Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)C.C([Li])CCC.[Cl:32][Si:33](Cl)([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCCCCC>[Cl:32][Si:33]([CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1)([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:10]1[C:9]2[CH2:8][C:7]3[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)[C:14]=2[CH:13]=[CH:12][C:11]=1[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Cl[Si](Cl)(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](Cl)(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.8 %

Procedure:
A 300 ml two-necked flask equipped with a three-way cock, a dropping funnel and a magnetic stirrer, was thoroughly purged with nitrogen. Into the flask was introduced 2,7-di-tert-butylfluorene 3.01 g (10.81 mmol), and dissolved by addition of dehydrated diethyl ether 60 ml. With cooling in an ice bath, 1.56 mol/L n-hexane solution of n-butyllithium, 6.9 ml (11.0 mmol), was added to the solution, and the mixture was stirred in a nitrogen atmosphere at room temperature for 20 hours. Separately, a 500 ml three-necked flask equipped with a 100 ml dropping funnel, a three-way cock and a magnetic stirrer was thoroughly purged with nitrogen, and dehydrated n-hexane 120 ml and dichlorodicyclohexylsilane 2.6 ml (11.0 mmol) were introduced into the flask. With the flask cooled in a dry ice/methanol bath, the above-prepared solution was dropwise added over a period of 1 hour by means of the dropping funnel. While allowing the liquid temperature to rise gradually to room temperature, the contents were stirred for 3 days in a nitrogen atmosphere. The resulting slurry was filtered to remove solids, and the solvent of the filtrate was distilled away under reduced pressure to obtain 5.5 g of chlorodicyclohexyl(2,7-di-tert-butylfluorenyl)silane as a light yellow solid (11.0 mmol, 100% yield). The 1H NMR spectrum as measured with respect to the chlorodicyclohexyl(2,7-di-tert-butylfluorenyl)silane is given below:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5ccccc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 232 mg of 2-naphthoaldehyde, 100 mg of acetic acid was added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 14 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.41 g of 7-methoxy-1-(2-(4-((naphthalen-2-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@@H:31]2[CH3:36])[CH2:29][CH2:28]1>>[CH:27]1([N:30]2[CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32][C@@H:31]2[CH3:36])[CH2:29][CH2:28]1
Reactant: C[C@H]1CNCCN1C1CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C4CC4)[C@@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-cyclopropyl-2-methylpiperazine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.09-0.71 (m, 4H) 0.87-1.23 (m, 3H) 3.43 (br. s., 1H) 2.36 (s, 3H) 2.48-2.65 (m, 1H) 2.72-3.14 (m, 3H) 3.43 (br. s., 2H) 4.05 (br. s., 1H) 7.59 (d, J=7.64 Hz, 1H) 7.66 (s, 1H) 7.70 (br. s., 1H) 8.00 (d, J=8.08 Hz, 1H) 8.09 (br. s., 1H) 8.34 (br. s., 1H) 8.44-8.50 (m, 1H); ESI-MS m/z [M+H]+ 443.3.
Reaction SMILES: [H-].[Na+:2].O1CCCC1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=1>C(O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([S:16]([O-:19])(=[O:17])=[O:18])[CH:10]=1.[Na+:2]
Reactant: Cc1cc(C)nc(S(=O)(=O)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)nc(S(=O)(=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
In a 50 ml flask, sodium hydride (60% in oil) (200 mg, 5 mmol) and tetrahydrofuran (10 ml) were charged, and then 4,6-dimethylpyridine-2-sulfonic acid (935 mg) was gradually added at room temperature. Then, the mixture was stirred at room temperature for about 30 minutes. After the addition of a small amount of ethanol to the reaction mixture, the precipitated crystal was recovered by filtration. The crystal was washed with ethyl acetate and diethyl ether successively and dried to obtain sodium 4,6-dimethyl-2-pyridinesulfonate (1.05 g) at a quantitative yield. Melting point, 257°-258° C.
Reaction SMILES: [S:1]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8])(=[O:3])=[O:2].[CH3:17][O:18][C:19]1[CH:40]=[CH:39][C:22]([C:23](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[S:1]([O:4][CH2:5][CH:6]([CH2:7][O:8][C:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:40][CH:39]=1)[OH:9])([C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CO)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OCC(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
(±)-2,3-Dihydroxypropyl tosylate (IV) (525 mg, 2.13 mmol, 1 eq.) was dissolved in pyridine (20 mL, anhydrous) and cooled to 0° C. 4,4′-Dimethoxytrityl chloride (758 mg, 2.24 mmol, 1.05 eq.) was added in 3 portions over 2 h and the reaction solution was allowed to warm up to rt. After 2 h, sat. aq. NaHCO3 (75 mL) was added to the reaction mixture, followed by extraction with CH2Cl2 (3×75 mL). The extract was dried with Na2SO4, filtered, concentrated in vacuo and dried by coevaporation with toluene (3×). Purification by flash column chromatography (SiO2, 1:2:97 NEt3/Et2O/CH2Cl2) gave V as a white powder (770.6 mg, 66%). 1H NMR (300 MHz, CD2Cl2/D2O): δ=7.74 (d, J=8.4 Hz, 2H, arom.), 7.36-7.21 (m, 11H, arom.), 6.82 (d, J=5.1 Hz, 4H, arom.), 4.10-3.98 (m, 2H, CH2OTs), 3.92-3.89 (m, 1H, CHOH), 3.78 (s, 6H, OCH3), 3.13-3.11 (m, 2H, CH2ODMT), 2.44 (s, 3H, C6H4CH3); 13C{1H} NMR (75.5 MHz, CD2Cl2/D2O): δ=159.3, 145.8, 145.3, 136.1, 133.1, 130.6, 129.6, 128.44, 128.41, 127.5, 127.4, 113.7, 86.9, 71.8, 69.3, 64.1, 55.8, 22.0; MS (EI): m/z. calcd for [C31H32O7S]+: 548.1869. found: 548.1867 [M]+. elemental analysis calcd (%) for C31H32O7S: C, 67.86; H, 5.88; found: C, 67.84; H, 5.93.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:51])[N:29]([C@H:31]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][N:41]([CH3:43])[CH3:42])[CH2:36][CH2:35]1)=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:44]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:51])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][N:41]([CH3:42])[CH3:43])[CH2:36][CH2:35]1)=[O:33])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 96.1 %

