Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13]I.[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCC(C#N)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(C)(C#N)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
A solution of 2-(3-chlorophenyl)butanenitrile (4.69 g, 26 mmol) and MeI (2.0 mL, 31 mmol) in DMSO (15 mL) was added dropwise to a stirred solution of NaH (60% dispersion in mineral oil (1.3 g, 31 mmol)) in DMSO (35 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at 0° C. and then brought to room temperature and stirred for 15 hours. The reaction mixture was quenched with water carefully and then diluted with EtOAc. The organic layer was separated, washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the desired compound as a light yellow oil (5.54 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3Cl)[CH:22]=2)=[O:20])[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:22]=2)=[O:20])[CH:13]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(Nc1cccnc1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)Nc5cccnc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid pyridin-3-ylamide by a procedure analogous to Example 1C. MS: 400 (MH+), HPLC Rf: 4.58 min.; HPLC purity 99%.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([OH:24])=O)=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][CH:8]2[CH2:7][CH2:6][N:5]([CH:2]([CH3:3])[CH3:4])[CH2:10][CH2:9]2)=[C:20]([CH3:21])[CH:19]=3)=[O:24])[CH2:34][CH2:35]1)=[O:29])[CH3:26]
Reactant: Cc1cc2[nH]c(C(=O)O)cc2cc1OC1CCN(C(C)C)CC1
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(C)cc3[nH]2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indole-2-carboxylic acid hydrochloride and 1-ethoxycarbonylpiperazine to afford the title compound as a light-yellow foam (65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:47])=[C:4]([CH:44]=[CH:45][CH:46]=1)[C:5]([N:7]([CH2:30][CH2:31][CH2:32][NH:33]C(=O)OCC1C=CC=CC=1)[C@@H:8]([C:12]1[N:13]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14](=[O:22])[C:15]2[N:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:9][C:10]#[CH:11])=[O:6].I[Si](C)(C)C.C([O-])(O)=O.[Na+].ClCCl>C(#N)C>[NH2:33][CH2:32][CH2:31][CH2:30][N:7]([C@@H:8]([C:12]1[N:13]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14](=[O:22])[C:15]2[N:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:9][C:10]#[CH:11])[C:5](=[O:6])[C:4]1[CH:44]=[CH:45][CH:46]=[C:2]([Cl:1])[C:3]=1[F:47]
Reactant: C#CC[C@H](c1nc2cccnc2c(=O)n1Nc1ccccc1)N(CCCNC(=O)OCc1ccccc1)C(=O)c1cccc(Cl)c1F
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: C#CC[C@H](c1nc2cccnc2c(=O)n1Nc1ccccc1)N(CCCN)C(=O)c1cccc(Cl)c1F
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
To a solution of (R)-benzyl 3-(3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamido)propylcarbamate (100 mg, 0.153 mmol) in acetonitrile (2 ml) was slowly added iodotrimethylsilane (83 μl, 0.613 mmol) at 0° C. After stirring for 10 minutes, 0.5 ml of sat.NaHCO3 solution was added to quench the reaction. 100 ml of dichloromethane was added to the reaction mixture, then washed with water (30 ml), brine (30 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC. The resulted product (TFA salt) was dissolved in dichloromethane (100 ml) and washed with sat.NaHCO3 solution (20 ml), sat.NaCl solution (20 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. To a solution of the residue in EtOAc (2 ml) was added HCl:EtOAc (3.0 M, 1.0 ml). The mixture was stirred at room temperature for 30 minutes and concentrated to afford (R)-N-(3-aminopropyl)-3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4 dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamide (40 mg, 44%, 2HCl) as a pale yellow solid, M.p. 198-200° C. LCMS: m/e 519 [M+H]. 1H NMR (CD3OD): δ 8.93 (s. 1H), 8.59 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.27 (d, J=6.4 Hz, 2H), 7.10 (s, 2H), 7.00 (m, 1H), 6.85 (s, 1H), 6.53 (s, 1H), 6.38 (s, 1H), 5.51 (s, 1H), 5.26 (s, 1H), 3.73-3.59 (m, 2H), 2.65-2.29 (m, 2H), 2.01-1.59 (m, 2H), 1.19 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C@H:4]([CH3:23])[N:5](C(OC(C)(C)C)=O)[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CNC(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](C)Nc1ccc2ccccc2c1
Reaction time: 48 h

