]>C(Cl)Cl.O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:4]2[CH2:5][CH:6]([O:26][CH3:24])[CH2:7]2)=[CH:18][N:17]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CON1CCC1
Reactant: CC(=O)O
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC1CN(Cc2ccc(Cl)nc2)C1
Reaction time: 0.5 h

Procedure:
To a slurry of methoxy azetidine HCL salt (24.2 g, 198 mmol, Eq: 1.00) in 400 mL of methylene chloride was added triethylamine (24.0 g, 33.1 ml, 237 mmol, Eq: 1.2). The precipitate formed went back into solution. Next 6-chloronicotinaldehyde (28 g, 198 mmol, Eq: 1.00) and acetic acid (22.6 ml, 396 mmol, Eq: 2.0) was added. Finally sodium triacetoxyhydroborate (41.9 g, 198 mmol, Eq: 1.00) was added in portions. The first 11 g were added and waited for the chunks to disperse. The second 11 g were then added and an aliquot was checked by TLC. Added the remainder still in portions and continued stirring the slurry. After completion of addition, by TLC, some aldehyde seems to remain so stirring was continued. After another 30 minutes it looked essentially done. Added 400 mL of water and an additional 200 mL of methylene chloride and separated layers. The aqueous phase was made basic with ˜400 mL of 1.0M NaOH and then extracted with 3 times 400 mL of methylene chloride. Concentrated to afford a thick colorless oil. Pumped down to constant weight 28.3 g (67.3%).
Reaction SMILES: [C:1](=[O:22])([O:12]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH:1]([OH:12])=[O:2].[C:32]1([CH:38]2[CH2:39][CH2:40][N:41]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:42][CH2:43]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCOC(=O)N2CCC(c3ccccc3)CC2)CC1
Product: O=CO
Temperature: 25 °C
Reaction time: 65 h
Yield: 79.5 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 680 mg, 2.2 mmol) was dissolved in DMF (20 mL). DIPEA (0.52 mL, 3.0 mmol) and 4-phenylpiperidine (322 mg, 2.0 mmol) were added and the reaction mixture was stirred at room temperature for 65 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (40 mL) and washed with 1 M aq Na2CO3 solution (6×50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%) to give 2-(4-methylpiperazin-1-yl)ethyl 4-phenylpiperidine-1-carboxylate formate (330 mg, 42%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:20]=[CH:19][C:13]([O:14][Si](C)(C)C)=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][CH:3]=1.Br[C:22]1C=CC(C(C2C=CC(O)=CC=2)=C)=CC=1.C[Si](C)(C)N[Si](C)(C)C.C(I)I>CCOCC.[Zn].Cl[Cu]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[CH:20]=[CH:19][C:13]([OH:14])=[CH:12][CH:11]=3)[CH2:22][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: C=C(c1ccc(Br)cc1)c1ccc(O[Si](C)(C)C)cc1
Agent: Cl[Cu]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Zn]
Solvent: ICI
Solvent: CCOCC
Product: Oc1ccc(C2(c3ccc(Br)cc3)CC2)cc1

Procedure:
Eg) A mixture of 457 mg of zinc dust and 692 mg of CuCl in 15 ml of ether is heated under reflux under argon. Subsequently, a solution of 934 mg of [4-[1-(4-bromo-phenyl)-vinyl]-phenoxy]-trimethyl-silane in 15 ml of ether, prepared from 748 mg of 4-[1-(4-bromo-phenyl)-vinyl]-phenol (Ex. Ef) and 14 ml of hexamethyldisilazane under reflux, is added dropwise and thereafter 0.56 ml of methylene iodide is added. The reaction mixture is heated under reflux and diluted with ether. The residue is washed with ether and the filtrate is washed with water, dried and concentrated. The crude product is purified over silica gel with ethyl acetate-hexane as the eluent. 4-(1-(4-Bromo-phenyl)-cyclopropyl)-phenol is obtained as a brown oil, MS: m/e 288 (M+H+, 1Br).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C([C:13]([O-:15])=[O:14])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[N+:1]1([O-:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](=[O:14])([OH:15])[NH2:1]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: c1ccncc1
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)O
Product: [O-][n+]1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of pyridine from Step 5 above (3.74 g, 5.66 mmol) in a CH2Cl2 MeOH mixture (180 mL/18 mL) was added 4.2 g (8.55 mmol) of MMPP in one portion. The resulting solution was stirred at room temperature for 5 h and purified directly by flash chromatography on silica gel (Gradient 100% CH2Cl2to 5% MeOH/CH2Cl2 to 5% (10% NH4OH/MeOH)/CH2Cl2) to afford 4 g of contaminated carbamate pyridine-N-oxide.