Procedure:
At 0° C., trifluoroacetic acid (18 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (1.05 g, 1.71 mmol) in dichloromethane (18 ml). The reaction mixture was stirred for 50 min at 0° C. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 846 mg of (2R)-N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [N+:1](F)([O-:3])=[O:2].S1(CCCC1)(=O)=O.B(F)(F)F.[CH3:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:20][CH:19]([F:35])[C:18]1=[O:36]>>[CH3:16][N:17]1[C:23]2[CH:24]=[CH:25][C:26]([N+:1]([O-:3])=[O:2])=[CH:27][C:22]=2[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:20][CH:19]([F:35])[C:18]1=[O:36]
Reactant: CN1C(=O)C(F)N=C(c2ccccc2Cl)c2ccccc21
Reactant: O=[N+]([O-])F
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Product: CN1C(=O)C(F)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Reaction time: 1 h

Procedure:
A solution of 0.8 g. of NO2F in 13 ml. of sulfolane is saturated with BF3 at 5°-10°. This solution is added dropwise to a stirred solution of 3.03 g. of 1-methyl-3-fluoro-5-o-chlorophenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one, obtainable from the corresponding 3-chloro compound and AgF, in 15 ml. of sulfolane at 10°-15°. The mixture is stirred for 1 hour more at 15°-25° and worked up in the customary manner to give 1-methyl-3-fluoro-5-o-chlorophenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:9]1[C:13]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:12]=2[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:9]1[C:13]2[CH:14]=[C:15]([C:34]#[N:35])[CH:16]=[CH:17][C:12]=2[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Reaction time: 0.33 h

Procedure:
1.74 (3.16 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-iodo-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (XIIb) were dissolved in 20 ml of dry DMF and stirred under a stream of nitrogen for 20 min. 482 mg (4.11 mmol) of zinc(II) cyanide and 292 mmol (0.25 mmol) of Pd[P(Ph)3]4 were added, and the reaction solution was stirred at 80° C. for 1.5 h. The cooled reaction solution was mixed with 70 ml of water and extracted with ethyl acetate (3×). The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 10-30% ethyl acetate in cyclohexane). Yield: 1.08 g (76%) of white solid
Reaction SMILES: [CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2]
Reactant: CCN(c1cc(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2ccc(N3CCN(C4CCN(C)CC4)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide (0.3 g, 0.51 mmol) and 1-methylpiperidin-4-one (0.086 g, 0.76 mmol) in dichloroethane (5 mL), acetic acid (0.18 g, 3.06 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by prep. HPLC to afford the title compound (0.12 g, 34.38%).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].Cl[C:17]([O:19][CH2:20][CH2:21][Cl:22])=[O:18]>COCCOC.O>[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:17](=[O:18])[O:19][CH2:20][CH2:21][Cl:22])([O-:8])=[O:7]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCCCl
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
135 g of calcium carbonate are added to a solution of 345.3 g of 2-nitroaniline in a mixture of 1020 g of monoethylene glycol dimethyl ether and 150 g of water and the mixture is heated to 78° C. 375 g of 2-chloroethyl chloroformate are then added in the course of 3 hours. The mixture is subsequently stirred at the reflux temperature for 1.5 hours, until the reaction is complete, and is cooled to 35° C., and the product is precipitated with water and ice. The product is filtered off, washed with water and dried.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])=[CH:22][CH:21]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: O=C(Nc1ccccc1)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c3nc[nH]c3n2)CC1