Procedure:
A solution of Intermediate 5 (12.46 g) in dichloromethane (124 ml) at 0° C. was treated dropwise with neat trifluoroacetic acid (120 ml). The resulting pale yellow solution was allowed to reach room temperature over 48 h. The solvent was subsequently removed and the crude product dissolved in the minimum volume of 1N hydrochloric acid at 0° C. The aqueous phase was extracted with dichloromethane to remove any impurities. The aqueous phase was then taken to pH 8.5, initially using solid sodium bicarbonate and then a few drops of 3N sodium hydroxide. A white precipitate formed which was filtered, and the residue washed with water and dried in vacuo (7.2 g 83%). TLC Rf 0.10 (EtOAc).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:15]1[CH2:20][CH2:19][CH:18]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH2:17][CH2:16]1
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (45 g) and dihydro-2H-pyran-4(3H)-one (24.74 g) in dichloromethane (1000 mL) was treated with sodium triacetoxyborohydride (61.9 g), stirred at room temperature for 16 hours, washed with 1M sodium hydroxide and dried with anhydrous sodium sulfate, filtered and concentrated. The concentrate was flash column chromatographed on silica gel with 10-20% methanol/dichloromethane.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC.CCOCC>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[O:16][CH2:15][CH2:14][O:6]1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1ccc(C2(CCCCl)OCCO2)cc1

Procedure:
This compound was synthesized as described under 5.a) with 20.0 g (101.6 mmol) of 4-chloro-1-(4-methylphenyl)-1-butanone (origin: Acros), 20 ml of ethylene glycol and ca. 1 g of p-toluenesulfonic acid in 120 ml of toluene to give 25.2 g (99%) of the crude compound, which was used for further functionalization. Column chromatography of 2 g (SiO2, heptane/ether 9:1) afforded 1.51 g of a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH:12]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2.C(N(CC)CC)C>ClCCl>[C:1]([NH:10][CH2:11][CH:12]1[C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:13]21[O:14][CH2:15][CH2:16][O:17]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2)c1ccccc1
Reaction time: 4 h
Yield: 74.7 %

Procedure:
A solution of benzoyl chloride (7.7 g) in anhydrous dichloromethane (10 cc) is added dropwise, in the course of 40 minutes and while the temperature of the reaction mixture is maintained at +5° C., to a solution, cooled to +5° C., of (RS)-6-aminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16.2 g) and triethylamine (5.6 g) in anhydrous dichloromethane (150 cc). The reaction mixture is then stirred for 4 hours at +25° C., thereafter washed with distilled water (125 cc) cooled to +5° C., dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in a mixture (50 cc) of acetonitrile and isopropyl ether (50:50 by volume). The crystals are drained and dried. (RS)-6-Benzamidomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16 g) is obtained in the form of white crystals. M.p. 162° C.
Reaction SMILES: C([O:14][C:15](=[O:40])[CH:16]([CH:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39])[NH:17][C:18](=[O:32])[C@H:19]([CH3:31])[NH:20]C(OCC1C=CC=CC=1)=O)(C1C=CC=CC=1)C1C=CC=CC=1.[BrH:41].C(OCC)C>C(O)(=O)C>[BrH:41].[NH2:20][C@H:19]([C:18]([NH:17][CH:16]([CH:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39])[C:15]([OH:40])=[O:14])=[O:32])[CH3:31]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(C(=O)OC(c1ccccc1)c1ccccc1)C1CC(=O)NC1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)NC(C(=O)O)C1CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5.3 g of benzyloxycarbonyl-L-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine benzhydryl ester was added 10 ml of a 30% solution of hydrogen bromide in acetic acid and the mixture was stirred at room temperature for one hour. To the reaction mixture was added ethyl ether and the resulting precipitate was collected by filtration. Yield 3.2 g.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]([SiH2:26][O:27][C:28]([CH3:35])([CH3:34])[C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)([CH3:25])([CH3:24])[CH3:23].CN1CCN(C)C1=O>C(OCC)(=O)C>[C:22]([SiH2:26][O:27][C:28]([CH3:35])([CH3:34])[C:29]1[N:30]=[CH:31][N:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:33]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Temperature: 140 °C
Yield: 33.1 %