Reaction SMILES: [I-].Cl[C:3]1C=CC=C[N+:4]=1C.C(N(CC)CC)C.Cl.CN.[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([OH:39])=O)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([NH:4][CH3:3])=[O:39])(=[O:22])[CH3:21]
Reactant: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: CN
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Under nitrogen, add 0.12 g of 2-chloro-1-methylpyridinium iodide, 0.32 ml of triethylamine and 0.04 ml of methylamine hydrochloride in dichloromethane to a solution of 0.13 g of the compound obtained in Step C in 20 ml of dichloromethane and then heat at reflux for 14 hours. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous sodium chloride solution. Extract and dry the organic phase over sodium sulfate and then filter and evaporate. Purify the compound by column chromatography on silica gel using as eluant a 19/1 dichloromethane/ethanol mixture. After triturating in diisopropyl ether, the title compound is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[CH:11]=[C:10]([NH2:12])[N:9]=[CH:8][N:7]=1.[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>>[CH3:16][O:15][CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1[N:7]=[CH:8][N:9]=[C:10]([NH:12][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:11]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: COCCN(CCOC)c1cc(N)ncn1
Agent: [H-]
Agent: [Na+]
Product: COCCN(CCOC)c1cc(Nc2ncc(C#N)s2)ncn1

Procedure:
N,N-bis(2-methoxyethyl)pyrimidine-4,6-diamine 6-2 (0.13 g, 0.58 mmol), sodium hydride (0.046 g, 1.16 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.083 g, 0.58 mmol) were treated as in Scheme 4 above. The product 6-3 was purified on a C18 preparative hplc column and isolated via lyophilization. Hi-Res MS: calc: 335.1285 found: 335.1282. 1H-NMR (DMSO): 8.39 ppm (s, 1H); 8.24 ppm (s, 1H); 6.22 ppm (s, 1H); 3.65 ppm (m, 4H); 3.51 ppm (m, 4H); 3.26 ppm (s, 6H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:10]=[C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][C:13]([C:21]2[N:26]=[C:25]([CH2:27]S([O-])(=O)=O)[CH:24]=[CH:23][CH:22]=2)=[N:12]1.C(OCC)(=O)C>CN(C=O)C.O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:27][C:25]2[N:26]=[C:21]([C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:11](=[O:10])[N:12]=3)[CH:22]=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CSc3ccncc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
4-Mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil, 0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.60 g, 1.72 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.11 g, 17%) as pale yellow crystals.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:6]=[C:7](SC)[NH:8][CH:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)#[N:5].C[O-].[Na+]>CO>[C:4]([NH:6][C:7]1[NH:2][N:3]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([CH3:18])[N:8]=1)#[N:5]
Reactant: NN
Reactant: CSC(=NC#N)NC(C)C(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1N=C(NC#N)NN=C1c1ccccc1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Hydrazine hydrate (4.55 g) was added to a solution of 2-(3-cyano-2-methyl-1-isothioureido)propiophenone (5.43 g) in methanol (20 ml), and the mixture was allowed to stand at room temperature for 1 hour. After addition of catalytic amount of sodium methoxide to the solution, the mixture was allowed to stand at room temperature for 2 hours with occasional shaking. The resultant preapitates were collected, washed successively with methanol, water and methanol and dried. Thus obtained product was dissolved with dimethylformamide (25 ml), the solution was filtered by suction and then water (25 ml) was added thereto little by little. After cooling, the resultant precipitates were collected by filtration, washed successively with ethanol, water and ethanol, and dried to give 3-cyanoamino-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (2.37 g), m.p. 244.5°~245° C. (decomp.).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C[C@@H:23]1[C:27]2[NH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:26]=2[C:25](=[O:40])[NH:24]1>>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9]([C:29]3[NH:28][C:27]4[CH2:23][NH:24][C:25](=[O:40])[C:26]=4[CH:30]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: COCCn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)CNC4=O)cccc2c1=O