Procedure:
937 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 300 mg of the product obtained in stage 1 above are added. 35 mg of the expected product are thus obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)=[O:9]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCCN1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of (S)-piperidine-2-carboxylic acid (10 mmol, 1.29 g) in MeOH (20 mL) is dropwise added thionyl chloride (30 mmol, 2.17 mL) at room temperature. The mixture is stirred at 2 hours, and then concentrated under reduced pressure. To the residue is added water (5 mL) and basified with potassium carbonate. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure to give (S)-piperidine-2-carboxylic acid methyl ester as a pale brown oil (800 mg, 56%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C([O-])=O>C(NC(C)C)(C)C>[CH2:17]([N:7]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=2[C:5]2[CH2:4][N:3]([CH2:1][CH3:2])[CH2:16][CH2:15][C:6]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)NC(C)C
Product: CCN1CCc2c(c3cc(C)ccc3n2Cc2ccccc2)C1
Yield: 28.6 %

Procedure:
Preparation of the title compound was carried out according to General Method 5. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (100 mg, 0.46 mmol) and benzyl chloride (0.11 ml, 0.9 mmol) in diisopropylamine (2 mL) were heated at 80° C. for 12 h to obtain 40 mg of 5-benzyl-2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:12]([C@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:11][CH2:10][C@H:9]([C@@H:12]([C@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:22][S:40]([CH3:39])(=[O:42])=[O:41])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OS(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2,3,5-Tri-O-benzyl-L-xylitol (10.2 g, 24.17 nmmol) is dissolved in dry methylene chloride (100 ml) containing triethylamine (10.1 mL, 72.5 mmol). The mixture is cooled to -10° C. and methane sulfonylchloride (3.93 mL, 50.75 mmol) is added dropwise. The mixture is stirred 30 minutes at -10° C. and washed with water. The organic layer is dried over sodium sulfate, filtered and put to dryness under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 4:6 mixture of ethyl acetate and cyclohexane yield 1,4-di-O-methanesulfonyl-2,3,5-tri-O-benzyl-L-xylitol as an oil (13.9 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C(OC(=O)C)(=O)C>>[CH3:12][N:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=[C:2]1[CH:1]=[CH:27][C:26]1[CH:29]=[CH:30][C:23]([C:21](=[O:22])[C:20]2[CH:31]=[CH:32][C:17]([C:16]([F:15])([F:33])[F:34])=[CH:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)n(C)c(=O)c12
Temperature: 140 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (508 mg) and 4-(4-trifluoromethylbenzoyl)benzaldehyde (751 mg) was added acetic anhydride (1.0 ml) and the mixture was stirred at 140° C. for 2 hours. This reaction mixture was concentrated and the residue was washed with n-hexane-diethyl ether and dried to provide 898 mg of yellow powder.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27]1=[CH:28][C:29]2[C:30]([CH:35]([O:38][Si](C(C)C)(C(C)C)C(C)C)[CH2:36][CH2:37]1)=[N:31][CH:32]=[CH:33][CH:34]=2>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27]1=[CH:28][C:29]2[C:30]([CH:35]([OH:38])[CH2:36][CH2:37]1)=[N:31][CH:32]=[CH:33][CH:34]=2
Reactant: CC(C)[Si](OC1CCC(c2cc(F)ccc2F)=Cc2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(c2cc(F)ccc2F)=Cc2cccnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
TBAF (0.954 mL, 0.954 mmol) was added to the THF (5 mL) solution of (E)-6-(2,5-difluorophenyl)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine (0.2049 g, 0.477 mmol) at rt. The reaction was stirred at room temperature for 6 hours. The solvent was removed via vacuum and the product was purified by flash column eluted with ethyl acetate in hexane from 0 to 50% to 100% (102.2 mg, 78%). MS(ESI)[M+H+]=274.23 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (dd, J=4.78, 1.26 Hz, 1 H) 7.51 (dd, J=7.81, 1.26 Hz, 1 H) 7.17-7.27 (m, 1 H) 6.87-7.05 (m, 3 H) 6.44 (s, 1 H) 5.74 (br.s., 1 H) 4.77 (dd, J=10.45, 2.64 Hz, 1 H) 2.79-2.93 (m, 1 H) 2.66-2.77 (m, 1 H) 2.48-2.60 (m, J=13.53, 5.45, 5.45, 2.77 Hz, 1 H) 1.97 -2.11 (m, 1 H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCCCC1c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 2-phenyl-cyclohexanone (10.0 g, 57 mmol) in CHCl3 (20 mL) at −10° C. a solution of bromine (9.6 g, 3.1 mL, 60 mmol) in CHCl3 (10 mL) was added and the reaction mixture was allowed to warm to 0° C. After for 2 hours the solvent was evaporated, methanol (30 mL) was added to the residue, cooled to 0° C., stirred for 30 minutes and the white solid was filtered off to give the title compound as a white solid (5.48 g, 38%).