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 333 mg (1.57 mmol) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-1H-imidazole and 1 ml of dry 1,3-dimethyl-2-imidazolidinone is heated to 140° C. (oil bath temperature) in a closed vial for 4 hours. After cooling, the orange solution is diluted with ethyl acetate and the organic phase washed with water and brine and dried over Na2SO4. Evaporation of the solvent gives an oil which is purified by medium pressure chromatography on silica gel with ethyl acetate/acetic acid 98:2 as eluent, yielding 53 mg of N-{6-[4-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-methanesulfonamide, m.p. >270° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>>[O:14]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:3][CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: CCOP(=O)(CCN1C(=O)c2ccccc2C1=O)OCC
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(2-bromoethyl)isoindoline-1,3-dione (8 g, 31.50 mmol, 1.00 equiv) and triethyl phosphite (6.2 g, 37.35 mmol, 1.19 equiv). The resulting solution was stirred for 18 h at 130° C. The resulting mixture was concentrated under vacuum. The crude product was re-crystallized from ether:n-hexane (1:2). This resulted in 5 g (48%) of diethyl 2-(1,3-dioxoisoindolin-2-yl)ethylphosphonate as a white solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][N:18](C)[CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[C:1]1([C:7]2([CH2:16][CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH3:19])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCC1(c2ccccc2)COc2ccccc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(CCC1(c2ccccc2)COc2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A mixture of 6.0 g (22.5 mole) of 2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine, 3.72 ml (27 mmole) beta,beta,beta-trichloroethyl chloroformate, 12.4 g (90 mmole) anhydrous K2CO3, and 100 ml anhydrous CH2Cl2 was stirred at room temperature overnight. Water was then added to dissolve the inorganics and the layers were separated. The organics were washed with water and dried over MgSO4. Filtration and evaporation gave an oil, which was chromatographed with HPLC using 80% CH2Cl2 /hexane as an eluent to give 6.4 g (66%) of an oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([N:25]=[N+]=[N-])(=O)=O)=CC=1.[BH4-].[Na+].O>C1COCC1.CCCCCC.[Cl-].[Na+].O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][C:13]=1[NH2:25])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solutuion of 5-chloro-thiophene-2-sulfonic acid tert-butylamide (310 mg, 1.22 mmol) in THF (10 mL) at −78° C. was added n-Buli (1.6 M in hexane, 1.7 mL, 2.7 mmol) dropwise. The resultant solution was warmed up to −30° C. and maintained at −20° C.–−30° C. for 10 min. It was rmixed with a solution of 4-methylbenzenesulfonyl azide (361 mg, 1.83 mmol) in THF (2 mL). The mixture was stirred at ambient temperature for 1 h before diluted with brine solution (30 mL) and washed with toluene (20 mL). The organic phase was separated and mixed with NaBH4 (500 mg, 13.2 mmol) and H2O (5 mL). The mixture was stirred for 2 h. at room temperature, then diluted with brine solution (50 mL) and washed with ethyl acetate (50 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 4:1) then provided 3a (250 mg) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:4]([F:17])[CH:3]=1.[I-:18].[Na+].CN(C)CCN>O1CCOCC1.N>[C:11]([Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([I:18])=[CH:3][C:4]=1[F:17])([CH3:10])[CH3:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1F
Agent: CN(C)CCN
Agent: N
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(I)cc1F
Temperature: 120 °C
Reaction time: 7 h