Yield: 51.3 %

Procedure:
This compound (138 mg, 51% yield) as a brown solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-8-iodo-3-(2-methoxyethyl)quinazolin-4(3H)-one (715) (273 mg, 0.68 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (706) (219 mg, 0.88 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (1H, br.), 7.90 (2H, m), 7.56 (1H, br.), 7.20 (1H, t, J=7.4 Hz), 6.83 (1H, s), 6.50 (1H, s), 4.27 (4H, m), 3.70 (2H, m), 3.35 (3H, s), 1.49 (9H, s). m/z (ESI, +ve) 395.9 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH2:27]([NH:29][CH3:30])[CH3:28]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([N:29]([CH2:27][CH3:28])[CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCNC
Solvent: ClCCl
Product: CCN(C)C(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.10 g, 2.8 mmol) in CH2Cl2 (10 mL) was added neat ethyl(methyl)amine (310 μL, 3.6 mmol) dropwise. The mixture was stirred at room temperature for 1 h. Solvents were removed by concentration. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-ethyl-3-methylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (1.09 g, 86% yield). 1H NMR (500 MHz, CDCl3) δ 1.15 (t, 3H, J=7.0 Hz), 2.05 (s, 3H), 2.06 (s, 3H), 2.11 (s, 3H), 2.13 (s, 3H), 3.08 (s, 3H), 3.74-3.81 (m, 3H), 4.16 (dd, 1H, J=2.0, 12.5 Hz), 4.27 (dd, 1H, J=4.5, 12.5 Hz), 5.14 (t, 1H, J=10.0 Hz), 5.26 (t, 1H, J=10.0 Hz), 5.34-5.40 (m, 2H), 5.78 (d, 1H, J=8.0 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:9]2([S:11][C:20]3[CH:21]=[C:22]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:17]([OH:23])=[C:18]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:19]=3)[CH2:10][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCCCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (3.00 g, 12.60 mmol) in methanol (10 mL) was added cyclohexanone (1.40 mL, 13.80 mmol) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at a room temperature for 2 hours and then heated under reflux for one hour. The mixture was allowed to cool. Thereafter, the generated precipitate was separated by a filtration and dried to synthesize objective bis(3,5-di-t-butyl-4-hydroxyphenylthio)cyclohexane (yield 2.50 g and 71%).
Reaction SMILES: BrBr.Cl[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[CH2:10]([SH:13])[CH2:11][CH3:12].[OH-].[K+]>C(Cl)Cl.CO>[C:7]([C:6]1([S:13][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5]1)(=[O:9])[CH3:8]
Reactant: CC(=O)CCCCl
Reactant: CCCS
Agent: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCSC1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
A solution of 134 g (0.83 mol) of bromine in 130 ml of methylene chloride is added dropwise at 10° C. with stirring to a solution of 100 g (0.83 mol) of 5-chloropentan-2-one in 400 ml of methylene chloride. The reaction mixture is stirred for a further hour at room temperature, then washed using water and dilute aqueous sodium carbonate solution and dried over sodium sulphate. The mixture is concentrated by stripping off the solvent under reduced pressure, and the residue is taken up in 200 ml of methanol and 63 g (0.83 mol) of n-propylmercaptan are added at 5° C. with stirring. A mixture of 93 g of potassium hydroxide powder in 500 ml of methanol is then added dropwise. The reaction mixture is initially stirred for 2 hours at room temperature and then for 4 hours at 40° C. The mixture is then concentrated by stripping off the solvent under reduced pressure and the remaining residue is taken up in methylene chloride. The organic solution is washed successively using water, dilute aqueous sodium hydroxide solution and again using water, then concentrated under reduced pressure and then subjected to a vacuum distillation. In this manner, 42 g (32% of theory) of 1-acetyl-1-propylmercaptocyclopropane of boiling point 107° C./20 mbar are obtained.