Procedure:
To 7.70 g (24.1 mmol) (4-bromo-2-fluoro-benzyloxy)-tert-butyl-dimethyl-silane (preparation 16a) in 8 mL 1,4-dioxane is added 937 mg (4.82 mmol) Cu(I)-iodide. The reaction mixture is flushed with argon and 7.23 g (48.2 mmol) sodium iodide and 1.03 mL (9.65 mmol) N,N-dimethylethylen-diamine are added. The mixture is stirred at 120° C. for 7 h in a sealed tube. The reaction mixture is diluted at RT with 5% aqueous NH3-solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed a few times with water, dried over MgSO4, filtered and the solvent is evaporated.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[N:5]1[C:9](=[O:10])CCC1=O.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:22](C(N)=O)=[CH:21][N:20]=2)[CH2:15][CH2:14]1.Cl>CO.ClCCl>[CH3:1][O:2][C:9](=[O:10])[NH:5][C:22]1[CH:21]=[N:20][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)=[CH:27][C:26]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34]
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(N)=O
Reactant: C[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Nc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: -5 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
2.15 ml (11.6 mMol) Sodium methoxide in methanol were added over 30 minutes to a suspension of 0.85 g (4.6 mMol) N-bromosuccinimide in 5.0 ml dichloromethane cooled to −5° C. The reaction mixture was stirred 16 hours at −5° C. Still at this temperature, a solution of 1.0 g (3.1 mMol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 5.0 ml methanol was added over 20 minutes and stirred for 5 hours. 7.1 ml (7.1 mMol) Aqueous HCl 1N and 20 ml dichloromethane were added. The phases were separated and the organic phase was washed with deionized water. The aqueous phases were extracted with dichloromethane, brought to pH=8 with aqueous NaOH 1N and further extracted with dichloromethane. The latter organic extracts were combined, dried (Na2SO4) and concentrated to yield 1.08 g (quant.) [6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester as a grey foam. MS (ISP): 341 (M+H+, 100), 284 (35).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]5[CH2:35][CH2:34][NH:33][CH2:32]5)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[CH:53]1([CH2:56][C:57](Cl)=[O:58])[CH2:55][CH2:54]1>ClCCl>[CH:53]1([CH2:56][C:57]([N:33]2[CH2:34][CH2:35][CH:31]([O:30][C:27]3[CH:28]=[CH:29][C:24]([CH:23]4[CH2:22][CH2:21][N:20]([C:36]([O:38][CH2:39][C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[O:37])[CH2:19][CH:18]4[O:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]5[O:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=5[CH:12]=4)=[CH:25][CH:26]=3)[CH2:32]2)=[O:58])[CH2:55][CH2:54]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CCNC4)cc3)cc21
Reactant: O=C(Cl)CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CCN(C(=O)CC5CC5)C4)cc3)cc21

Procedure:
The solution of 0.120 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(pyrrolidin-3-yloxy)phenyl]piperidine-1-carboxylate in 4.0 ml of dichloromethane is cooled to 0° C. with stirring and admixed with 0.032 ml of triethylamine. 0.031 ml of cyclopropylacetyl chloride in 0.40 ml of dichloromethane is slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 1 hour. The reaction mixture is poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a pink oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.18.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.[C:11](#[N:14])[CH:12]=C>C(#N)C>[CH2:1]1[N:6]([CH2:12][C:11]#[N:14])[CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12
Reactant: C=CC#N
Reactant: C1CCN2CCNCC2C1
Solvent: CC#N
Product: N#CCN1CCN2CCCCC2C1

Procedure:
8 g of octahydro-2H-pyrido[1,2-a]pyrazine and 12 ml of acrylonitrile are refluxed for 48 hours in 150 ml of acetonitrile. The solvent is then removed in vacuo to yield 11 g of a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][C@H:3]1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]=1)=[O:21].[H-].[Na+].Br[CH2:40][C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42]>CN(C)C=O>[C:43]([C:41]([CH2:40][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][C@@H:3]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]=2)=[O:21])[C:2]1=[O:1])=[O:42])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)Cc1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3NC2=O)c1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)urea (4.93 g) was added to a suspension of 60% sodium hydride (440 mg) in anhydrous N,N-dimethylformamide (50 ml) under ice-cooling, the mixture was stirred for one hour. Bromomethyl tert-butylketone (1.97 g) was added thereto, the resultant mixture was stirred at room temperature for one hour, the reaction mixture was poured into ice-water, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After dried over anhydrous sodium sulfate, the mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to thereby obtain 5.07 g of the title compound (Yield: 86%).
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].C(O)(=O)C.[CH:19](=O)[CH2:20][CH3:21]>C(O)C>[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][N:14]=[CH:19][CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCC=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCC=NNc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stirring for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated via filtration, washed with water and dried in air to obtain N-(3-nitro-phenyl)-N′-propylidene-hydrazine, which was used directly in the next step.