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>C1COCC1.[Cl-].[Cl-].C1(C(=[Zr+2](C2C3C=CC=CC=3C3C2=CC=CC=3)C2C=CC=C2)C)C=CC=CC=1>[CH:17]1([C:16]2[CH:15]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:23][CH2:24][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: CC(c1ccccc1)=[Zr+2](C1C=CC=C1)C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(c2ccccc2CCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
(Phenyl(methyl)methylene)(9-fluorenyl)(cyclopentadienyl)zirconium dichloride ##STR9## A solution of 67.8 mmol of fluorenyllithium of 50 cm3 of THF was added at room temperature to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of THF. The mixture was stirred at room temperature for 2 hours, and 60 cm3 of water were added. The substance which precipitated was filtered off with suction, washed with diethyl ether and dried in an oil-pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)ethylbenzene (correct elemental analyses; 1H-NMR spectrum) were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[C:15]([CH3:42])=[C:16]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][C:28]([N:33]5[CH2:37][CH2:36][CH2:35][C:34]5=[O:38])=[CH:29][CH:30]=4)[NH:25][C:24]=3[C:23]([C:39]([NH2:41])=[O:40])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.Cl>C(O)(C)C>[CH3:42][C:15]1[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:19][CH:18]=[CH:17][C:16]=1[C:20]1[C:32]2[C:31]3[C:26](=[CH:27][C:28]([N:33]4[CH2:37][CH2:36][CH2:35][C:34]4=[O:38])=[CH:29][CH:30]=3)[NH:25][C:24]=2[C:23]([C:39]([NH2:41])=[O:40])=[CH:22][CH:21]=1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N4CCCC4=O)ccc3c12
Reactant: Cc1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2ncnc(Nc3cccc(-c4ccc(C(N)=O)c5[nH]c6cc(N7CCCC7=O)ccc6c45)c3C)c2c1
Temperature: 140 °C
Yield: 20 %

Procedure:
A suspension of 4-chloro-6-methylquinazoline (prepared by the procedure used in Steps 1 and 2 of the preparation of Intermediate 32-1, 16.81 mg, 0.094 mmol) and 4-(3-amino-2-methylphenyl)-7-(2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide (Intermediate 65-1, 25 mg, 0.063 mmol) in isopropanol (0.75 mL) was treated with hydrogen chloride (4 M in 1,4-dioxane) (0.019 mL, 0.075 mmol) and heated by microwave irradiation in a sealed tube at 140° C. for 45 min. The mixture was concentrated and the residue was purified by preparative HPLC. The residue from concentration of the appropriate effluent fractions was partitioned between NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried and concentrated to provide 4-(2-methyl-3-(6-methylquinazolin-4-ylamino)phenyl)-7-(2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide as a tan solid (7.4 mg, 20%). 1H NMR (400 MHz, methanol-d4) δ 8.43 (1H, s), 8.22 (1H, s), 7.97 (1H, d, J=7.7 Hz), 7.84 (1H, d, J=1.3 Hz), 7.67-7.77 (2H, m), 7.46-7.58 (2H, m), 7.36 (1H, dd, J=7.3, 1.5 Hz), 7.21-7.30 (2H, m), 7.13 (1H, d, J=7.9 Hz), 3.98-4.07 (2H, m), 2.65 (2H, t, J=8.1 Hz), 2.60 (3H, s), 2.18-2.28 (2H, m), 1.96 (3H, s). Mass spectrum m/z 541.5 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:51]4[CH2:52][CH2:53][C@H:49]([O:48][CH3:47])[CH2:50]4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: CO[C@H]1CCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CC[C@H](OC)C2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with (S)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3340.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][CH:7](O)[CH3:8].Cl.[O:11]1[CH2:16][CH2:15][N:14]([N:17]=[CH:18][C:19]2[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[O:32][CH2:31][CH:30]([CH2:36][C:37]([OH:39])=[O:38])[CH2:29]4)=[O:24])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1>>[ClH:3].[O:11]1[CH2:16][CH2:15][N:14]([N:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[O:32][CH2:31][CH:30]([CH2:36][C:37]([O:39][CH2:8][CH2:7][O:6][CH3:5])=[O:38])[CH2:29]4)=[O:24])=[CH:40][CH:41]=2)[CH2:13][CH2:12]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1COc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1
Reactant: COC(C)O
Agent: Cl
Product: COCCOC(=O)CC1COc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1
Reaction time: 0.17 h

Procedure:
Thionyl chloride (0.4 ml) was dropwise added to methoxyethanol (5 ml) with ice cooling and stirred for 10 minutes at the intact temperature. To the resulting solution the compound (0.2 g) obtained in Example 5 was added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the concentrated residue was washed with ethyl ether to obtain the entitled compound (0.12 g).